Abstract
Although L-DOPA revolutionized in the treatment of Parkinson’s disease, most patients developed motor complications after several years of treatment. Adjunctive therapy to L-DOPA with drugs related to dopaminergic signaling may reduce its dose without decreasing the therapeutic efficiency and thus ameliorates its adverse effects. It has been shown that 3,4-diaminopyridine (3,4-DAP), a K channel blocker, increased dopamine release from striatal slices by increasing neuronal firing in striatal dopaminergic terminals. The current study investigates whether 3,4-DAP may enhance L-DOPA-induced dopamine (DA) release from striatal slices by increasing neuronal firing in striatal dopaminergic terminals. The effects of L-DOPA and 3,4-DAP on spontaneous DA and DOPAC release were tested in vitro, on acute rat striatal slices prepared from non-treated and 6-hydroxydopamine-pre-treated rats. DA and DOPAC levels were determined by HPLC methods. When 3,4-diaminopyridine was combined with L-DOPA, the observed effect was considerably greater than the increases induced by L-DOPA or 3,4-DAP alone in normoxic and neurodegenerative conditions produced by FeSO4 and 6-hydroxydopamine. Furthermore, L-DOPA plus 3,4-DAP also ameliorated DOPAC levels in neurodegenerative conditions. These data indicate that 3,4 DAP plus L-DOPA activates striatal dopaminergic terminals by increasing the DA release and, thus, could be considered as a promising finding in treatment of acute and chronic injury in dopaminergic neurons.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ahlskog JE, Muenter MD (2001) Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 16(3):448–458. https://doi.org/10.1002/mds.1090
Aidi-Knani S, Regaya I, Amalric M, Mourre C (2015) Kv4 channel blockade reduces motor and neuropsychiatric symptoms in rodent models of Parkinson’s disease. Behav Pharmacol 26:91–100. https://doi.org/10.1097/FBP.0000000000000107
Andreani A, Leoni A, Locatelli A, Morigi R, Rambaldi M, Pietra C, Villetti G (2000) 4-Aminopyridine derivatives with antiamnesic activity. Eur J Med Chem 35(1):77–82. https://doi.org/10.1016/s0223-5234(00)00103-3
Barnes S, Whitham EM, Davies JA (1989) Effects of potassium channel blockade on endogenous glutamate release from cerebellar slices. Brain Res 486(1):89–94. https://doi.org/10.1016/0006-8993(89)91281-x
Becker JB (1990) Direct effect of 17 beta-estradiol on striatum: Sex differences in dopamine release. Synapse 5:157–164. https://doi.org/10.1002/syn.890050211
Berg D, Gerlach M, Youdim MBH, Double KL, Zecca L, Riederer P, Becker G (2001) Brain iron and their relevance to Parkinson’s disease. J Neurochem 79:225–236. https://doi.org/10.1046/j.1471-4159.2001.00608.x
Boireau A, Richard F, Olivier V, Aubeneau M, Miquet JM, Dubédat P, Laduron P, Doble A, Blanchard JC (1991) Differential effects of potassium channel blockers on dopamine release from rat striatal slices. J Pharm Pharmacol 43(11):798–801. https://doi.org/10.1111/j.2042-7158.1991.tb03485.xCitations:9
Brooks DJ, Leinonen M, Kuoppamäki M, Nissinen H (2008) Five-year efficacy and safety of levodopa/DDCI and entacapone in patients with Parkinson’s disease. J Neural Transm 115(6):843–849. https://doi.org/10.1007/s00702-008-0025-8Epub 2008 Feb 8
Buyukuysal RL, Ulus IH, Aydin S, Kiran BK (1995) 3, 4-Diaminopyridine and choline increase in vivo acetylcholine release in rat striatum. Eur J Pharmacol 281(2):179–185. https://doi.org/10.1016/0014-2999(95)00241-c
Cansev M, Ulus IH, Wang L, Maher TJ, Wurtman RJ (2008) Restorative effects of uridine plus docosahexaenoic acid in a rat model of Parkinson’s disease. Neurosci Res 62(3):206–209. https://doi.org/10.1016/j.neures.2008.07.005
Cedarbaum JM, Gandy SE, Mcdowell FH (1991) Early initiation of Levodopa treatment does not promote the development of motor response fluctuations, Dyskinesias, or dementia in Parkinsons-disease. Neurology 41(5):622–629. https://doi.org/10.1212/WNL.41.5.622
Damsma G, Biessels PTM, Westerink BHC, De Vries JB, Horn AS (1988) Differential effects of 4-aminopyridine and 2,4-diaminopyridine in the in vivo release of acetylcholine and dopamine in freely moving rats measured by intrastriatal dialysis. Eur J Pharmacol 145(1):15–20. https://doi.org/10.1016/0014-2999(88)90343-3
Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909. https://doi.org/10.1016/s0896-6273(03)00568-3
Demircan C, Gul Z, Buyukuysal RL (2014) High glutamate attenuates S100B and LDH outputs from rat cortical slices enhanced by either oxygen–glucose deprivation or menadione. Neurochem Res 39(7):1232–1244. https://doi.org/10.1007/s11064-014-1301-7
Devos D, Defebvre L, Bordet R (2010) Dopaminergic and non-dopaminergic pharmacological hypotheses for gait disorders in Parkinson’s disease. Fundam Clin Pharmacol 24(4):407e21. https://doi.org/10.1111/j.1472-8206.2009.00798.x
Dorsey ER, Bloem BR (2018) The Parkinson pandemic—a call to action. JAMA Neurol 75(1):9–10. https://doi.org/10.1001/jamaneurol.2017.3299
Franciosi S, Ryu JK, Choi HB, Radov L, Kim SU, McLarnon JG (2006) Broad-spectrum effects of 4-aminopyridine to modulate amyloid β1–42-induced cell signaling and functional responses in human microglia. J Neurosci 26(45):11652–11664. https://doi.org/10.1523/JNEUROSCI.2490-06.2006
Freeman GB, Mykytyn V, Gibson GE (1987) Differential alteration of dopamine, acetylcholine, and glutamate release during anoxia and/or 3,4-diaminopyridine treatment. Neurochem Res 12(11):1019–1027
GBD 2015 Neurological Disorders Collaborator Group (2017) Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol 16(11):877–897. https://doi.org/10.1016/S1474-4422(17)30299-5
Gobel K, Wedell JH, Herrmann AM, Wachsmuth L, Pankratz S (2013) 4-Aminopyridine ameliorates mobility but not disease course in an animal model of multiple sclerosis. Exp Neurol 248:62–71. https://doi.org/10.1016/j.expneurol.2013.05.016Epub 2013 Jun 5
Gonzalez-Hernandez T, Barroso-Chinea P, De La Cruz MI, Del Mar P-DM, Rodriguez M (2004) Expression of dopamine and vesicular monoamine transporters and differential vulnerability of mesostriatal dopaminergic neurons. J Comp Neurol 478:198–215. https://doi.org/10.1002/cne.20323
Gul Z, Demircan C, Bagdas D, Buyukuysal RL (2016) Protective effects of chlorogenic acid and its metabolites on hydrogen peroxide-induced alterations in rat brain slices: a comparative study with resveratrol. Neurochem Res 41(8):2075–2085. https://doi.org/10.1007/s11064-016-1919-8
Gul Z, Buyukuysal MC, Buyukuysal RL (2020a) Brain slice viability determined under normoxic and oxidative stress conditions: involvement of slice quantity in the medium. Neurol Res 42(3):228–238. https://doi.org/10.1080/01616412.2020.1723299
Gul Z, Demircan C, Bagdas D, Buyukuysal RL (2020b) Aging protects rat cortical slices against to oxygen-glucose deprivation induced damage. Int J Neurosci. https://doi.org/10.1080/00207454.2020.1730830
Gursoy M, Buyukuysal RL (2008) Resveratrol protects rat striatal slices against anoxia-induced dopamine release. Neurochem Res 33(9):1838–1844. https://doi.org/10.1007/s11064-008-9645-5
Haghdoost-Yazdi H, Faraji A, Fraidouni N, Movahedi M, Hadibeygi E, Vaezi F (2011) Significant effects of 4-aminopyridine and tetraethylammonium in the treatment of 6-hydroxydopamine-induced Parkinson’s disease. Behav Brain Res 223(1):70–74. https://doi.org/10.1016/j.bbr.2011.04.021
Haghdoost-Yazdi H, Piri H, Najafipour R, Faraji A, Fraidouni N, Dargahi T (2017) Blockade of fast A-type and TEA-sensitive potassium channels provide an antiparkinsonian effect in a 6-OHDA animal model. Neurosciences (Riyadh) 22:44–50. https://doi.org/10.17712/nsj.2017.1.20160266
Hayes KC (2004) The use of 4-aminopyridine (fampridine) in demyelinating disorders. CNS Drug Rev 10(4):295–316. https://doi.org/10.1111/j.1527-3458.2004.tb00029.x
Hu CL, Liu Z, Zeng XM, Liu ZQ, Chen XH, Zhang ZH, Mei YA (2006) 4-aminopyridine, a Kv channel antagonist, prevents apoptosis of rat cerebellar granule neurons. Neuropharmacol 51(4):737–746. https://doi.org/10.1016/j.neuropharm.2006.05.013
Kalia LV, Brotchie JM, Fox SH (2013) Novel nondopaminergic targets for motor features of Parkinson’s disease: review of recent trials. Mov Disord 28(2):131e44. https://doi.org/10.1002/mds.25273Epub 2012 Dec 5
Kannan K, Jain SK (2000) Oxidative stress and apoptosis. Pathophysiology 7:153–163. https://doi.org/10.1016/s0928-4680(00)00053-5
Kim HJ, Jeon BS, Jenner P (2017) Hallmarks of treatment aspects: Parkinson’s disease throughout centuries including l-Dopa. Int Rev Neurobiol 132:295–343. https://doi.org/10.1016/bs.irn.2017.01.006
Kirik D, Rosenblad C, Björklund A (1998) Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Exp Neurol 152(2):259–277. https://doi.org/10.1006/exnr.1998.6848
Kurlan R (2005) “Levodopa phobia”: a new iatrogenic cause of disability in Parkinson disease. Neurology 64(5):923–924. https://doi.org/10.1212/01.WNL.0000152880.77812.5B
Leung G, Sun W, Brookes S, Smith D, Shi R (2011) Potassium channel blocker, 4-aminopyridine-3-methanol, restores axonal conduction in spinal cord of an animal model of multiple sclerosis. Exp Neurol 227(1):232–235. https://doi.org/10.1016/j.expneurol.2010.11.004Epub 2010 Nov 17
Li S, Wei D, Mao Z, Chen L, Yan X, Li Y (2017) Design, synthesis, immunocytochemistry evaluation, and molecular docking investigation of several 4-aminopyridine derivatives as potential neuroprotective agents for treating Parkinson’s disease. Bioorg Chem 73:63–75. https://doi.org/10.1016/j.bioorg.2017.05.010Epub 2017 May 31
Liss B, Franz O, Sewing S, Bruns R, Neuhoff H, Roeper J (2001) Tuning pacemaker frequency of individual dopaminergic neurons by Kv4. 3L and KChip3. 1 transcription. EMBO J 20:5715–5724. https://doi.org/10.1093/emboj/20.20.5715
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Luca CC, Singer C (2013) 4-Aminopyridine improves freezing of gait in Parkinson’s disease. J Neurol 260(10):2662–2664. https://doi.org/10.1007/s00415-013-7090-0
Luca CC, Nadayil G, Dong C, Nahab FB, Field-Fote E, Singer C (2017) Dalfampridine in Parkinson’s disease related gait dysfunction: a randomized double-blind trial. J Neurol Sci 379:7–11. https://doi.org/10.1016/j.jns.2017.05.011
Luthman J, Fredriksson A, Sundstrom E, Jonsson G, Archer T (1989) Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: motor behavior and monoamine alterations at adult stage. Behav Brain Res 33:267–277. https://doi.org/10.1016/S0166-4328(89)80121-4
Maffie JK, Dvoretskova E, Bougis PE, Martin-Eauclaire MF, Rudy B (2013) Dipeptidyl-peptidase-like-proteins confer high sensitivity to the scorpion toxin AmmTX3 to Kv4-mediated A-type K channels. J Physiol 591:2419–2427. https://doi.org/10.1113/jphysiol.2012.248831
Mainero C, Inghilleri M, Pantano P, Conte A, Lenzi D, Frasca V, Bozzao L, Pozzilli C (2004) Enhanced brain motor activity in patients with MS after a single dose of 3,4-diaminopyridine. Neurology 62(11):2044–2050. https://doi.org/10.1212/01.wnl.0000129263.14219.a8
McDermott JL, Liu B, Dluzen DE (1994) Sex differences and effects of estrogen on dopamine and DOPAC release from the striatum of male and female CD-1 mice. Exp Neurol 125:306–311. https://doi.org/10.1006/exnr.1994.1034
Mefford IN, Gilberg M, Barchas JD (1980) Simultaneous determination of catecholamines and unconjugated 3, 4-dihydroxyphenylacetic acid in brain tissue by ion-pairing reverse-phase high-performance liquid chromatography with electrochemical detection. Anal Biochem 104(2):469–472. https://doi.org/10.1016/0003-2697(80)90101-3
Nutt JG, Horak FB, Bloem BR (2011) Milestones in gait, balance, and falling. Mov Disord 26(6):1166–1174. https://doi.org/10.1002/mds.23588
Ogita K, Okuda H, Watanabe M, Nagashima R, Sugiyama C, Yoneda Y (2005) In vivo treatment with the K+ channel blocker 4-aminopyridine protects against kainate-induced neuronal cell death through activation of NMDA receptors in murine hippocampus. Neuropharmacol 48(6):810–821. https://doi.org/10.1016/j.neuropharm.2004.12.018
Ries V, Hertting G, Jackisch R (1996) Properties of 3,4-diaminopyridine-evoked dopamine and acetylcholine release in rabbit caudate nucleus slices: involvement of facilitatory adenosine A2 receptors or nitric oxide? Brain Res 743:303–314. https://doi.org/10.1016/S0006-8993(96)01102-X
Scheer HW, Lavoie PA (1991) Mechanism of aminopyridine-induced release of [3H]dopamine from rat brain synaptosomes. Gen Pharmacol 22(1):169–172. https://doi.org/10.1016/0306-3623(91)90329-5
Shieh CC, Coghlan M, Sullivan JP, Gopalakrishnan M (2000) Potassium channels: molecular defects, diseases, and therapeutic opportunities. Pharmacol Rev 52(4):557–594. Doi: 10.1.1.322.385&rep=rep1&type=pdf.
Shulman LM (2007) Gender differences in Parkinson’s disease. Gend Med 4(1):8–18. https://doi.org/10.1016/s1550-8579(07)80003-9
Sun W, Smith D, Fu Y, Cheng JX, Bryn S, Borgens R (2010) Novel potassium channel blocker, 4-AP-3-MeOH, inhibits fast potassium channels and restores axonal conduction in injured guinea pig spinal cord white matter. J Neurophysiol 103:469–478. https://doi.org/10.1152/jn.00154.2009
Taherian R, Ahmadi MA (2016) 4-aminopyridine decreases MPTP induced behavioral disturbances in animal model of Parkinson’s disease. Int Clin Neurosci J 2:142–146
Vacher H, Alami M, Crest M, Possani LD, Bougis PE, MartinEauclaire MF (2002) Expanding the scorpion toxin a-KTX 15 family with AmmTX3 from Androctonus mauretanicus. FEBS J 269:6037–6041. https://doi.org/10.1046/j.1432-1033.2002.03294.x
Wu ZZ, Li DP, Chen SR, Pan HL (2009) Aminopyridines potentiate synaptic and neuromuscular transmission by targeting the voltage-activated calcium channel beta subunit. J Biol Chem 284(52):36453–36461. https://doi.org/10.1074/jbc.M109.075523
Wurtman RJ, Hefti F, Melamed E (1980) Precursor control of neurotransmitter synthesis. Pharmacol Rev 32(4):315–335
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors report no conflict or interest.
Additional information
Communicated by Bill J Yates.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Gul, Z., Duyu, G., Altinbas, B. et al. K channel blockage with 3,4-diaminopyridine potentiates the effect of L-DOPA on dopamine release in striatal slices prepared from 6-OHDA pre-treated rats. Exp Brain Res 238, 2539–2548 (2020). https://doi.org/10.1007/s00221-020-05912-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00221-020-05912-w