Could metformin be therapeutically useful in Huntington’s disease?

References

Abd-Elrahman, K.S. and Ferguson, S.S.G. (2019). Modulation of mTOR and CREB pathways following mGluR5 blockade contribute to improved Huntington’s pathology in zQ175 mice. Mol. Brain 12, 35.10.1186/s13041-019-0456-1Search in Google Scholar PubMed PubMed Central

Abd-Elrahman, K.S., Hamilton, A., Hutchinson, S.R., Liu, F., Russell, R.C., and Ferguson, S.S.G. (2017). mGluR5 antagonism increases autophagy and prevents disease progression in the zQ175 mouse model of Huntington’s disease. Sci. Signal. 10, eaan6387. doi: 10.1126/scisignal.aan6387.10.1126/scisignal.aan6387Search in Google Scholar PubMed

Abd-Elsameea, A.A., Moustaf, A.A., and Mohamed, A.M. (2014). Modulation of the oxidative stress by metformin in the cerebrum of rats exposed to global cerebral ischemia and ischemia/reperfusion. Eur. Rev. Med. Pharmacol. Sci. 18, 2387–2392.Search in Google Scholar

Ahmad, W. and Ebert, P.R. (2017). Metformin attenuates Aβ pathology mediated through levamisole sensitive nicotinic acetylcholine receptors in a C. elegans model of Alzheimer’s disease. Mol. Neurobiol. 54, 5427–5439.10.1007/s12035-016-0085-ySearch in Google Scholar PubMed

Ahmed, S., Mahmood, Z., Javed, A., Hashmi, S.N., Zerr, I., Zafar, S., and Zahid, S. (2017). Effect of metformin on adult hippocampal neurogenesis: comparison with donepezil and links to cognition. J. Mol. Neurosci. 62, 88–98.10.1007/s12031-017-0915-zSearch in Google Scholar PubMed

Alagiakrishnan, K., Sankaralingam, S., Ghosh, M., Mereu, L., and Senior, P. (2013). Antidiabetic drugs and their potential role in treating mild cognitive impairment and Alzheimer’s disease. Discov. Med. 16, 277–286.Search in Google Scholar

Alzheimer’s Association. (2016). 2016 Alzheimer’s disease facts and figures. Alzheimers Dement. 12, 459–509.10.1016/j.jalz.2016.03.001Search in Google Scholar PubMed

Anderson, K.A., Ribar, T.J., Lin, F., Noeldner, P.K., Green, M.F., Muehlbauer, M.J., Witters, L.A., Kemp, B.E., and Means, A.R. (2008). Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell. Metab. 7, 377–388.10.1016/j.cmet.2008.02.011Search in Google Scholar PubMed

Apostolidis, S.A., Rodríguez-Rodríguez, N., Suárez-Fueyo, A., Dioufa, N., Ozcan, E., Crispín, J.C., Tsokos, M.G., and Tsokos, G.C. (2016). Phosphatase PP2A is requisite for the function of regulatory T cells. Nat. Immunol. 17, 556–564.10.1038/ni.3390Search in Google Scholar PubMed PubMed Central

Aranda-Orgillés, B., Trockenbacher, A., Winter, J., Aigner, J., Köhler, A., Jastrzebska, E., Stahl, J., Müller, E.C., Otto, A., Wanker, E.E., et al. (2008). The Opitz syndrome gene product MID1 assembles a microtubule-associated ribonucleoprotein complex. Hum. Genet. 123, 163–176.10.1007/s00439-007-0456-6Search in Google Scholar PubMed PubMed Central

Arbeláez-Quintero, I. and Palacios, M. (2017). To use or not to use metformin in cerebral ischemia: a review of the application of metformin in stroke rodents. Stroke Res. Treat. 2017, 9756429.10.1155/2017/9756429Search in Google Scholar PubMed PubMed Central

Arnoux, I., Willam, M., Griesche, N., Krummeich, J., Watari, H., Offermann, N., Weber, S., Narayan Dey, P., Chen, C., Monteiro, O., et al. (2018). Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease. eLife 7, e38744.10.7554/eLife.38744Search in Google Scholar PubMed PubMed Central

Arteaga-Bracho, E.E., Gulinello, M., Winchester, M.L., Pichamoorthy, N., Petronglo, J.R., Zambrano, A.D., Inocencio, J., De Jesus, C.D., Louie, J.O., Gokhan, S., et al. (2016). Postnatal and adult consequences of loss of huntingtin during development: implications for Huntington’s disease. Neurobiol. Dis. 96, 144–155.10.1016/j.nbd.2016.09.006Search in Google Scholar PubMed PubMed Central

Asadbegi, M., Yaghmaei, P., Salehi, I., Ebrahim-Habibi, A., and Komaki, A. (2016). Neuroprotective effects of metformin against Aβ-mediated inhibition of long-term potentiation in rats fed a high-fat diet. Brain Res. Bull. 121, 178–185.10.1016/j.brainresbull.2016.02.005Search in Google Scholar PubMed

Ashabi, G., Khalaj, L., Khodagholi, F., Goudarzvand, M., and Sarkaki, A. (2015). Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia. Metab. Brain Dis. 30, 747–754.10.1007/s11011-014-9632-2Search in Google Scholar PubMed

Ashkenazi, A., Bento, C.F., Ricketts, T., Vicinanza, M., Siddiqi, F., Pavel, M., Squitieri, F., Hardenberg, M.C., Imarisio, S., Menzies, F.M., et al. (2017). Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 545, 108–111.10.1038/nature22078Search in Google Scholar PubMed PubMed Central

Bañez-Coronel, M., Porta, S., Kagerbauer, B., Mateu-Huertas, E., Pantano, L., Ferrer, I., Guzmán, M., Estivill, X., and Martí, E. (2012). A pathogenic mechanism in Huntington’s disease involves small CAG-repeated RNAs with neurotoxic activity. PLoS Genet. 8, e1002481.10.1371/journal.pgen.1002481Search in Google Scholar PubMed PubMed Central

Barini, E., Antico, O., Zhao, Y., Asta, F., Tucci, V., Catelani, T., Marotta, R., Xu, H., and Gasparini, L. (2016). Metformin promotes τ aggregation and exacerbates abnormal behavior in a mouse model of tauopathy. Mol. Neurodegener. 11, 16.10.1186/s13024-016-0082-7Search in Google Scholar PubMed PubMed Central

Bar-Yosef, T., Damri, O., and Agam, G. (2019). Dual role of autophagy in diseases of the central nervous system. Front. Cell. Neurosci. 13, 196.10.3389/fncel.2019.00196Search in Google Scholar PubMed PubMed Central

Bates, G.P., Dorsey, R., Gusella, J.F., Hayden, M.R., Kay, C., Leavitt, B.R., Nance, M., Ross, C.A., Scahill, R.I., Wetzel, R., et al. (2015). Huntington disease. Nat. Rev. Dis. Primers. 1, 15005.10.1038/nrdp.2015.5Search in Google Scholar PubMed

Bayliss, J.A., Lemus, M.B., Santos, V.V., Deo, M., Davies, J.S., Kemp, B.E., Elsworth, J.D., and Andrews, Z.B. (2016). Metformin prevents nigrostriatal dopamine degeneration independent of AMPK activation in dopamine neurons. PLoS One 11, e0159381.10.1371/journal.pone.0159381Search in Google Scholar PubMed PubMed Central

Ben Sahra, I., Regazzetti, C., Robert, G., Laurent, K., Le Marchand-Brustel, Y., Auberger, P., Tanti, J.F., Giorgetti-Peraldi, S., and Bost, F. (2011). Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 71, 4366–4372.10.1158/0008-5472.CAN-10-1769Search in Google Scholar PubMed

Berthier, A., Payá, M., García-Cabrero, A.M., Ballester, M.I., Heredia, M., Serratosa, J.M., Sánchez, M.P., and Sanz, P. (2016). Pharmacological interventions to ameliorate neuropathological symptoms in a mouse model of Lafora disease. Mol. Neurobiol. 53, 1296–1309.10.1007/s12035-015-9091-8Search in Google Scholar PubMed PubMed Central

Bharadwaj, P., Wijesekara, N., Liyanapathirana, M., Newsholme, P., Ittner, L., Fraser, P., and Verdile, G. (2017). The link between type 2 diabetes and neurodegeneration: roles for amyloid-β, amylin, and τ proteins. J. Alzheimers Dis. 59, 421–432.10.3233/JAD-161192Search in Google Scholar PubMed

Bialik, S., Dasari, S.K., and Kimchi, A. (2018). Autophagy-dependent cell death – where, how and why a cell eats itself to death. J. Cell. Sci. 131, pii: jcs215152. doi: 10.1242/jcs.215152.10.1242/jcs.215152Search in Google Scholar PubMed

Biosa, A., Outeiro, T.F., Bubacco, L., and Bisaglia, M. (2018). Diabetes mellitus as a risk factor for Parkinson’s disease: a molecular point of view. Mol. Neurobiol. 55, 8754–8763.10.1007/s12035-018-1025-9Search in Google Scholar PubMed

Bisulli, F., Muccioli, L., d’Orsi, G., Canafoglia, L., Freri, E., Licchetta, L., Mostacci, B., Riguzzi, P., Pondrelli, F., Avolio, C., et al. (2019). Treatment with metformin in twelve patients with Lafora disease. Orphanet. J. Rare Dis. 14, 149.10.1186/s13023-019-1132-3Search in Google Scholar PubMed PubMed Central

Brakedal, B., Flønes, I., Reiter, S.F., Torkildsen, Ø., Dölle, C., Assmus, J., Haugarvoll, K., and Tzoulis, C. (2017). Glitazone use associated with reduced risk of Parkinson’s disease. Mov. Disord. 32, 1594–1599.10.1002/mds.27128Search in Google Scholar PubMed PubMed Central

Burkewitz, K., Zhang, Y., and Mair, W.B. (2014). AMPK at the nexus of energetics and aging. Cell. Metab. 20, 10–25.10.1016/j.cmet.2014.03.002Search in Google Scholar PubMed PubMed Central

Burrows, D.J., McGown, A., Jain, S.A., De Felice, M., Ramesh, T.M., Sharrack, B., and Majid, A. (2019). Animal models of multiple sclerosis: from rodents to zebrafish. Mult. Scler. 25, 306–324.10.1177/1352458518805246Search in Google Scholar PubMed

Byrne, F.M., Cheetham, S., Vickers, S., and Chapman, V. (2015). Characterisation of pain responses in the high fat diet/streptozotocin model of diabetes and the analgesic effects of antidiabetic treatments. J. Diabetes Res. 2015, 752481.10.1155/2015/752481Search in Google Scholar PubMed PubMed Central

Campbell, J.M., Stephenson, M.D., de Courten, B., Chapman, I., Bellman, S.M., and Aromataris, E. (2018). Metformin use associated with reduced risk of dementia in patients with diabetes: a systematic review and meta-analysis. J. Alzheimers Dis. 65, 1225–1236.10.3233/JAD-180263Search in Google Scholar PubMed PubMed Central

Canals, J.M., Pineda, J.R., Torres-Peraza, J.F., Bosch, M., Martín-Ibañez, R., Muñoz, M.T., Mengod, G., Ernfors, P., and Alberch, J. (2004). Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington’s disease. J. Neurosci. 24, 7727–7739.10.1523/JNEUROSCI.1197-04.2004Search in Google Scholar PubMed PubMed Central

Caron, N.S., Dorsey, E.R., and Hayden, M.R. (2018). Therapeutic approaches to Huntington disease: from the bench to the clinic. Nat. Rev. Drug Discov. 17, 729–750.10.1038/nrd.2018.133Search in Google Scholar PubMed

Chang, J., Jung, H.H., Yang, J.Y., Lee, S., Choi, J., Im, G.J., and Chae, S.W. (2014). Protective effect of metformin against cisplatin-induced ototoxicity in an auditory cell line. J. Assoc. Res. Otolaryngol. 15, 149–158.10.1007/s10162-013-0431-ySearch in Google Scholar PubMed PubMed Central

Chatterjee, S. and Mudher, A. (2018). Alzheimer’s disease and type 2 diabetes: a critical assessment of the shared pathological traits. Front. Neurosci. 12, 383.10.3389/fnins.2018.00383Search in Google Scholar PubMed PubMed Central

Chen, Y., Zhou, K., Wang, R., Liu, Y., Kwak, Y.D., Ma, T., Thompson, R.C., Zhao, Y., Smith, L., Gasparini, L., et al. (2009). Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer’s amyloid peptides via up-regulating BACE1 transcription. Proc. Natl. Acad. Sci. U.S.A. 106, 3907–3912.10.1073/pnas.0807991106Search in Google Scholar PubMed PubMed Central

Chen, J.L., Luo, C., Pu, D., Zhang, G.Q., Zhao, Y.X., Sun, Y., Zhao, K.X., Liao, Z.Y., Lv, A.K., Zhu, S.Y., et al. (2019). Metformin attenuates diabetes-induced τ hyperphosphorylation in vitro and in vivo by enhancing autophagic clearance. Exp. Neurol. 311, 44–56.10.1016/j.expneurol.2018.09.008Search in Google Scholar PubMed

Cheng, Y.Y., Leu, H.B., Chen, T.J., Chen, C.L., Kuo, C.H., Lee, S.D., and Kao, C.L. (2014). Metformin-inclusive therapy reduces the risk of stroke in patients with diabetes: a 4-year follow-up study. J. Stroke Cerebrovasc. Dis. 23, e99–e105.10.1016/j.jstrokecerebrovasdis.2013.09.001Search in Google Scholar PubMed

Chiang, M.C., Cheng, Y.C., Chen, S.J., Yen, C.H., and Huang, R.N. (2016). Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against amyloid-β-induced mitochondrial dysfunction. Exp. Cell. Res. 347, 322–331.10.1016/j.yexcr.2016.08.013Search in Google Scholar PubMed

Chung, M.M., Nicol, C.J., Cheng, Y.C., Lin, K.H., Chen, Y.L., Pei, D., Lin, C.H., Shih, Y.N., Yen, C.H., Chen, S.J., et al. (2017). Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs. Exp. Cell. Res. 352, 75–83.10.1016/j.yexcr.2017.01.017Search in Google Scholar PubMed

Clarke, J.R., Ribeiro, F.C., Frozza, R.L., De Felice, F.G., and Lourenco, M.V. (2018). Metabolic dysfunction in Alzheimer’s disease: from basic neurobiology to clinical approaches. J. Alzheimers Dis. 64, S405–S426.10.3233/JAD-179911Search in Google Scholar PubMed

Croce, K.R. and Yamamoto, A. (2019). A role for autophagy in Huntington’s disease. Neurobiol. Dis. 122, 16–22.10.1016/j.nbd.2018.08.010Search in Google Scholar PubMed PubMed Central

Crotti, A. and Glass, C.K. (2015). The choreography of neuroinflammation in Huntington’s disease. Trends Immunol. 36, 364–373.10.1016/j.it.2015.04.007Search in Google Scholar PubMed PubMed Central

Crotti, A., Benner, C., Kerman, B.E., Gosselin, D., Lagier-Tourenne, C., Zuccato, C., Cattaneo, E., Gage, F.H., Cleveland, D.W., and Glass, C.K. (2014). Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat. Neurosci. 17, 513–521.10.1038/nn.3668Search in Google Scholar PubMed PubMed Central

Curry, D.W., Stutz, B., Andrews, Z.B., and Elsworth, J.D. (2018). Targeting AMPK signaling as a neuroprotective strategy in Parkinson’s disease. J. Parkinsons Dis. 8, 161–181.10.3233/JPD-171296Search in Google Scholar PubMed PubMed Central

Dadwal, P., Mahmud, N., Sinai, L., Azimi, A., Fatt, M., Wondisford, F.E., Miller, F.D., and Morshead, C.M. (2015). Activating endogenous neural precursor cells using Metformin leads to neural repair and functional recovery in a model of childhood brain injury. Stem Cell Rep. 5, 166–173.10.1016/j.stemcr.2015.06.011Search in Google Scholar PubMed PubMed Central

Demir, U., Koehler, A., Schneider, R., Schweiger, S., and Klocker, H. (2014). Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells. BMC Cancer 14, 52.10.1186/1471-2407-14-52Search in Google Scholar PubMed PubMed Central

Denton, D. and Kumar, S. (2019). Autophagy-dependent cell death. Cell Death Differ. 26, 605–616.10.1038/s41418-018-0252-ySearch in Google Scholar PubMed PubMed Central

DeYoung, M.P., Horak, P., Sofer, A., Sgroi, D., and Ellisen, L.W. (2008). Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 22, 239–251.10.1101/gad.1617608Search in Google Scholar PubMed PubMed Central

DiTacchio, K.A., Heinemann, S.F., and Dziewczapolski, G. (2015). Metformin treatment alters memory function in a mouse model of Alzheimer’s disease. J. Alzheimers Dis. 44, 43–48.10.3233/JAD-141332Search in Google Scholar PubMed PubMed Central

Domise, M., Sauvé, F., Didier, S., Caillerez, R., Bégard, S., Carrier, S., Colin, M., Marinangeli, C., Buée, L., and Vingtdeux, V. (2019). Neuronal AMP-activated protein kinase hyper-activation induces synaptic loss by an autophagy-mediated process. Cell Death Dis. 10, 221.10.1038/s41419-019-1464-xSearch in Google Scholar PubMed PubMed Central

Dragatsis, I., Levine, M.S., and Zeitlin, S. (2000). Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat. Genet. 26, 300–306.10.1038/81593Search in Google Scholar PubMed

Duan, W., Guo, Z., Jiang, H., Ware, M., Li, X.J., and Mattson, M.P. (2003). Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc. Natl. Acad. Sci. U.S.A. 100, 2911–2916.10.1073/pnas.0536856100Search in Google Scholar PubMed PubMed Central

Dulovic, M., Jovanovic, M., Xilouri, M., Stefanis, L., Harhaji-Trajkovic, L., Kravic-Stevovic, T., Paunovic, V., Ardah, M.T., El-Agnaf, O.M.A., Kostic, V., et al. (2014). The protective role of AMP-activated protein kinase in α-synuclein neurotoxicity in vitro. Neurobiol. Dis. 63, 1–11.10.1016/j.nbd.2013.11.002Search in Google Scholar PubMed

Duyao, M.P., Auerbach, A.B., Ryan, A., Persichetti, F., Barnes, G.T., McNeil, S.M., Ge, P., Vonsattel, J.P., Gusella, J.F., and Joyner, A.L. (1995). Inactivation of the mouse Huntington’s disease gene homolog Hdh. Science 269, 407–410.10.1126/science.7618107Search in Google Scholar PubMed

Dy, A.B.C., Tassone, F., Eldeeb, M., Salcedo-Arellano, M.J., Tartaglia, N., and Hagerman, R. (2018). Metformin as targeted treatment in fragile X syndrome. Clin. Genet. 93, 216–222.10.1111/cge.13039Search in Google Scholar PubMed PubMed Central

Elbaz, A., Carcaillon, L., Kab, S., and Moisan, F. (2016). Epidemiology of Parkinson’s disease. Rev. Neurol. (Paris) 172, 14–26.10.1016/j.neurol.2015.09.012Search in Google Scholar PubMed

El-Mir, M.Y., Nogueira, V., Fontaine, E., Avéret, N., Rigoulet, M., and Leverve, X. (2000). Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 275, 223–228.10.1074/jbc.275.1.223Search in Google Scholar PubMed

El-Mir, M.Y., Detaille, D., R-Villanueva, G., Delgado-Esteban, M., Guigas, B., Attia, S., Fontaine, E., Almeida, A., and Leverve, X. (2008). Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J. Mol. Neurosci. 34, 77–87.10.1007/s12031-007-9002-1Search in Google Scholar PubMed

Ettcheto, M., Cano, A., Busquets, O., Manzine, P.R., Sánchez-López, E., Castro-Torres, R.D., Beas-Zarate, C., Verdaguer, E., García, M.L., Olloquequi, J., et al. (2019). A metabolic perspective of late onset Alzheimer’s disease. Pharmacol. Res. 145, 104255.10.1016/j.phrs.2019.104255Search in Google Scholar PubMed

Fan, J., Li, D., Chen, H.S., Huang, J.G., Xu, J.F., Zhu, W.W., Chen, J.G., and Wang, F. (2019). Metformin produces anxiolytic-like effects in rats by facilitating GABA_A receptor trafficking to membrane. Br. J. Pharmacol. 176, 297–316.10.1111/bph.14519Search in Google Scholar PubMed PubMed Central

Farina, F., Lambert, E., Commeau, L., Lejeune, F.X., Roudier, N., Fonte, C., Parker, J.A., Boddaert, J., Verny, M., Baulieu, E.E., et al. (2017). The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease. Sci. Rep. 7, 4014.10.1038/s41598-017-04256-wSearch in Google Scholar PubMed PubMed Central

Farr, S.A., Roesler, E., Niehoff, M.L., Roby, D.A., McKee, A., and Morley, J.E. (2019). Metformin improves learning and memory in the SAMP8 mouse model of Alzheimer’s disease. J. Alzheimers Dis. 68, 1699–1710.10.3233/JAD-181240Search in Google Scholar PubMed

Fatt, M., Hsu, K., He, L., Wondisford, F., Miller, F.D., Kaplan, D.R., and Wang, J. (2015). Metformin acts on two different molecular pathways to enhance adult neural precursor proliferation/self-renewal and differentiation. Stem Cell Rep. 5, 988–995.10.1016/j.stemcr.2015.10.014Search in Google Scholar PubMed PubMed Central

Foretz, M., Guigas, B., Bertrand, L., Pollak, M., and Viollet, B. (2014). Metformin: from mechanisms of action to therapies. Cell. Metab. 20, 953–966.10.1016/j.cmet.2014.09.018Search in Google Scholar PubMed

Gafni, J., Hermel, E., Young, J.E., Wellington, C.L., Hayden, M.R., and Ellerby, L.M. (2004). Inhibition of calpain cleavage of huntingtin reduces toxicity: accumulation of calpain/caspase fragments in the nucleus. J. Biol. Chem. 279, 20211–20220.10.1074/jbc.M401267200Search in Google Scholar PubMed

Galimberti, D. and Scarpini, E. (2017). Pioglitazone for the treatment of Alzheimer’s disease. Expert Opin. Invest. Drugs 26, 97–101.10.1080/13543784.2017.1265504Search in Google Scholar PubMed

Gantois, I., Khoutorsky, A., Popic, J., Aguilar-Valles, A., Freemantle, E., Cao, R., Sharma, V., Pooters, T., Nagpal, A., Skalecka, A., et al. (2017). Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nat. Med. 23, 674–677.10.1038/nm.4335Search in Google Scholar PubMed

Gantois, I., Popic, J., Khoutorsky, A., and Sonenberg, N. (2019).Metformin for treatment of fragile X syndrome and other neurological disorders. Annu. Rev. Med. 70, 167–181.10.1146/annurev-med-081117-041238Search in Google Scholar PubMed

Ge, X.H., Zhu, G.J., Geng, D.Q., Zhang, H.Z., He, J.M., Guo, A.Z., Ma, L.L., and Yu, D.H. (2017). Metformin protects the brain against ischemia/reperfusion injury through PI3K/Akt1/JNK3 signaling pathways in rats. Physiol. Behav. 170, 115–123.10.1016/j.physbeh.2016.12.021Search in Google Scholar PubMed

Ghadernezhad, N., Khalaj, L., Pazoki-Toroudi, H., Mirmasoumi, M., and Ashabi, G. (2016). Metformin pretreatment enhanced learning and memory in cerebral forebrain ischaemia: the role of the AMPK/BDNF/P70SK signalling pathway. Pharm. Biol. 54, 2211–2219.10.3109/13880209.2016.1150306Search in Google Scholar PubMed

Gil, J.M. and Rego, A.C. (2009). The R6 lines of transgenic mice: a model for screening new therapies for Huntington’s disease. Brain Res. Rev. 59, 410–431.10.1016/j.brainresrev.2008.12.001Search in Google Scholar

Graham, R.K., Deng, Y., Slow, E.J., Haigh, B., Bissada, N., Lu, G., Pearson, J., Shehadeh, J., Bertram, L., Murphy, Z., et al. (2006). Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125, 1179–1191.10.1016/j.cell.2006.04.026Search in Google Scholar

Greer, E.L., Banko, M.R., and Brunet, A. (2009). AMP-activated protein kinase and FoxO transcription factors in dietary restriction-induced longevity. Annu. N. Y. Acad. Sci. 1170, 688–692.10.1111/j.1749-6632.2009.04019.xSearch in Google Scholar

Griesche, N., Schilling, J., Weber, S., Rohm, M., Pesch, V., Matthes, F., Auburger, G., and Krauss, S. (2016). Regulation of mRNA translation by MID1: a common mechanism of expanded CAG repeat RNAs. Front. Cell. Neurosci. 10, 226.10.3389/fncel.2016.00226Search in Google Scholar

Guiney, S.J., Adlard, P.A., Bush, A.I., Finkelstein, D.I., and Ayton, S. (2017). Ferroptosis and cell death mechanisms in Parkinson’s disease. Neurochem. Int. 104, 34–48.10.1016/j.neuint.2017.01.004Search in Google Scholar

Guo, Y., Wang, F., Li, H., Liang, H., Li, Y., Gao, Z., and He, X. (2018). Metformin protects against spinal cord injury by regulating autophagy via the mTOR signaling pathway. Neurochem. Res. 43, 1111–1117.10.1007/s11064-018-2525-8Search in Google Scholar

Gupta, A., Bisht, B., and Dey, C.S. (2011). Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes. Neuropharmacology 60, 910–920.10.1016/j.neuropharm.2011.01.033Search in Google Scholar

Gwinn, D.M., Shackelford, D.B., Egan, D.F., Mihaylova, M.M., Mery, A., Vasquez, D.S., Turk, B.E., and Shaw, R.J. (2008). AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226.10.1016/j.molcel.2008.03.003Search in Google Scholar

Hagerman, R.J., Berry-Kravis, E., Hazlett, H.C., Bailey, D.B., Moine, H., Kooy, R.F., Tassone, F., Gantois, I., Sonenberg, N., Mandel, J.L., et al. (2017). Fragile X syndrome. Nat. Rev. Dis. Primers 3, 17065.10.1038/nrdp.2017.65Search in Google Scholar

Hara, K., Maruki, Y., Long, X., Yoshino, K.I., Oshiro, N., Hidayat, S., Tokunaga, C., Avruch, J., and Yonezawa, K. (2002). Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177–189.10.1016/S0092-8674(02)00833-4Search in Google Scholar

Harada, S., Fujita-Hamabe, W., and Tokuyama, S. (2010). The importance of regulation of blood glucose levels through activation of peripheral 5′-AMP-activated protein kinase on ischemic neuronal damage. Brain Res. 1351, 254–263.10.1016/j.brainres.2010.06.052Search in Google Scholar PubMed

Hersch, S.M., Schifitto, G., Oakes, D., Bredlau, A.L., Meyers, C.M., Nahin, R., Rosas, H.D., and Huntington Study Group CREST-E Investigators and Coordinators. (2017). The CREST-E study of creatine for Huntington disease: a randomized controlled trial. Neurology 89, 594–601.10.1212/WNL.0000000000004209Search in Google Scholar PubMed PubMed Central

Hervás, D., Fornés-Ferrer, V., Gómez-Escribano, A.P., Sequedo, M.D., Peiró, C., Millán, J.M., and Vázquez-Manrique, R.P. (2017). Metformin intake associates with better cognitive function in patients with Huntington’s disease. PLoS One 12, e0179283.10.1371/journal.pone.0179283Search in Google Scholar PubMed PubMed Central

Hettich, M.M., Matthes, F., Ryan, D.P., Griesche, N., Schröder, S., Dorn, S., Krauβ, S., and Ehninger, D. (2014). The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex. PLoS One 9, e102420.10.1371/journal.pone.0102420Search in Google Scholar PubMed PubMed Central

Hill, J.L., Kobori, N., Zhao, J., Rozas, N.S., Hylin, M.J., Moore, A.N., and Dash, P.K. (2016). Traumatic brain injury decreases AMP-activated protein kinase activity and pharmacological enhancement of its activity improves cognitive outcome. J. Neurochem. 139, 106–119.10.1111/jnc.13726Search in Google Scholar PubMed PubMed Central

Hindupur, S.K., González, A., and Hall, M.N. (2015). The opposing actions of target of rapamycin and AMP-activated protein kinase in cell growth control. Cold Spring Harb. Perspect. Biol. 7, a019141.10.1101/cshperspect.a019141Search in Google Scholar PubMed PubMed Central

Hinz, M. and Scheidereit, C. (2014). The IκB kinase complex in NF-κB regulation and beyond. EMBO Rep. 15, 46–61.10.1002/embr.201337983Search in Google Scholar PubMed PubMed Central

Hsiao, H.Y., Chen, Y.C., Chen, H.M., Tu, P.H., and Chern, Y. (2013). A critical role of astrocyte-mediated nuclear factor-κB-dependent inflammation in Huntington’s disease. Hum. Mol. Genet. 22, 1826–1842.10.1093/hmg/ddt036Search in Google Scholar PubMed

Hunter, J., Rivero-Arias, O., Angelov, A., Kim, E., Fotheringham, I., and Leal, J. (2014). Epidemiology of fragile X syndrome: a systematic review and meta-analysis. Am. J. Med. Genet. A 164A, 1648–1658.10.1002/ajmg.a.36511Search in Google Scholar PubMed

Hussein, A.M., Eldosoky, M., El-Shafey, M., El-Mesery, M., Ali, A.N., Abbas, K.M., and Abulseoud, O.A. (2019). Effects of metformin on apoptosis and α-synuclein in a rat model of pentylenetetrazole-induced epilepsy. Can. J. Physiol. Pharmacol. 97, 37–46.10.1139/cjpp-2018-0266Search in Google Scholar PubMed

Hwang, I.K., Kim, I.Y., Joo, E.J., Shin, J.H., Choi, J.W., Won, M.H., Yoon, Y.S., and Seong, J.K. (2010). Metformin normalizes type 2 diabetes-induced decrease in cell proliferation and neuroblast differentiation in the rat dentate gyrus. Neurochem. Res. 35, 645–650.10.1007/s11064-009-0115-5Search in Google Scholar

Imfeld, P., Bodmer, M., Jick, S.S., and Meier, C.R. (2012). Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a population-based case-control study. J. Am. Geriatr. Soc. 60, 916–921.10.1111/j.1532-5415.2012.03916.xSearch in Google Scholar

Inoki, K., Zhu, T., and Guan, K.L. (2003). TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590.10.1016/S0092-8674(03)00929-2Search in Google Scholar

Ismaiel, A.A.K., Espinosa-Oliva, A.M., Santiago, M., García-Quintanilla, A., Oliva-Martín, M.J., Herrera, A.J., Venero, J.L., and de Pablos, R.M. (2016). Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system. Toxicol. Appl. Pharmacol. 298, 19–30.10.1016/j.taap.2016.03.004Search in Google Scholar PubMed

Jia, J., Cheng, J., Ni, J., and Zhen, X. (2015). Neuropharmacological actions of metformin in stroke. Curr. Neuropharmacol. 13, 389–394.10.2174/1570159X13666150205143555Search in Google Scholar

Jin, Q., Cheng, J., Liu, Y., Wu, J., Wang, X., Wei, S., Zhou, X., Qin, Z., Jia, J., and Zhen, X. (2014). Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke. Brain Behav. Immun. 40, 131–142.10.1016/j.bbi.2014.03.003Search in Google Scholar PubMed

Jin, J., Gu, H., Anders, N.M., Ren, T., Jiang, M., Tao, M., Peng, Q., Rudek, M.A., and Duan, W. (2016). Metformin protects cells from mutant Huntingtin toxicity through activation of AMPK and modulation of mitochondrial dynamics. Neuromol. Med. 18, 581–592.10.1007/s12017-016-8412-zSearch in Google Scholar PubMed PubMed Central

Joseph, B.K., Liu, H.Y., Francisco, J., Pandya, D., Donigan, M., Gallo-Ebert, C., Giordano, C., Bata, A., and Nickels, J.T. (2015). Inhibition of AMP kinase by the protein phosphatase 2A heterotrimer, PP2APpp2r2d. J. Biol. Chem. 290, 10588–10598.10.1074/jbc.M114.626259Search in Google Scholar PubMed PubMed Central

Ju, T.C., Chen, H.M., Lin, J.T., Chang, C.P., Chang, W.C., Kang, J.J., Sun, C.P., Tao, M.H., Tu, P.H., Chang, C., et al. (2011). Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington’s disease. J. Cell. Biol. 194, 209–227.10.1083/jcb.201105010Search in Google Scholar PubMed PubMed Central

Ju, T.C., Chen, H.M., Chen, Y.C., Chang, C.P., Chang, C., and Chern, Y. (2014). AMPK-α1 functions downstream of oxidative stress to mediate neuronal atrophy in Huntington’s disease. Biochim. Biophys. Acta 1842, 1668–1680.10.1016/j.bbadis.2014.06.012Search in Google Scholar PubMed

Kalender, A., Selvaraj, A., Kim, S.Y., Gulati, P., Brûlé, S., Viollet, B., Kemp, B.E., Bardeesy, N., Dennis, P., Schlager, J.J., et al. (2010). Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell. Metab. 11, 390–401.10.1016/j.cmet.2010.03.014Search in Google Scholar PubMed PubMed Central

Kaneb, H.M., Sharp, P.S., Rahmani-Kondori, N., and Wells, D.J. (2011). Metformin treatment has no beneficial effect in a dose-response survival study in the SOD1(G93A) mouse model of ALS and is harmful in female mice. PLoS One 6, e24189.10.1371/journal.pone.0024189Search in Google Scholar PubMed PubMed Central

Kang, H., Khang, R., Ham, S., Jeong, G.R., Kim, H., Jo, M., Lee, B.D., Lee, Y.I., Jo, A., Park, C., et al. (2017a). Activation of the ATF2/CREB-PGC-1α pathway by metformin leads to dopaminergic neuroprotection. Oncotarget 8, 48603–48618.10.18632/oncotarget.18122Search in Google Scholar PubMed PubMed Central

Kang, S.S., Zhang, Z., Liu, X., Manfredsson, F.P., He, L., Iuvone, P.M., Cao, X., Sun, Y.E., Jin, L., and Ye, K. (2017b). α-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation. Proc. Natl. Acad. Sci. U.S.A. 114, 1183–1188.10.1073/pnas.1618627114Search in Google Scholar PubMed PubMed Central

Katic, M. and Kahn, C.R. (2005). The role of insulin and IGF-1 signaling in longevity. Cell. Mol. Life Sci. 62, 320–343.10.1007/s00018-004-4297-ySearch in Google Scholar PubMed

Katila, N., Bhurtel, S., Shadfar, S., Srivastav, S., Neupane, S., Ojha, U., Jeong, G.S., and Choi, D.Y. (2017). Metformin lowers α-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson’s disease.Neuropharmacology 125, 396–407.10.1016/j.neuropharm.2017.08.015Search in Google Scholar PubMed

Kazyken, D., Magnuson, B., Bodur, C., Acosta-Jaquez, H.A., Zhang, D., Tong, X., Barnes, T.M., Steinl, G.K., Patterson, N.E., Altheim, C.H., et al. (2019). AMPK directly activates mTORC2 to promote cell survival during acute energetic stress. Sci. Signal. 12, pii: eaav3249. doi: 10.1126/scisignal.aav3249.10.1126/scisignal.aav3249Search in Google Scholar PubMed PubMed Central

Khoshnan, A., Ko, J., Watkin, E.E., Paige, L.A., Reinhart, P.H., and Patterson, P.H. (2004). Activation of the IκB kinase complex and nuclear factor-κB contributes to mutant huntingtin neurotoxicity. J. Neurosci. 24, 7999–8008.10.1523/JNEUROSCI.2675-04.2004Search in Google Scholar PubMed PubMed Central

Khoshnan, A., Sabbaugh, A., Calamini, B., Marinero, S.A., Dunn, D.E., Yoo, J.H., Ko, J., Lo, D.C., and Patterson, P.H. (2017). IKKβ and mutant huntingtin interactions regulate the expression of IL-34: implications for microglial-mediated neurodegeneration in HD. Hum. Mol. Genet. 26, 4267–4277.10.1093/hmg/ddx315Search in Google Scholar PubMed PubMed Central

Kickstein, E., Krauss, S., Thornhill, P., Rutschow, D., Zeller, R., Sharkey, J., Williamson, R., Fuchs, M., Köhler, A., Glossmann, H., et al. (2010). Biguanide metformin acts on τ phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc. Natl. Acad. Sci. U.S.A. 107, 21830–21835.10.1073/pnas.0912793107Search in Google Scholar PubMed PubMed Central

Kim, Y.J., Yi, Y., Sapp, E., Wang, Y., Cuiffo, B., Kegel, K.B., Qin, Z.H., Aronin, N., and DiFiglia, M. (2001). Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington’s disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Proc. Natl. Acad. Sci. U.S.A. 98, 12784–12789.10.1073/pnas.221451398Search in Google Scholar

Kim, D.H., Sarbassov, D.D., Ali, S.M., King, J.E., Latek, R.R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D.M. (2002). mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175.10.1016/S0092-8674(02)00808-5Search in Google Scholar

Kim, M., Roh, J.K., Yoon, B.W., Kang, L., Kim, Y.J., Aronin, N., and DiFiglia, M. (2003). Huntingtin is degraded to small fragments by calpain after ischemic injury. Exp. Neurol. 183, 109–115.10.1016/S0014-4886(03)00132-8Search in Google Scholar

Kim, Y.J., Sapp, E., Cuiffo, B.G., Sobin, L., Yoder, J., Kegel, K.B., Qin, Z.H., Detloff, P., Aronin, N., and DiFiglia, M. (2006). Lysosomal proteases are involved in generation of N-terminal huntingtin fragments. Neurobiol. Dis. 22, 346–356.10.1016/j.nbd.2005.11.012Search in Google Scholar PubMed

Kim, D.H., Park, M.H., Lee, E.K., Choi, Y.J., Chung, K.W., Moon, K.M., Kim, M.J., An, H.J., Park, J.W., Kim, N.D., et al. (2015). The roles of FoxOs in modulation of aging by calorie restriction. Biogerontology 16, 1–14.10.1007/s10522-014-9519-ySearch in Google Scholar PubMed

King, M.A., Hands, S., Hafiz, F., Mizushima, N., Tolkovsky, A.M., and Wyttenbach, A. (2008). Rapamycin inhibits polyglutamine aggregation independently of autophagy by reducing protein synthesis. Mol. Pharmacol. 73, 1052–1063.10.1124/mol.107.043398Search in Google Scholar PubMed

Koenig, A.M., Mechanic-Hamilton, D., Xie, S.X., Combs, M.F., Cappola, A.R., Xie, L., Detre, J.A., Wolk, D.A., and Arnold, S.E. (2017). Effects of the insulin sensitizer Metformin in Alzheimer disease: pilot data from a randomized placebo-controlled crossover study. Alzheimer Dis. Assoc. Disord. 31, 107–113.10.1097/WAD.0000000000000202Search in Google Scholar PubMed PubMed Central

Krauss, S., Griesche, N., Jastrzebska, E., Chen, C., Rutschow, D., Achmüller, C., Dorn, S., Boesch, S.M., Lalowski, M., Wanker, E., et al. (2013). Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1-PP2A protein complex. Nat. Commun. 4, 1511.10.1038/ncomms2514Search in Google Scholar PubMed

Kuan, Y.C., Huang, K.W., Lin, C.L., Hu, C.J., and Kao, C.H. (2017). Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Prog. Neuropsychopharmacol. Biol. Psychiatry. 79, 77–83.10.1016/j.pnpbp.2017.06.002Search in Google Scholar PubMed

Kuhla, A., Brichmann, E., Rühlmann, C., Thiele, R., Meuth, L., and Vollmar, B. (2019). Metformin therapy aggravates neurodegenerative processes in ApoE^−/− mice. J. Alzheimers Dis. 68, 1415–1427.10.3233/JAD-181017Search in Google Scholar PubMed

Labbadia, J. and Morimoto, R. (2013). Huntington’s disease: underlying molecular mechanisms and emerging concepts. Trends Biochem. Sci. 38, 378–385.10.1016/j.tibs.2013.05.003Search in Google Scholar PubMed PubMed Central

Labuschagne, I., Cassidy, A.M., Scahill, R.I., Johnson, E.B., Rees, E., O’Regan, A., Queller, S., Frost, C., Leavitt, B.R., Dürr, A., et al. (2016). Visuospatial processing deficits linked to posterior brain regions in premanifest and early stage Huntington’s disease. J. Int. Neuropsychol. Soc. 22, 595–608.10.1017/S1355617716000321Search in Google Scholar PubMed

Landwehrmeyer, G.B., Fitzer-Attas, C.J., Giuliano, J.D., Gonçalves, N., Anderson, K.E., Cardoso, F., Ferreira, J.J., Mestre, T.A., Stout, J.C., and Sampaio, C. (2017). Data analytics from Enroll-HD, a global clinical research platform for Huntington’s disease. Mov. Disord. Clin. Pract. 4, 212–224.10.1002/mdc3.12388Search in Google Scholar PubMed PubMed Central

Lane, D.J.R., Ayton, S., and Bush, A.I. (2018). Iron and Alzheimer’s disease: an update on emerging mechanisms. J. Alzheimers Dis. 64, S379–S395.10.3233/JAD-179944Search in Google Scholar PubMed

Languren, G., Montiel, T., Ramírez-Lugo, L., Balderas, I., Sánchez-Chávez, G., Sotres-Bayón, F., Bermúdez-Rattoni, F., and Massieu, L. (2019). Recurrent moderate hypoglycemia exacerbates oxidative damage and neuronal death leading to cognitive dysfunction after the hypoglycemic coma. J. Cereb. Blood Flow Metab. 39, 808–821.10.1177/0271678X17733640Search in Google Scholar PubMed PubMed Central

Lee, J.H., Tecedor, L., Chen, Y.H., Monteys, A.M., Sowada, M.J., Thompson, L.M., and Davidson, B.L. (2015). Reinstating aberrant mTORC1 activity in Huntington’s disease mice improves disease phenotypes. Neuron 85, 303–315.10.1016/j.neuron.2014.12.019Search in Google Scholar PubMed PubMed Central

Leech, T., Chattipakorn, N., and Chattipakorn, S.C. (2019). The beneficial roles of metformin on the brain with cerebral ischaemia/reperfusion injury. Pharmacol. Res. 146, 104261.10.1016/j.phrs.2019.104261Search in Google Scholar PubMed

Li, J., Benashski, S.E., Venna, V.R., and McCullough, L.D. (2010). Effects of metformin in experimental stroke. Stroke 41, 2645–2652.10.1161/STROKEAHA.110.589697Search in Google Scholar PubMed PubMed Central

Li, J., Deng, J., Sheng, W., and Zuo, Z. (2012). Metformin attenuates Alzheimer’s disease-like neuropathology in obese, leptin-resistant mice. Pharmacol. Biochem. Behav. 101, 564–574.10.1016/j.pbb.2012.03.002Search in Google Scholar PubMed PubMed Central

Lin, C.H., Tallaksen-Greene, S., Chien, W.M., Cearley, J.A., Jackson, W.S., Crouse, A.B., Ren, S., Li, X.J., Albin, R.L., and Detloff, P.J. (2001). Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum. Mol. Genet. 10, 137–144.10.1093/hmg/10.2.137Search in Google Scholar PubMed

Lin, Y., Wang, K., Ma, C., Wang, X., Gong, Z., Zhang, R., Zang, D., and Cheng, Y. (2018). Evaluation of metformin on cognitive improvement in patients with non-dementia vascular cognitive impairment and abnormal glucose metabolism. Front. Aging Neurosci. 10, 227.10.3389/fnagi.2018.00227Search in Google Scholar PubMed PubMed Central

Ling, Y.Z., Li, Z.Y., Ou-Yang, H.D., Ma, C., Wu, S.L., Wei, J.Y., Ding, H.H., Zhang, X.L., Liu, M., Liu, C.C., et al. (2017). The inhibition of spinal synaptic plasticity mediated by activation of AMP-activated protein kinase signaling alleviates the acute pain induced by oxaliplatin. Exp. Neurol. 288, 85–93.10.1016/j.expneurol.2016.11.009Search in Google Scholar PubMed

Lipton, J.O. and Sahin, M. (2014). The neurology of mTOR. Neuron 84, 275–291.10.1016/j.neuron.2014.09.034Search in Google Scholar PubMed PubMed Central

Liu, Y., Tang, G., Li, Y., Wang, Y., Chen, X., Gu, X., Zhang, Z., Wang, Y., and Yang, G.Y. (2014a). Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion. J. Neuroinflamm. 11, 177.10.1186/s12974-014-0177-4Search in Google Scholar PubMed PubMed Central

Liu, Y., Tang, G., Zhang, Z., Wang, Y., and Yang, G.Y. (2014b). Metformin promotes focal angiogenesis and neurogenesis in mice following middle cerebral artery occlusion. Neurosci Lett. 579, 46–51.10.1016/j.neulet.2014.07.006Search in Google Scholar PubMed

Lu, M., Su, C., Qiao, C., Bian, Y., Ding, J., and Hu, G. (2016). Metformin prevents dopaminergic neuron death in MPTP/P-induced mouse model of Parkinson’s disease via autophagy and mitochondrial ROS clearance. Int. J. Neuropsychopharmacol. 19.10.1093/ijnp/pyw047Search in Google Scholar PubMed PubMed Central

Luchsinger, J.A., Perez, T., Chang, H., Mehta, P., Steffener, J., Pradabhan, G., Ichise, M., Manly, J., Devanand, D.P., and Bagiella, E. (2016). Metformin in amnestic mild cognitive impairment: results of a pilot randomized placebo controlled clinical trial. J. Alzheimers Dis. 51, 501–514.10.3233/JAD-150493Search in Google Scholar PubMed PubMed Central

Ludman, T. and Melemedjian, O.K. (2019). Bortezomib and metformin opposingly regulate the expression of hypoxia-inducible factor α and the consequent development of chemotherapy-induced painful peripheral neuropathy. Mol. Pain 15, 1744806919850043.10.1177/1744806919850043Search in Google Scholar PubMed PubMed Central

Luo, C., Wang, X., Huang, H., Mao, X., Zhou, H., and Liu, Z. (2019). Effect of metformin on antipsychotic-induced metabolic dysfunction: the potential role of gut-brain axis. Front. Pharmacol. 10, 371.10.3389/fphar.2019.00371Search in Google Scholar PubMed PubMed Central

Ma, T.C., Buescher, J.L., Oatis, B., Funk, J.A., Nash, A.J., Carrier, R.L., and Hoyt, K.R. (2007). Metformin therapy in a transgenic mouse model of Huntington’s disease. Neurosci. Lett. 411, 98–103.10.1016/j.neulet.2006.10.039Search in Google Scholar PubMed

Ma, J., Yu, H., Liu, J., Chen, Y., Wang, Q., and Xiang, L. (2015). Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin. Eur. J. Pharmacol. 764, 599–606.10.1016/j.ejphar.2015.06.010Search in Google Scholar PubMed

Ma, J., Liu, J., Yu, H., Chen, Y., Wang, Q., and Xiang, L. (2016). Beneficial effect of Metformin on nerve regeneration and functional recovery after sciatic nerve crush injury in diabetic rats. Neurochem. Res. 41, 1130–1137.10.1007/s11064-015-1803-ySearch in Google Scholar PubMed

Magnuson, B., Ekim, B., and Fingar, D.C. (2012). Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem. J. 441, 1–21.10.1042/BJ20110892Search in Google Scholar PubMed

Mairet-Coello, G., Courchet, J., Pieraut, S., Courchet, V., Maximov, A., and Polleux, F. (2013). The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Aβ oligomers through τ phosphorylation. Neuron 78, 94–108.10.1016/j.neuron.2013.02.003Search in Google Scholar PubMed PubMed Central

Manzo, E., Lorenzini, I., Barrameda, D., O’Conner, A.G., Barrows, J.M., Starr, A., Kovalik, T., Rabichow, B.E., Lehmkuhl, E.M., Shreiner, D.D., et al. (2019). Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS. eLife. 8, pii: e45114. doi: 10.7554/eLife.45114.10.7554/eLife.45114Search in Google Scholar PubMed PubMed Central

Mao-Ying, Q.L., Kavelaars, A., Krukowski, K., Huo, X.J., Zhou, W., Price, T.J., Cleeland, C., and Heijnen, C.J. (2014). The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model. PLoS One 9, e100701.10.1371/journal.pone.0100701Search in Google Scholar PubMed PubMed Central

Marinangeli, C., Didier, S., and Vingtdeux, V. (2016). AMPK in neurodegenerative diseases: implications and therapeutic perspectives. Curr. Drug Targets. 17, 890–907.10.2174/1389450117666160201105645Search in Google Scholar PubMed

Markowicz-Piasecka, M., Sikora, J., Szydłowska, A., Skupień, A., Mikiciuk-Olasik, E., and Huttunen, K.M. (2017). Metformin – a future therapy for neurodegenerative diseases. Pharm. Res. 34, 2614–2627.10.1007/s11095-017-2199-ySearch in Google Scholar PubMed PubMed Central

Markowicz-Piasecka, M., Huttunen, K.M., and Sikora, J. (2018). Metformin and its sulphonamide derivative simultaneously potentiateanti-cholinesterase activity of donepezil and inhibit β-amyloid aggregation. J. Enzyme Inhib. Med. Chem. 33, 1309–1322.10.1080/14756366.2018.1499627Search in Google Scholar PubMed PubMed Central

Martí, E. (2016). RNA toxicity induced by expanded CAG repeats in Huntington’s disease. Brain Pathol. 26, 779–786.10.1111/bpa.12427Search in Google Scholar PubMed PubMed Central

Masaldan, S., Belaidi, A.A., Ayton, S., and Bush, A.I. (2019). Cellular senescence and iron dyshomeostasis in Alzheimer’s disease. Pharmaceuticals (Basel, Switzerland) 12. pii: E93. doi: 10.3390/ph12020093.10.3390/ph12020093Search in Google Scholar PubMed PubMed Central

Matthes, F., Hettich, M.M., Schilling, J., Flores-Dominguez, D., Blank, N., Wiglenda, T., Buntru, A., Wolf, H., Weber, S., Vorberg, I., et al. (2018). Inhibition of the MID1 protein complex: a novel approach targeting APP protein synthesis. Cell Death Discov. 4, 4.10.1038/s41420-017-0003-8Search in Google Scholar PubMed PubMed Central

McColgan, P. and Tabrizi, S.J. (2017). Huntington’s disease: a clinical review. Eur. J. Neurol. 25, 24–34.10.1111/ene.13413Search in Google Scholar PubMed

McGarry, A., McDermott, M., Kieburtz, K., de Blieck, E.A., Beal, F., Marder, K., Ross, C., Shoulson, I., Gilbert, P., Mallonee, W.M., et al. (2017). A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease. Neurology 88, 152–159.10.1212/WNL.0000000000003478Search in Google Scholar PubMed PubMed Central

Mehrabi, S., Sanadgol, N., Barati, M., Shahbazi, A., Vahabzadeh, G., Barzroudi, M., Seifi, M., Gholipourmalekabadi, M., and Golab, F. (2018). Evaluation of metformin effects in the chronic phase of spontaneous seizures in pilocarpine model of temporal lobe epilepsy. Metab. Brain Dis. 33, 107–114.10.1007/s11011-017-0132-zSearch in Google Scholar PubMed

Melemedjian, O.K., Asiedu, M.N., Tillu, D.V., Sanoja, R., Yan, J., Lark, A., Khoutorsky, A., Johnson, J., Peebles, K.A., Lepow, T., et al. (2011). Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain. Mol. Pain 7, 70.10.1186/1744-8069-7-70Search in Google Scholar PubMed PubMed Central

Menalled, L.B., Kudwa, A.E., Miller, S., Fitzpatrick, J., Watson-Johnson, J., Keating, N., Ruiz, M., Mushlin, R., Alosio, W., McConnell, K., et al. (2012). Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington’s disease: zQ175. PLoS One 7, e49838.10.1371/journal.pone.0049838Search in Google Scholar PubMed PubMed Central

Mielke, J.G., Taghibiglou, C., and Wang, Y.T. (2006). Endogenous insulin signaling protects cultured neurons from oxygen-glucose deprivation-induced cell death. Neuroscience 143, 165–173.10.1016/j.neuroscience.2006.07.055Search in Google Scholar PubMed

Mima, Y., Kuwashiro, T., Yasaka, M., Tsurusaki, Y., Nakamura, A., Wakugawa, Y., and Okada, Y. (2016). Impact of metformin on the severity and outcomes of acute ischemic stroke in patients with type 2 diabetes mellitus. J. Stroke Cerebrovasc. Dis. 25, 436–446.10.1016/j.jstrokecerebrovasdis.2015.10.016Search in Google Scholar PubMed

Möller, T. (2010). Neuroinflammation in Huntington’s disease. J. Neural Transm. 117, 1001–1008.10.1007/s00702-010-0430-7Search in Google Scholar PubMed

Montojo, M.T., Aganzo, M., and González, N. (2017). Huntington’s disease and diabetes: chronological sequence of its association. J. Huntington’s Dis. 6, 179–188.10.3233/JHD-170253Search in Google Scholar PubMed PubMed Central

Moore, E.M., Mander, A.G., Ames, D., Kotowicz, M.A., Carne, R.P., Brodaty, H., Woodward, M., Boundy, K., Ellis, K.A., Bush, A.I., et al. (2013). Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 36, 2981–2987.10.2337/dc13-0229Search in Google Scholar PubMed PubMed Central

Moran, C., Callisaya, M.L., Srikanth, V., and Arvanitakis, Z. (2019). Diabetes therapies for dementia. Curr. Neurol. Neurosci. Rep. 19, 58.10.1007/s11910-019-0973-4Search in Google Scholar PubMed

Morgunova, G.V. and Klebanov, A.A. (2019). Age-related AMP-activated protein kinase alterations: from cellular energetics to longevity. Cell. Biochem. Funct. 37, 169–176.10.1002/cbf.3384Search in Google Scholar PubMed

Morley, J.F., Brignull, H.R., Weyers, J.J., and Morimoto, R.I. (2002). The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 99, 10417–10422.10.1073/pnas.152161099Search in Google Scholar PubMed PubMed Central

Morsi, M., Maher, A., Aboelmagd, O., Johar, D., and Bernstein, L. (2018). A shared comparison of diabetes mellitus and neurodegenerative disorders. J. Cell. Biochem. 119, 1249–1256.10.1002/jcb.26261Search in Google Scholar PubMed

Mostafa, D.K., Ismail, C.A., and Ghareeb, D.A. (2016). Differential metformin dose-dependent effects on cognition in rats: role of Akt. Psychopharmacology (Berl.) 233, 2513–2524.10.1007/s00213-016-4301-2Search in Google Scholar PubMed

Mujica-Mota, M.A., Salehi, P., Devic, S., and Daniel, S.J. (2014). Safety and otoprotection of metformin in radiation-induced sensorineural hearing loss in the guinea pig. Otolaryngol. Head Neck Surg. 150, 859–865.10.1177/0194599814521013Search in Google Scholar PubMed

Muri, L., Le, N.D., Zemp, J., Grandgirard, D., and Leib, S.L. (2019). Metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitis. J. Neuroinflammation. 16, 156.10.1186/s12974-019-1549-6Search in Google Scholar PubMed PubMed Central

Najafi, M., Cheki, M., Rezapoor, S., Geraily, G., Motevaseli, E., Carnovale, C., Clementi, E., and Shirazi, A. (2018). Metformin: prevention of genomic instability and cancer: a review. Mutat. Res. Genet. Toxicol. Environ. Mutagen 827, 1–8.10.1016/j.mrgentox.2018.01.007Search in Google Scholar PubMed

Nandini, H.S., Paudel, Y.N., and Krishna, K.L. (2019). Envisioning the neuroprotective effect of metformin in experimental epilepsy: a portrait of molecular crosstalk. Life Sci. 233, 116686.10.1016/j.lfs.2019.116686Search in Google Scholar

Nasir, J., Floresco, S.B., O’Kusky, J.R., Diewert, V.M., Richman, J.M., Zeisler, J., Borowski, A., Marth, J.D., Phillips, A.G., and Hayden, M.R. (1995). Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81, 811–823.10.1016/0092-8674(95)90542-1Search in Google Scholar

Nath, N., Khan, M., Paintlia, M.K., Singh, I., Hoda, M.N., and Giri, S. (2009). Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J. Immunol. 182, 8005–8014.10.4049/jimmunol.0803563Search in Google Scholar PubMed PubMed Central

Neueder, A. and Bates, G.P. (2018). RNA related pathology in Huntington’s disease. Adv. Exp. Med. Biol. 1049, 85–101.10.1007/978-3-319-71779-1_4Search in Google Scholar PubMed

Niccoli, T., Cabecinha, M., Tillmann, A., Kerr, F., Wong, C.T., Cardenes, D., Vincent, A.J., Bettedi, L., Li, L., Grönke, S., et al. (2016). Increased glucose transport into neurons rescues Aβ toxicity in Drosophila. Curr. Biol. 26, 2291–2300.10.1016/j.cub.2016.07.017Search in Google Scholar PubMed PubMed Central

Nitschke, F., Ahonen, S.J., Nitschke, S., Mitra, S., and Minassian, B.A. (2018). Lafora disease – from pathogenesis to treatment strategies. Nat. Rev. Neurol. 14, 606–617.10.1038/s41582-018-0057-0Search in Google Scholar PubMed PubMed Central

Ochaba, J., Fote, G., Kachemov, M., Thein, S., Yeung, S.Y., Lau, A.L., Hernandez, S., Lim, R.G., Casale, M., Neel, M.J., et al. (2019). IKKβ slows Huntington’s disease progression in R6/1 mice. Proc. Natl. Acad. Sci. U.S.A. 116, 10952–10961.10.1073/pnas.1814246116Search in Google Scholar PubMed PubMed Central

Ona, V.O., Li, M., Vonsattel, J.P., Andrews, L.J., Khan, S.Q., Chung, W.M., Frey, A.S., Menon, A.S., Li, X.J., Stieg, P.E., et al. (1999). Inhibition of caspase-1 slows disease progression in a mouse model of Huntington’s disease. Nature 399, 263–267.10.1038/20446Search in Google Scholar PubMed

Onken, B. and Driscoll, M. (2010). Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans healthspan via AMPK, LKB1, and SKN-1. PLoS One 5, e8758.10.1371/journal.pone.0008758Search in Google Scholar PubMed PubMed Central

Ou, Z., Kong, X., Sun, X., He, X., Zhang, L., Gong, Z., Huang, J., Xu, B., Long, D., Li, J., et al. (2018). Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behav. Immun. 69, 351–363.10.1016/j.bbi.2017.12.009Search in Google Scholar PubMed

Owen, M.R., Doran, E., and Halestrap, A.P. (2000). Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348(Pt 3), 607–614.10.1042/bj3480607Search in Google Scholar

Paintlia, A.S., Mohan, S., and Singh, I. (2013a). Combinatorial effect of metformin and lovastatin impedes T-cell autoimmunity and neurodegeneration in experimental autoimmune encephalomyelitis. J. Clin. Cell. Immunol. 4. doi: 10.4172/2155-9899.1000149.10.4172/2155-9899.1000149Search in Google Scholar PubMed PubMed Central

Paintlia, A.S., Paintlia, M.K., Mohan, S., Singh, A.K., and Singh, I. (2013b). AMP-activated protein kinase signaling protects oligodendrocytes that restore central nervous system functions in an experimental autoimmune encephalomyelitis model. Am. J. Pathol. 183, 526–541.10.1016/j.ajpath.2013.04.030Search in Google Scholar PubMed PubMed Central

Park, J.M., Jung, C.H., Seo, M., Otto, N.M., Grunwald, D., Kim, K.H., Moriarity, B., Kim, Y.M., Starker, C., Nho, R.S., et al. (2016). The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14. Autophagy 12, 547–564.10.1080/15548627.2016.1140293Search in Google Scholar PubMed PubMed Central

Patil, S.P., Jain, P.D., Ghumatkar, P.J., Tambe, R., and Sathaye, S. (2014). Neuroprotective effect of metformin in MPTP-induced Parkinson’s disease in mice. Neuroscience 277, 747–754.10.1016/j.neuroscience.2014.07.046Search in Google Scholar PubMed

Peixoto, C.A., Oliveira, W.H.D., Araújo, S.M.D.R., and Nunes, A.K.S. (2017a). AMPK activation: role in the signaling pathways of neuroinflammation and neurodegeneration. Exp. Neurol. 298, 31–41.10.1016/j.expneurol.2017.08.013Search in Google Scholar PubMed

Peixoto, L.G., Teixeira, R.R., Vilela, D.D., Barbosa, L.N., Caixeta, D.C., Deconte, S.R., de Assis de Araújo, F., Sabino-Silva, R., and Espindola, F.S. (2017b). Metformin attenuates the TLR4 inflammatory pathway in skeletal muscle of diabetic rats. Acta Diabetol. 54, 943–951.10.1007/s00592-017-1027-5Search in Google Scholar PubMed

Pérez-Revuelta, B.I., Hettich, M.M., Ciociaro, A., Rotermund, C., Kahle, P.J., Krauss, S., and Di Monte, D.A. (2014). Metformin lowers Ser-129 phosphorylated α-synuclein levels via mTOR-dependent protein phosphatase 2A activation. Cell Death Dis. 5, e1209.10.1038/cddis.2014.175Search in Google Scholar PubMed PubMed Central

Pernicova, I. and Korbonits, M. (2014). Metformin-mode of action and clinical implications for diabetes and cancer. Nat. Rev. Endocrinol. 10, 143–156.10.1038/nrendo.2013.256Search in Google Scholar PubMed

Picone, P., Nuzzo, D., Caruana, L., Messina, E., Barera, A., Vasto, S., and Di Carlo, M. (2015). Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-κB activation: use of insulin to attenuate metformin’s effect. Biochim. Biophys. Acta 1853, 1046–1059.10.1016/j.bbamcr.2015.01.017Search in Google Scholar PubMed

Picone, P., Vilasi, S., Librizzi, F., Contardi, M., Nuzzo, D., Caruana, L., Baldassano, S., Amato, A., Mulè, F., San Biagio, P.L., et al. (2016). Biological and biophysics aspects of metformin-induced effects: cortex mitochondrial dysfunction and promotion of toxic amyloid pre-fibrillar aggregates. Aging 8, 1718–1734.10.18632/aging.101004Search in Google Scholar PubMed PubMed Central

Pinto, R.M., Dragileva, E., Kirby, A., Lloret, A., Lopez, E., St Claire, J., Panigrahi, G.B., Hou, C., Holloway, K., Gillis, T., et al. (2013). Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington’s disease mice: genome-wide and candidate approaches. PLoS Genet. 9, e1003930.10.1371/journal.pgen.1003930Search in Google Scholar PubMed PubMed Central

Poirier, M.A., Jiang, H., and Ross, C.A. (2005). A structure-based analysis of huntingtin mutant polyglutamine aggregation and toxicity: evidence for a compact β-sheet structure. Hum. Mol. Genet. 14, 765–774.10.1093/hmg/ddi071Search in Google Scholar PubMed

Porceddu, P.F., Ishola, I.O., Contu, L., and Morelli, M. (2016). Metformin prevented dopaminergic neurotoxicity induced by 3,4-methylenedioxymethamphetamine administration. Neurotoxicol. Res. 30, 101–109.10.1007/s12640-016-9633-5Search in Google Scholar PubMed

Porter, K.M., Ward, M., Hughes, C.F., O’Kane, M., Hoey, L., McCann, A., Molloy, A.M., Cunningham, C., Casey, M., Tracey, F., et al. (2019). Hyperglycemia and metformin use are associated with B-vitamin deficiency and cognitive dysfunction in older adults. J. Clin. Endocrinol. Metab. 104, 4837–4847.10.1210/jc.2018-01791Search in Google Scholar PubMed

Protic, D., Aydin, E.Y., Tassone, F., Tan, M.M., Hagerman, R.J., and Schneider, A. (2019). Cognitive and behavioral improvement in adults with fragile X syndrome treated with metformin – two cases. Mol. Genet. Genom. Med. 7, e00745.10.1002/mgg3.745Search in Google Scholar PubMed PubMed Central

Rabanal-Ruiz, Y., Otten, E.G., and Korolchuk, V.I. (2017). mTORC1 as the main gateway to autophagy. Essays Biochem. 61, 565–584.10.1042/EBC20170027Search in Google Scholar PubMed PubMed Central

Ratovitski, T., Gucek, M., Jiang, H., Chighladze, E., Waldron, E., D’Ambola, J., Hou, Z., Liang, Y., Poirier, M.A., Hirschhorn, R.R., et al. (2009). Mutant huntingtin N-terminal fragments of specific size mediate aggregation and toxicity in neuronal cells. J. Biol. Chem. 284, 10855–10867.10.1074/jbc.M804813200Search in Google Scholar PubMed PubMed Central

Ravikumar, B., Vacher, C., Berger, Z., Davies, J.E., Luo, S., Oroz, L.G., Scaravilli, F., Easton, D.F., Duden, R., O’Kane, C.J., et al. (2004). Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585–595.10.1038/ng1362Search in Google Scholar PubMed

Rawlins, M.D., Wexler, N.S., Wexler, A.R., Tabrizi, S.J., Douglas, I., Evans, S.J.W., and Smeeth, L. (2016). The prevalence of Huntington’s disease. Neuroepidemiology 46, 144–153.10.1159/000443738Search in Google Scholar PubMed

Rojas, L.B.A. and Gomes, M.B. (2013). Metformin: an old but still the best treatment for type 2 diabetes. Diabetol. Metab. Syndr. 5, 6.10.1186/1758-5996-5-6Search in Google Scholar PubMed PubMed Central

Roscic, A., Baldo, B., Crochemore, C., Marcellin, D., and Paganetti, P. (2011). Induction of autophagy with catalytic mTOR inhibitors reduces huntingtin aggregates in a neuronal cell model. J. Neurochem. 119, 398–407.10.1111/j.1471-4159.2011.07435.xSearch in Google Scholar PubMed

Rotermund, C., Machetanz, G., and Fitzgerald, J.C. (2018). The therapeutic potential of metformin in neurodegenerative diseases. Front. Endocrinol. 9, 400.10.3389/fendo.2018.00400Search in Google Scholar PubMed PubMed Central

Rubio Osornio, M.D.C., Custodio Ramírez, V., Calderón Gámez, D., Paz Tres, C., Carvajal Aguilera, K.G., and Phillips Farfán, B.V. (2018). Metformin plus caloric restriction show anti-epileptic effects mediated by mTOR pathway inhibition. Cell Mol. Neurobiol. 38, 1425–1438.10.1007/s10571-018-0611-8Search in Google Scholar PubMed

Ruderman, N.B., Xu, X.J., Nelson, L., Cacicedo, J.M., Saha, A.K., Lan, F., and Ido, Y. (2010). AMPK and SIRT1: a long-standing partnership? Am. J. Physiol. Endocrinol. Metab. 298, E751–E760.10.1152/ajpendo.00745.2009Search in Google Scholar PubMed PubMed Central

Rué, L., Bañez-Coronel, M., Creus-Muncunill, J., Giralt, A., Alcalá-Vida, R., Mentxaka, G., Kagerbauer, B., Zomeño-Abellán, M.T., Aranda, Z., Venturi, V., et al. (2016). Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels. J. Clin. Invest. 126, 4319–4330.10.1172/JCI83185Search in Google Scholar PubMed PubMed Central

Rui, Y.N., Xu, Z., Patel, B., Chen, Z., Chen, D., Tito, A., David, G., Sun, Y., Stimming, E.F., Bellen, H.J., et al. (2015). Huntingtin functions as a scaffold for selective macroautophagy. Nat. Cell. Biol. 17, 262–275.10.1038/ncb3101Search in Google Scholar PubMed PubMed Central

Russe, O.Q., Möser, C.V., Kynast, K.L., King, T.S., Stephan, H., Geisslinger, G., and Niederberger, E. (2013). Activation of the AMP-activated protein kinase reduces inflammatory nociception. J. Pain 14, 1330–1340.10.1016/j.jpain.2013.05.012Search in Google Scholar PubMed

Ryu, Y.K., Park, H.Y., Go, J., Choi, D.H., Kim, Y.H., Hwang, J.H., Noh, J.R., Lee, T.G., Lee, C.H., and Kim, K.S. (2018). Metformin inhibits the development of L-DOPA-induced dyskinesia in a murine model of Parkinson’s disease. Mol. Neurobiol. 55, 5715–5726.10.1007/s12035-017-0752-7Search in Google Scholar PubMed

Salminen, A., Hyttinen, J.M.T., and Kaarniranta, K. (2011). AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J. Mol. Med. 89, 667–676.10.1007/s00109-011-0748-0Search in Google Scholar PubMed PubMed Central

Salminen, A., Kaarniranta, K., and Kauppinen, A. (2016). Age-related changes in AMPK activation: role for AMPK phosphatases and inhibitory phosphorylation by upstream signaling pathways. Ageing Res. Rev. 28, 15–26.10.1016/j.arr.2016.04.003Search in Google Scholar PubMed

Sancak, Y., Peterson, T.R., Shaul, Y.D., Lindquist, R.A., Thoreen, C.C., Bar-Peled, L., and Sabatini, D.M. (2008). The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501.10.1126/science.1157535Search in Google Scholar PubMed PubMed Central

Sanchis, A., García-Gimeno, M.A., Cañada-Martínez, A.J., Sequedo, M.D., Millán, J.M., Sanz, P., and Vázquez-Manrique, R.P. (2019). Metformin treatment reduces motor and neuropsychiatric phenotypes in the zQ175 mouse model of Huntington disease. Exp. Mol. Med. 51, 65.10.1038/s12276-019-0264-9Search in Google Scholar PubMed PubMed Central

Santo, E.E. and Paik, J. (2018). FOXO in neural cells and diseases of the nervous system. Curr. Top. Dev. Biol. 127, 105–118.10.1016/bs.ctdb.2017.10.002Search in Google Scholar PubMed PubMed Central

Sarbassov, D.D., Ali, S.M., Kim, D.H., Guertin, D.A., Latek, R.R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D.M. (2004). Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302.10.1016/j.cub.2004.06.054Search in Google Scholar PubMed

Sarbassov, D.D., Guertin, D.A., Ali, S.M., and Sabatini, D.M. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101.10.1126/science.1106148Search in Google Scholar PubMed

Sarkar, S., Ravikumar, B., Floto, R.A., and Rubinsztein, D.C. (2009). Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ. 16, 46–56.10.1038/cdd.2008.110Search in Google Scholar PubMed

Sathasivam, K., Neueder, A., Gipson, T.A., Landles, C., Benjamin, A.C., Bondulich, M.K., Smith, D.L., Faull, R.L.M., Roos, R.A.C., Howland, D., et al. (2013). Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc. Natl. Acad. Sci. U.S.A. 110, 2366–2370.10.1073/pnas.1221891110Search in Google Scholar PubMed PubMed Central

Saudou, F. and Humbert, S. (2016). The biology of Huntingtin. Neuron 89, 910–926.10.1016/j.neuron.2016.02.003Search in Google Scholar PubMed

Saudubray, J.M. and Garcia-Cazorla, A. (2018). An overview of inborn errors of metabolism affecting the brain: from neurodevelopment to neurodegenerative disorders. Dialogues Clin. Neurosci. 20, 301–325.10.31887/DCNS.2018.20.4/jmsaudubraySearch in Google Scholar

Saxton, R.A. and Sabatini, D.M. (2017). mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976.10.1016/j.cell.2017.02.004Search in Google Scholar PubMed PubMed Central

Son, S.M., Shin, H.J., Byun, J., Kook, S.Y., Moon, M., Chang, Y.J., and Mook-Jung, I. (2016). Metformin facilitates amyloid-β generation by β- and γ-secretases via autophagy activation. J. Alzheimers Dis. 51, 1197–1208.10.3233/JAD-151200Search in Google Scholar PubMed

Strand, A.D., Baquet, Z.C., Aragaki, A.K., Holmans, P., Yang, L., Cleren, C., Beal, M.F., Jones, L., Kooperberg, C., Olson, J.M., et al. (2007). Expression profiling of Huntington’s disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration. J. Neurosci. 27, 11758–11768.10.1523/JNEUROSCI.2461-07.2007Search in Google Scholar PubMed PubMed Central

Subramaniam, S., Sixt, K.M., Barrow, R., and Snyder, S.H. (2009). Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science 324, 1327–1330.10.1126/science.1172871Search in Google Scholar PubMed PubMed Central

Sun, Y., Tian, T., Gao, J., Liu, X., Hou, H., Cao, R., Li, B., Quan, M., and Guo, L. (2016). Metformin ameliorates the development of experimental autoimmune encephalomyelitis by regulating T helper 17 and regulatory T cells in mice. J. Neuroimmunol. 292, 58–67.10.1016/j.jneuroim.2016.01.014Search in Google Scholar PubMed

Swarnkar, S., Chen, Y., Pryor, W.M., Shahani, N., Page, D.T., and Subramaniam, S. (2015). Ectopic expression of the striatal-enriched GTPase Rhes elicits cerebellar degeneration and an ataxia phenotype in Huntington’s disease. Neurobiol. Dis. 82, 66–77.10.1016/j.nbd.2015.05.011Search in Google Scholar PubMed

Tabrizi, S.J., Leavitt, B.R., Landwehrmeyer, G.B., Wild, E.J., Saft, C., Barker, R.A., Blair, N.F., Craufurd, D., Priller, J., Rickards, H., et al. (2019). Targeting Huntingtin expression in patients with Huntington’s disease. N. Engl. J. Med. 380, 2307–2316.10.1056/NEJMoa1900907Search in Google Scholar PubMed

Taheri, A., Emami, M., Asadipour, E., Kasirzadeh, S., Rouini, M.R., Najafi, A., Heshmat, R., Abdollahi, M., and Mojtahedzadeh, M. (2019). A randomized controlled trial on the efficacy, safety, and pharmacokinetics of metformin in severe traumatic brain injury. J. Neurol. 266, 1988–1997.10.1007/s00415-019-09366-1Search in Google Scholar PubMed

Tanokashira, D., Kurata, E., Fukuokaya, W., Kawabe, K., Kashiwada, M., Takeuchi, H., Nakazato, M., and Taguchi, A. (2018). Metformin treatment ameliorates diabetes-associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1. FEBS Open Bio 8, 1104–1118.10.1002/2211-5463.12436Search in Google Scholar PubMed PubMed Central

Tao, L., Li, D., Liu, H., Jiang, F., Xu, Y., Cao, Y., Gao, R., and Chen, G. (2018). Neuroprotective effects of metformin on traumatic brain injury in rats associated with NF-κB and MAPK signaling pathway. Brain Res. Bull. 140, 154–161.10.1016/j.brainresbull.2018.04.008Search in Google Scholar PubMed

Tayara, K., Espinosa-Oliva, A.M., García-Domínguez, I., Ismaiel, A.A., Boza-Serrano, A., Deierborg, T., Machado, A., Herrera, A.J., Venero, J.L., and de Pablos, R.M. (2018). Divergent effects of metformin on an inflammatory model of Parkinson’s disease. Front. Cell. Neurosci. 12, 440.10.3389/fncel.2018.00440Search in Google Scholar

Templeman, N.M. and Murphy, C.T. (2018). Regulation of reproduction and longevity by nutrient-sensing pathways. J. Cell. Biol. 217, 93–106.10.1083/jcb.201707168Search in Google Scholar

The Huntington’s Disease Collaborative Research Group. (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72, 971–983.10.1016/0092-8674(93)90585-ESearch in Google Scholar

Thompson, L.M., Aiken, C.T., Kaltenbach, L.S., Agrawal, N., Illes, K., Khoshnan, A., Martinez-Vincente, M., Arrasate, M., O’Rourke, J.G., Khashwji, H., et al. (2009). IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J. Cell. Biol. 187, 1083–1099.10.1083/jcb.200909067Search in Google Scholar PubMed PubMed Central

Timmons, J.A., Volmar, C.H., Crossland, H., Phillips, B.E., Sood, S., Janczura, K.J., Törmäkangas, T., Kujala, U.M., Kraus, W.E., Atherton, P.J., et al. (2019). Longevity-related molecular pathways are subject to midlife ‘switch’ in humans. Aging Cell 18, e12970.10.1111/acel.12970Search in Google Scholar PubMed PubMed Central

Tomasoni, R. and Mondino, A. (2011). The tuberous sclerosis complex: balancing proliferation and survival. Biochem. Soc. Trans. 39, 466–471.10.1042/BST0390466Search in Google Scholar PubMed

Trettel, F., Rigamonti, D., Hilditch-Maguire, P., Wheeler, V.C., Sharp, A.H., Persichetti, F., Cattaneo, E., and MacDonald, M.E. (2000). Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells. Hum. Mol. Genet. 9, 2799–2809.10.1093/hmg/9.19.2799Search in Google Scholar PubMed

Ullah, I., Ullah, N., Naseer, M.I., Lee, H.Y., and Kim, M.O.K. (2012). Neuroprotection with metformin and thymoquinone against ethanol-induced apoptotic neurodegeneration in prenatal rat cortical neurons. BMC Neurosci. 13, 11.10.1186/1471-2202-13-11Search in Google Scholar PubMed PubMed Central

Vancura, A., Bu, P., Bhagwat, M., Zeng, J., and Vancurova, I. (2018). Metformin as an anticancer agent. Trends Pharmacol. Sci. 39, 867–878.10.1016/j.tips.2018.07.006Search in Google Scholar PubMed PubMed Central

Vázquez-Manrique, R.P., Farina, F., Cambon, K., Dolores Sequedo, M., Parker, A.J., Millán, J.M., Weiss, A., Déglon, N., and Neri, C. (2016). AMPK activation protects from neuronal dysfunction and vulnerability across nematode, cellular and mouse models of Huntington’s disease. Hum. Mol. Genet. 25, 1043–1058.10.1093/hmg/ddv513Search in Google Scholar PubMed PubMed Central

Veldman, M.B. and Yang, X.W. (2018). Molecular insights into cortico-striatal miscommunications in Huntington’s disease. Curr. Opin. Neurobiol. 48, 79–89.10.1016/j.conb.2017.10.019Search in Google Scholar PubMed PubMed Central

Viollet, B., Guigas, B., Sanz Garcia, N., Leclerc, J., Foretz, M., and Andreelli, F. (2012). Cellular and molecular mechanisms of metformin: an overview. Clin. Sci. (Lond.) 122, 253–270.10.1042/CS20110386Search in Google Scholar PubMed PubMed Central

Vuong, K., Canning, C.G., Menant, J.C., and Loy, C.T. (2018). Gait, balance, and falls in Huntington disease. Handb. Clin. Neurol. 159, 251–260.10.1016/B978-0-444-63916-5.00016-1Search in Google Scholar PubMed

Wahlqvist, M.L., Lee, M.S., Hsu, C.C., Chuang, S.Y., Lee, J.T., and Tsai, H.N. (2012). Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson’s disease occurring with type 2 diabetes in a Taiwanese population cohort. Parkinsonism Relat. Disord. 18, 753–758.10.1016/j.parkreldis.2012.03.010Search in Google Scholar PubMed

Wang, T., Yu, Q., Chen, J., Deng, B., Qian, L., and Le, Y. (2010). PP2A mediated AMPK inhibition promotes HSP70 expression in heat shock response. PLoS One 5, pii: e13096. doi: 10.1371/journal.pone.0013096.10.1371/journal.pone.0013096Search in Google Scholar PubMed PubMed Central

Wang, J., Gallagher, D., DeVito, L.M., Cancino, G.I., Tsui, D., He, L., Keller, G.M., Frankland, P.W., Kaplan, D.R., and Miller, F.D. (2012). Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell. Stem Cell 11, 23–35.10.1016/j.stem.2012.03.016Search in Google Scholar PubMed

Wang, C., Liu, C., Gao, K., Zhao, H., Zhou, Z., Shen, Z., Guo, Y., Li, Z., Yao, T., and Mei, X. (2016). Metformin preconditioning provide neuroprotection through enhancement of autophagy and suppression of inflammation and apoptosis after spinal cord injury. Biochem. Biophys. Res. Commun. 477, 534–540.10.1016/j.bbrc.2016.05.148Search in Google Scholar PubMed

Wang, L., Cai, Y., and Fan, X. (2018). Metformin administration during early postnatal life rescues autistic-like behaviors in the BTBR T+ Itpr3tf/J mouse model of autism. Front. Behav. Neurosci. 12, 290.10.3389/fnbeh.2018.00290Search in Google Scholar PubMed PubMed Central

Wang, X., Luo, C., Mao, X.Y., Li, X., Yin, J.Y., Zhang, W., Zhou, H.H., and Liu, Z.Q. (2019). Metformin reverses the schizophrenia-like behaviors induced by MK-801 in rats. Brain Res. 1719, 30–39.10.1016/j.brainres.2019.05.023Search in Google Scholar PubMed

Williams, T., Courchet, J., Viollet, B., Brenman, J.E., and Polleux, F. (2011). AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress. Proc. Natl. Acad. Sci. U.S.A. 108, 5849–5854.10.1073/pnas.1013660108Search in Google Scholar PubMed PubMed Central

Wlodarchak, N. and Xing, Y. (2016). PP2A as a master regulator of the cell cycle. Crit. Rev. Biochem. Mol. Biol. 51, 162–184.10.3109/10409238.2016.1143913Search in Google Scholar PubMed PubMed Central

Wold, M.S., Lim, J., Lachance, V., Deng, Z., and Yue, Z. (2016). ULK1-mediated phosphorylation of ATG14 promotes autophagy and is impaired in Huntington’s disease models. Mol. Neurodegener. 11, 76.10.1186/s13024-016-0141-0Search in Google Scholar PubMed PubMed Central

Wu, Y., Song, P., Xu, J., Zhang, M., and Zou, M.H. (2007). Activation of protein phosphatase 2A by palmitate inhibits AMP-activated protein kinase. J. Biol. Chem. 282, 9777–9788.10.1074/jbc.M608310200Search in Google Scholar PubMed

Wyttenbach, A., Hands, S., King, M.A., Lipkow, K., and Tolkovsky, A.M. (2008). Amelioration of protein misfolding disease by rapamycin: translation or autophagy? Autophagy 4, 542–545.10.4161/auto.6059Search in Google Scholar PubMed

Xu, Y., Liu, C., Chen, S., Ye, Y., Guo, M., Ren, Q., Liu, L., Zhang, H., Xu, C., Zhou, Q., et al. (2014). Activation of AMPK and inactivation of Akt result in suppression of mTOR-mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson’s disease. Cell. Signal. 26, 1680–1689.10.1016/j.cellsig.2014.04.009Search in Google Scholar PubMed PubMed Central

Yan, L., Mieulet, V., Burgess, D., Findlay, G.M., Sully, K., Procter, J., Goris, J., Janssens, V., Morrice, N.A., and Lamb, R.F. (2010). PP2A T61 epsilon is an inhibitor of MAP4K3 in nutrient signaling to mTOR. Mol. Cell. 37, 633–642.10.1016/j.molcel.2010.01.031Search in Google Scholar PubMed

Yan, Q., Han, C., Wang, G., Waddington, J.L., Zheng, L., and Zhen, X. (2017). Activation of AMPK/mTORC1-mediated autophagy by metformin reverses Clk1 deficiency-sensitized dopaminergic neuronal death. Mol. Pharmacol. 92, 640–652.10.1124/mol.117.109512Search in Google Scholar PubMed

Yang, Y., Zhu, B., Zheng, F., Li, Y., Zhang, Y., Hu, Y., and Wang, X. (2017). Chronic metformin treatment facilitates seizure termination. Biochem. Biophys. Res. Commun. 484, 450–455.10.1016/j.bbrc.2017.01.157Search in Google Scholar PubMed

Yimer, E.M., Surur, A., Wondafrash, D.Z., and Gebre, A.K. (2019). The effect of metformin in experimentally induced animal models of epileptic seizure. Behav. Neurol. 2019, 6234758.10.1155/2019/6234758Search in Google Scholar PubMed PubMed Central

Yuan, R., Wang, Y., Li, Q., Zhen, F., Li, X., Lai, Q., Hu, P., Wang, X., Zhu, Y., Fan, H., et al. (2019). Metformin reduces neuronal damage and promotes neuroblast proliferation and differentiation in a cerebral ischemia/reperfusion rat model. Neuroreport 30, 232–240.10.1097/WNR.0000000000001190Search in Google Scholar PubMed

Zeitler, B., Froelich, S., Marlen, K., Shivak, D.A., Yu, Q., Li, D., Pearl, J.R., Miller, J.C., Zhang, L., Paschon, D.E., et al. (2019). Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease. Nat. Med. 25, 1131–1142.10.1038/s41591-019-0478-3Search in Google Scholar PubMed

Zeitlin, S., Liu, J.P., Chapman, D.L., Papaioannou, V.E., and Efstratiadis, A. (1995). Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat. Genet. 11, 155–163.10.1038/ng1095-155Search in Google Scholar PubMed

Zhang, D., Xuan, J., Zheng, B.B., Zhou, Y.L., Lin, Y., Wu, Y.S., Zhou, Y.F., Huang, Y.X., Wang, Q., Shen, L.Y., et al. (2017a). Metformin improves functional recovery after spinal cord injury via autophagy flux stimulation. Mol. Neurobiol. 54, 3327–3341.10.1007/s12035-016-9895-1Search in Google Scholar PubMed

Zhang, J., Cai, Q., Jiang, M., Liu, Y., Gu, H., Guo, J., Sun, H., Fang, J., and Jin, L. (2017b). Mesencephalic astrocyte-derived neurotrophic factor alleviated 6-OHDA-induced cell damage via ROS-AMPK/mTOR mediated autophagic inhibition. Exp. Gerontol. 89, 45–56.10.1016/j.exger.2017.01.010Search in Google Scholar PubMed

Zhang, J., Culp, M.L., Craver, J.G., and Darley-Usmar, V. (2018). Mitochondrial function and autophagy: integrating proteotoxic, redox, and metabolic stress in Parkinson’s disease. J. Neurochem. 144, 691–709.10.1111/jnc.14308Search in Google Scholar PubMed PubMed Central

Zhang, J., Lin, Y., Dai, X., Fang, W., Wu, X., and Chen, X. (2019). Metformin treatment improves the spatial memory of aged mice in an APOE genotype-dependent manner. FASEB J. 33, 7748–7757.10.1096/fj.201802718RSearch in Google Scholar PubMed

Zhao, M., Li, X.W., Chen, D.Z., Hao, F., Tao, S.X., Yu, H.Y., Cheng, R., and Liu, H. (2019a). Neuro-protective role of metformin in patients with acute stroke and type 2 diabetes mellitus via AMPK/mammalian target of rapamycin (mTOR) signaling pathway and oxidative stress. Med. Sci. Monit. 25, 2186–2194.10.12659/MSM.911250Search in Google Scholar PubMed PubMed Central

Zhao, X., Zeng, Z., Gaur, U., Fang, J., Peng, T., Li, S., and Zheng, W. (2019b). Metformin protects PC12 cells and hippocampal neurons from H₂O₂-induced oxidative damage through activation of AMPK pathway. J. Cell. Physiol. (in press). Available at: https://doi.org/10.1002/jcp.28337.10.1002/jcp.28337Search in Google Scholar PubMed

Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001). Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174.10.1172/JCI13505Search in Google Scholar PubMed PubMed Central

Zhou, C., Sun, R., Zhuang, S., Sun, C., Jiang, Y., Cui, Y., Li, S., Xiao, Y., Du, Y., Gu, H., et al. (2016a). Metformin prevents cerebellar granule neurons against glutamate-induced neurotoxicity. Brain Res. Bull. 121, 241–245.10.1016/j.brainresbull.2016.02.009Search in Google Scholar PubMed

Zhou, W., Kavelaars, A., and Heijnen, C.J. (2016b). Metformin prevents cisplatin-induced cognitive impairment and brain damage in mice. PLoS One 11, e0151890.10.1371/journal.pone.0151890Search in Google Scholar PubMed PubMed Central

Zhou, J., Massey, S., Story, D., and Li, L. (2018). Metformin: an old drug with new applications. Int. J. Mol. Sci. 19, pii: E2863. doi: 10.3390/ijms19102863.10.3390/ijms19102863Search in Google Scholar PubMed PubMed Central

Zhou, B., Liu, J., Kang, R., Klionsky, D.J., Kroemer, G., and Tang, D. (2019). Ferroptosis is a type of autophagy-dependent cell death. Semin. Cancer Biol. pii: S1044-579X(19)30006-9. doi: 10.1016/j.semcancer.2019.03.002.10.1016/j.semcancer.2019.03.002Search in Google Scholar PubMed

Zhu, X.C., Jiang, T., Zhang, Q.Q., Cao, L., Tan, M.S., Wang, H.F., Ding, Z.Z., Tan, L., and Yu, J.T. (2015). Chronic metformin preconditioning provides neuroprotection via suppression of NF-κB-mediated inflammatory pathway in rats with permanent cerebral ischemia. Mol. Neurobiol. 52, 375–385.10.1007/s12035-014-8866-7Search in Google Scholar PubMed

Zimbron, J., Khandaker, G.M., Toschi, C., Jones, P.B., and Fernandez-Egea, E. (2016). A systematic review and meta-analysis of randomised controlled trials of treatments for clozapine-induced obesity and metabolic syndrome. Eur. Neuropsychopharmacol. 26, 1353–1365.10.1016/j.euroneuro.2016.07.010Search in Google Scholar PubMed