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Effects of Hyperthermia on TRPV1 and TRPV4 Channels Expression and Oxidative Markers in Mouse Brain

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Abstract

Heat stress increases the core body temperature through the pathogenic process. The pathogenic process leads to the release of free radicals, such as superoxide production. Heat stress in the central nervous system (CNS) can cause neuronal damage and symptoms such as delirium, coma, and convulsion. TRPV1 (Transient Receptor Potential Vanilloid1) and TRPV4 genes are members of the TRPV family, including integral membrane proteins that act as calcium-permeable channels. These channels act as thermosensors and have essential roles in the cellular regulation of heat responses. The objective of this study is to examine the effect of general heat stress on the expression of TRPV1 and TRPV4 channels. Furthermore, oxidative markers were measured in the brain of the same heat-stressed mice. Our results show that heat stress leads to a significant upregulation of TRPV1 expression within 21–42 days, while TRPV4 expression decreased significantly in a time-dependent manner. Alterations in the oxidative markers were also observed in the heat-stressed mice.

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References

  • Albukrek D, Bakon M, Moran D, Faibel M, Epstein Y, Moran D (1997) Heat-stroke-induced cerebellar atrophy: clinical course, CT and MRI findings. Neuroradiology 39(3):195–197

    Article  CAS  PubMed  Google Scholar 

  • Bai J-Z, Lipski J (2010) Differential expression of TRPM2 and TRPV4 channels and their potential role in oxidative stress-induced cell death in organotypic hippocampal culture. Neurotoxicology 31(2):204–214

    Article  CAS  PubMed  Google Scholar 

  • Belhadj Slimen I, Najar T, Ghram A, Dabbebi H, Ben Mrad M, Abdrabbah M (2014) Reactive oxygen species, heat stress and oxidative-induced mitochondrial damage. A review. Int J Hyperth 30(7):513–523

    Article  CAS  Google Scholar 

  • Benfenati V, Amiry-Moghaddam M, Caprini M, Mylonakou M, Rapisarda C, Ottersen O, Ferroni S (2007) Expression and functional characterization of transient receptor potential vanilloid-related channel 4 (TRPV4) in rat cortical astrocytes. Neuroscience 148(4):876–892

    Article  CAS  PubMed  Google Scholar 

  • Bouchama A, Dehbi M, Chaves-Carballo E (2007) Cooling and hemodynamic management in heatstroke: practical recommendations. Crit Care 11(3):R54

    Article  PubMed  PubMed Central  Google Scholar 

  • Bouchama A, Knochel JP (2002) Heat stroke. N Engl J Med 346(25):1978–1988

    Article  CAS  PubMed  Google Scholar 

  • Breinholt V, Lauridsen S, Dragsted L (1999) Differential effects of dietary flavonoids on drug metabolizing and antioxidant enzymes in female rat. Xenobiotica 29(12):1227–1240

    Article  CAS  PubMed  Google Scholar 

  • Cao D-S, Yu S-Q, Premkumar LS (2009) Modulation of transient receptor potential vanilloid 4-mediated membrane currents and synaptic transmission by protein kinase C. Mol Pain. https://doi.org/10.1186/1744-8069-5-5

    Article  PubMed  PubMed Central  Google Scholar 

  • Caterina MJ, Leffler A, Malmberg A, Martin W, Trafton J, Petersen-Zeitz K, Koltzenburg M, Basbaum A, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288(5464):306–313

    Article  CAS  PubMed  Google Scholar 

  • Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389(6653):816

    Article  CAS  PubMed  Google Scholar 

  • Christie S, Wittert GA, Li H, Page AJ (2018). Involvement of TRPV1 channels in energy homeostasis. Front Endocrinol. https://doi.org/10.3389/fendo.2018.00420

    Article  Google Scholar 

  • Chrousos GP, Gold PW (1992) The concepts of stress and stress system disorders: overview of physical and behavioral homeostasis. JAMA 267(9):1244–1252

    Article  CAS  PubMed  Google Scholar 

  • Ciura S, Bourque CW (2006) Transient receptor potential vanilloid 1 is required for intrinsic osmoreception in organum vasculosum lamina terminalis neurons and for normal thirst responses to systemic hyperosmolality. J Neurosci 26(35):9069–9075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Constantin CE, Mair N, Sailer CA, Andratsch M, Xu Z-Z, Blumer MJ, Scherbakov N, Davis JB, Bluethmann H, Ji R-R (2008) Endogenous tumor necrosis factor α (TNFα) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model. J Neurosci 28(19):5072–5081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Easterling DR, Meehl GA, Parmesan C, Changnon SA, Karl TR, Mearns LO (2000) Climate extremes: observations, modeling, and impacts. Science 289(5487):2068–2074

    Article  CAS  PubMed  Google Scholar 

  • El-Orabi NF, Rogers CB, Edwards HG, Schwartz DD (2011) Heat-induced inhibition of superoxide dismutase and accumulation of reactive oxygen species leads to HT-22 neuronal cell death. J Therm Biol 36(1):49–56

    Article  CAS  Google Scholar 

  • El Karim I, McCrudden MT, Linden GJ, Abdullah H, Curtis TM, McGahon M, About I, Irwin C, Lundy FT (2015) TNF-α-induced p38MAPK activation regulates TRPA1 and TRPV4 activity in odontoblast-like cells. Am J Pathol 185(11):2994–3002

    Article  PubMed  CAS  Google Scholar 

  • Esterbauer H, Cheeseman KH (1990) [42] Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods Enzymol 186:407–421

    Article  CAS  PubMed  Google Scholar 

  • Fusi C, Materazzi S, Minocci D, Maio V, Oranges T, Massi D, Nassini R (2014) Transient receptor potential vanilloid 4 (TRPV4) is downregulated in keratinocytes in human non-melanoma skin cancer. J Investig Dermatol 134(9):2408–2417

    Article  CAS  PubMed  Google Scholar 

  • Gaoua N (2010) Cognitive function in hot environments: a question of methodology. Scand J Med Sci Sports 20:60–70

    Article  PubMed  Google Scholar 

  • Hancock PA, Vasmatzidis I (2003) Effects of heat stress on cognitive performance: the current state of knowledge. Int J Hyperth 19(3):355–372

    Article  CAS  Google Scholar 

  • Hara Y, Wakamori M, Ishii M, Maeno E, Nishida M, Yoshida T, Yamada H, Shimizu S, Mori E, Kudoh J (2002) LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol Cell 9(1):163–173

    Article  CAS  PubMed  Google Scholar 

  • Harikai N, Tomogane K, Miyamoto M, Shimada K, Onodera S, Tashiro S-I (2003) Dynamic responses to acute heat stress between 34 C and 38.5 C, and characteristics of heat stress response in mice. Biol Pharm Bull 26(5):701–708

    Article  CAS  PubMed  Google Scholar 

  • Ho KW, Ward NJ, Calkins DJ (2012) TRPV1: a stress response protein in the central nervous system. Am J Neurodegener Dis 1(1):1

    PubMed  PubMed Central  Google Scholar 

  • Hoshi Y, Okabe K, Shibasaki K, Funatsu T, Matsuki N, Ikegaya Y, Koyama R (2018) Ischemic brain injury leads to brain edema via hyperthermia-induced TRPV4 activation. J Neurosci. https://doi.org/10.1523/JNEUROSCI.2888-17.2018

    Article  PubMed  PubMed Central  Google Scholar 

  • Huang W-X, Min J-W, Liu Y-Q, He X-H, Peng B-W (2014) Expression of TRPV1 in the C57BL/6 mice brain hippocampus and cortex during development. NeuroReport 25(6):379–385

    Article  CAS  PubMed  Google Scholar 

  • Ji R-R, Samad TA, Jin S-X, Schmoll R, Woolf CJ (2002) p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36(1):57–68

    Article  CAS  PubMed  Google Scholar 

  • Jian B, Hsieh C-H, Chen J, Choudhry M, Bland K, Chaudry I, Raju R (2008) Activation of endoplasmic reticulum stress response following trauma-hemorrhage. Biochim Biophys Acta Mol Basis Dis 1782(11):621–626

    Article  CAS  Google Scholar 

  • Kanamaru T, Kamimura N, Yokota T, Iuchi K, Nishimaki K, Takami S, Akashiba H, Shitaka Y, Katsura K-I, Kimura K (2015) Oxidative stress accelerates amyloid deposition and memory impairment in a double-transgenic mouse model of Alzheimer’s disease. Neurosci Lett 587:126–131

    Article  CAS  PubMed  Google Scholar 

  • Kauer JA, Gibson HE (2009) Hot flash: TRPV channels in the brain. Trends Neurosci 32(4):215–224

    Article  CAS  PubMed  Google Scholar 

  • Kim HG, Kim T-M, Park G, Lee TH, Oh MS (2013) Repeated heat exposure impairs nigrostriatal dopaminergic neurons in mice. Biol Pharm Bull 36(10):1556–1561

    Article  CAS  PubMed  Google Scholar 

  • Kiyatkin EA (2007) Physiological and pathological brain hyperthermia. Prog Brain Res 162:219–243

    Article  CAS  PubMed  Google Scholar 

  • Kregel KC, Tipton CM, Seals DR (1990) Thermal adjustments to nonexertional heat stress in mature and senescent Fischer 344 rats. J Appl Physiol 68(4):1337–1342

    Article  CAS  PubMed  Google Scholar 

  • Kunert-Keil C, Bisping F, Krüger J, Brinkmeier H (2006) Tissue-specific expression of TRP channel genes in the mouse and its variation in three different mouse strains. BMC Genomics 7(1):159

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Levine S (1991) What is stress? In: Stress, neurobiology and neuroendocrinology. Marcel Dekker, New York, pp 3–21

  • Li J-J, Oberley LW (1997) Overexpression of manganese-containing superoxide dismutase confers resistance to the cytotoxicity of tumor necrosis factor α and/or hyperthermia. Cancer Res 57(10):1991–1998

    CAS  PubMed  Google Scholar 

  • Lin M, Liu H, Yang Y (1997) Involvement of interleukin-1 receptor mechanisms in development of arterial hypotension in rat heatstroke. Am J Physiol Heart Circ Physiol 273(4):H2072–H2077

    Article  CAS  Google Scholar 

  • Lipski J, Park TI, Li D, Lee SC, Trevarton AJ, Chung KK, Freestone PS, Bai J-Z (2006) Involvement of TRP-like channels in the acute ischemic response of hippocampal CA1 neurons in brain slices. Brain Res 1077(1):187–199

    Article  CAS  PubMed  Google Scholar 

  • Llinás RR (1988) The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function. Science 242(4886):1654–1664

    Article  PubMed  Google Scholar 

  • Lu Q, Harris VA, Sun X, Hou Y, Black SM (2013) Ca2+/calmodulin-dependent protein kinase II contributes to hypoxic ischemic cell death in neonatal hippocampal slice cultures. PLoS ONE 8(8):e70750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marty A (1989) The physiological role of calcium-dependent channels. Trends Neurosci 12(11):420–424

    Article  CAS  PubMed  Google Scholar 

  • Matsuki S, Iuchi Y, Ikeda Y, Sasagawa I, Tomita Y, Fujii J (2003) Suppression of cytochrome c release and apoptosis in testes with heat stress by minocycline. Biochem Biophys Res Commun 312(3):843–849

    Article  CAS  PubMed  Google Scholar 

  • Menigoz A, Boudes M (2011) The expression pattern of TRPV1 in brain. J Neurosci 31(37):13025–13027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mizuno A, Matsumoto N, Imai M, Suzuki M (2003) Impaired osmotic sensation in mice lacking TRPV4. Am J Physiol Cell Physiol 285(1):C96–C101

    Article  CAS  PubMed  Google Scholar 

  • Moran D, Horowitz M, Meiri U, Laor A, Pandolf K (1999) The physiological strain index applied to heat-stressed rats. J Appl Physiol 86(3):895–901

    Article  CAS  PubMed  Google Scholar 

  • Moseley PL (1997) Heat shock proteins and heat adaptation of the whole organism. J Appl Physiol 83(5):1413–1417

    Article  CAS  PubMed  Google Scholar 

  • Nazıroğlu M (2012) Molecular role of catalase on oxidative stress-induced Ca2+ signaling and TRP cation channel activation in nervous system. J Recept Signal Transduct 32(3):134–141

    Article  CAS  Google Scholar 

  • Nilius B, Owsianik G (2011) The transient receptor potential family of ion channels. Genome Biol 12(3):218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70(1):158–169

    CAS  PubMed  Google Scholar 

  • Parellada M, Moreno C, Mac-Dowell K, Leza JC, Giraldez M, Bailón C, Castro C, Miranda-Azpiazu P, Fraguas D, Arango C (2012) Plasma antioxidant capacity is reduced in Asperger syndrome. J Psychiatr Res 46(3):394–401

    Article  PubMed  Google Scholar 

  • Park C-H, Lee MJ, Ahn J, Kim S, Kim HH, Kim KH, Eun HC, Chung JH (2004) Heat shock-induced matrix metalloproteinase (MMP)-1 and MMP-3 are mediated through ERK and JNK activation and via an autocrine interleukin-6 loop. J Investig Dermatol 123(6):1012–1019

    Article  CAS  PubMed  Google Scholar 

  • Pedersen SF, Nilius B (2007) Transient receptor potential channels in mechanosensing and cell volume regulation. Methods Enzymol 428:183–207

    Article  CAS  PubMed  Google Scholar 

  • Pires PW, Earley S (2017) Redox regulation of transient receptor potential channels in the endothelium. Microcirculation 24(3):e12329

    Article  CAS  Google Scholar 

  • Pivovarova NB, Andrews SB (2010) Calcium-dependent mitochondrial function and dysfunction in neurons. FEBS J 277(18):3622–3636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Puntambekar P, Mukherjea D, Jajoo S, Ramkumar V (2005) Essential role of Rac1/NADPH oxidase in nerve growth factor induction of TRPV1 expression. J Neurochem 95(6):1689–1703

    Article  CAS  PubMed  Google Scholar 

  • Rooney C, McMichael AJ, Kovats RS, Coleman MP (1998) Excess mortality in England and Wales, and in Greater London, during the 1995 heat wave. J Epidemiol Community Health 52(8):482–486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roux PP, Topisirovic I (2012) Regulation of mRNA translation by signaling pathways. Cold Spring Harb Perspect Biol 4(11):a012252

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Selye H (1936) A syndrome produced by diverse nocuous agents. Nature 138(3479):32

    Article  Google Scholar 

  • Sharma HS (2006) Hyperthermia induced brain oedema: current status and future perspectives. Indian J Med Res 123(5):629

    PubMed  Google Scholar 

  • Sharma HS, Sharma A, Moessler H, Muresanu DF (2012) Neuroprotective effects of cerebrolysin, a combination of different active fragments of neurotrophic factors and peptides on the whole body hyperthermia-induced neurotoxicity: modulatory roles of co-morbidity factors and nanoparticle intoxication. Int Rev Neurobiol 102:249–276

    Article  CAS  PubMed  Google Scholar 

  • Sharma P, Evans A, Parker P, Evans F (1991) NADPH-oxidase activation by protein kinase C-isotypes. Biochem Biophys Res Commun 177(3):1033–1040

    Article  CAS  PubMed  Google Scholar 

  • Shibasaki K, Sugio S, Takao K, Yamanaka A, Miyakawa T, Tominaga M, Ishizaki Y (2015) TRPV4 activation at the physiological temperature is a critical determinant of neuronal excitability and behavior. Pflügers Arch Eur J Physiol 467(12):2495–2507

    Article  CAS  Google Scholar 

  • Sinha RK (2007) An approach to estimate EEG power spectrum as an index of heat stress using backpropagation artificial neural network. Med Eng Phys 29(1):120–124

    Article  PubMed  Google Scholar 

  • Sun G, Qian S, Jiang Q, Liu K, Li B, Li M, Zhao L, Zhou Z, von Deneen KM, Liu Y (2013) Hyperthermia-induced disruption of functional connectivity in the human brain network. PLoS ONE 8(4):e61157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun G, Yang X, Jiang Q, Liu K, Li B, Li L, Zhao L, Li M (2012) Hyperthermia impairs the executive function using the Attention Network Test. Int J Hyperth 28(7):621–626

    Article  Google Scholar 

  • Tsushima H, Mori M (2006) Antidipsogenic effects of a TRPV4 agonist, 4α-phorbol 12, 13-didecanoate, injected into the cerebroventricle. Am J Physiol Regul Integr Comp Physiol 290(6):R1736–R1741

    Article  CAS  PubMed  Google Scholar 

  • Vincent F, Acevedo A, Nguyen MT, Dourado M, DeFalco J, Gustafson A, Spiro P, Emerling DE, Kelly MG, Duncton MA (2009) Identification and characterization of novel TRPV4 modulators. Biochem Biophys Res Commun 389(3):490–494

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Huang J, Wang L, Chen C, Yang D, Jin M, Bai C, Song Y (2017a) Urban particulate matter triggers lung inflammation via the ROS-MAPK-NF-κB signaling pathway. J Thorac Dis 9(11):4398

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang SE, Ko SY, Jo S, Choi M, Lee SH, Jo H-R, Seo JY, Lee SH, Kim Y-S, Jung SJ (2017b) TRPV1 regulates stress responses through HDAC2. Cell Rep 19(2):401–412

    Article  CAS  PubMed  Google Scholar 

  • Wehage E, Eisfeld J, Heiner I, Jüngling E, Zitt C, Lückhoff A (2002) Activation of the cation channel long transient receptor potential channel 2 (LTRPC2) by hydrogen peroxide A splice variant reveals a mode of activation independent of ADP-ribose. J Biol Chem 277(26):23150–23156

    Article  CAS  PubMed  Google Scholar 

  • White MG, Emery M, Nonner D, Barrett JN (2003) Caspase activation contributes to delayed death of heat-stressed striatal neurons. J Neurochem 87(4):958–968

    Article  CAS  PubMed  Google Scholar 

  • White MG, Luca LE, Nonner D, Saleh O, Hu B, Barrett EF, Barrett JN (2007) Cellular mechanisms of neuronal damage from hyperthermia. Prog Brain Res 162:347–371

    Article  CAS  PubMed  Google Scholar 

  • Xiao C, Mileva-Seitz V, Seroude L, Robertson RM (2007) Targeting HSP70 to motoneurons protects locomotor activity from hyperthermia in Drosophila. Dev Neurobiol 67(4):438–455

    Article  CAS  PubMed  Google Scholar 

  • Yan J, Bao E, Yu J (2009) Heat shock protein 60 expression in heart, liver and kidney of broilers exposed to high temperature. Res Vet Sci 86(3):533–538

    Article  CAS  PubMed  Google Scholar 

  • Yang Y-L, Lin M-T (1999) Heat shock protein expression protects against cerebral ischemia and monoamine overload in rat heatstroke. Am J Physiol Heart Circ Physiol 276(6):H1961–H1967

    Article  CAS  Google Scholar 

  • Yousefi H, Alihemmati A, Karimi P, Alipour MR, Habibi P, Ahmadiasl N (2017) Effect of genistein on expression of pancreatic SIRT1, inflammatory cytokines and histological changes in ovariectomized diabetic rat. Iran J Basic Med Sci 20(4):423

    PubMed  PubMed Central  Google Scholar 

  • Zeller L, Novack V, Barski L, Jotkowitz A, Almog Y (2011) Exertional heatstroke: clinical characteristics, diagnostic and therapeutic considerations. Eur J Intern Med 22(3):296–299

    Article  PubMed  Google Scholar 

  • Zhang F, Yang H, Wang Z, Mergler S, Liu H, Kawakita T, Tachado SD, Pan Z, Capó-Aponte JE, Pleyer U (2007) Transient receptor potential vanilloid 1 activation induces inflammatory cytokine release in corneal epithelium through MAPK signaling. J Cell Physiol 213(3):730–739

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the Neuroscience Research Center of the Tabriz University of Medical Science. Dr. Mehdi Farhoudi’s Lab, from the East Azerbaijan Science and Technology Park and Dr. Pouran Karimi Lab in Tabriz Iran for their cooperation and support. And we also thank Dr. Anna Garcia-Elias from the Montreal Heart Institute in Canada for her advice.

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MAHF, LMF conceived and designed the study. AA, MG carried out the experiments, acquired the results, MG designed used primers. AA, LMF, MG analyzed and explicated results and drafted the manuscript. LR prepared tissue sections and analyzed the immunohistochemistry results. Each named author reviewed and approved the manuscript. All authors confirm that this manuscript has not been previously published and is not currently under consideration by any other journal.

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Correspondence to Leila Mehdizadeh Fanid.

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Aghazadeh, A., Feizi, M.A.H., Fanid, L.M. et al. Effects of Hyperthermia on TRPV1 and TRPV4 Channels Expression and Oxidative Markers in Mouse Brain. Cell Mol Neurobiol 41, 1453–1465 (2021). https://doi.org/10.1007/s10571-020-00909-z

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