1932

Abstract

The motor symptoms of Parkinson's disease (PD) mainly arise from degeneration of dopamine neurons within the substantia nigra. As no disease-modifying PD therapies are available, and side effects limit long-term benefits of current symptomatic therapies, novel treatment approaches are needed. The ongoing phase III clinical study STEADY-PD is investigating the potential of the dihydropyridine isradipine, an L-type Ca2+ channel (LTCC) blocker, for neuroprotective PD therapy. Here we review the clinical and preclinical rationale for this trial and discuss potential reasons for the ambiguous outcomes of in vivo animal model studies that address PD-protective dihydropyridine effects. We summarize current views about the roles of Cav1.2 and Cav1.3 LTCC isoforms for substantia nigra neuron function, and their high vulnerability to degenerative stressors, and for PD pathophysiology. We discuss different dihydropyridine sensitivities of LTCC isoforms in view of their potential as drug targets for PD neuroprotection, and we conclude by considering how these aspects could guide further drug development.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-010818-021214
2019-01-06
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/59/1/annurev-pharmtox-010818-021214.html?itemId=/content/journals/10.1146/annurev-pharmtox-010818-021214&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P et al. 2017. Parkinson disease. Nat. Rev. Dis. Primers 3:17013
    [Google Scholar]
  2. 2.  Collier TJ, Kanaan NM, Kordower JH 2017. Aging and Parkinson's disease: different sides of the same coin?. Mov. Disord. 32:983–90
    [Google Scholar]
  3. 3.  Swart T, Hurley MJ 2016. Calcium channel antagonists as disease-modifying therapy for Parkinson's disease: therapeutic rationale and current status. CNS Drugs 30:1127–35
    [Google Scholar]
  4. 4.  Damier P, Hirsch EC, Agid Y, Graybiel AM 1999. The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. Brain 122:Pt. 81437–48
    [Google Scholar]
  5. 5.  Hirsch E, Graybiel AM, Agid YA 1988. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature 334:345–48
    [Google Scholar]
  6. 6.  Surmeier DJ, Obeso JA, Halliday GM 2017. Selective neuronal vulnerability in Parkinson disease. Nat. Rev. Neurosci. 18:101–13
    [Google Scholar]
  7. 7.  Sanchez-Padilla J, Guzman JN, Ilijic E, Kondapalli J, Galtieri DJ et al. 2014. Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase. Nat. Neurosci. 17:832–40
    [Google Scholar]
  8. 8.  Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E 2003. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24:197–211
    [Google Scholar]
  9. 9.  Giguère N, Burke Nanni S, Trudeau LE 2018. On cell loss and selective vulnerability of neuronal populations in Parkinson's disease. Front. Neurol. 9:455
    [Google Scholar]
  10. 10.  Schapira AHV, Chaudhuri KR, Jenner P 2017. Non-motor features of Parkinson disease. Nat. Rev. Neurosci. 18:435–50
    [Google Scholar]
  11. 11.  Singleton A, Hardy J 2016. The evolution of genetics: Alzheimer's and Parkinson's diseases. Neuron 90:1154–63
    [Google Scholar]
  12. 12.  Duda J, Pötschke C, Liss B 2016. Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease. J. Neurochem. 139:Suppl. 1156–78
    [Google Scholar]
  13. 13.  Michel PP, Hirsch EC, Hunot S 2016. Understanding dopaminergic cell death pathways in Parkinson disease. Neuron 90:675–91
    [Google Scholar]
  14. 14.  Gegg ME, Schapira AHV 2018. The role of glucocerebrosidase in Parkinson disease pathogenesis. FEBS J 285:3591–603
    [Google Scholar]
  15. 15.  Obeso JA, Stamelou M, Goetz CG, Poewe W, Lang AE et al. 2017. Past, present, and future of Parkinson's disease: a special essay on the 200th Anniversary of the Shaking Palsy. Mov. Disord. 32:1264–310
    [Google Scholar]
  16. 16.  Schulz JB, Hausmann L, Hardy J 2016. 199 years of Parkinson disease—What have we learned and what is the path to the future?. J. Neurochem. 139:Suppl. 13–7
    [Google Scholar]
  17. 17.  Zaichick SV, McGrath KM, Caraveo G 2017. The role of Ca2+ signaling in Parkinson's disease. Dis. Model. Mech. 10:519–35
    [Google Scholar]
  18. 18.  Oertel W, Schulz JB 2016. Current and experimental treatments of Parkinson disease: a guide for neuroscientists. J. Neurochem. 139:Suppl. 1325–37
    [Google Scholar]
  19. 19.  Delenclos M, Jones DR, McLean PJ, Uitti RJ 2016. Biomarkers in Parkinson's disease: advances and strategies. Parkinsonism Relat. Disord. 22:Suppl. 1S106–10
    [Google Scholar]
  20. 20.  Brundin P, Dave KD, Kordower JH 2017. Therapeutic approaches to target α-synuclein pathology. Exp. Neurol. 298:225–35
    [Google Scholar]
  21. 21.  Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D et al. 2017. Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet 390:1664–75
    [Google Scholar]
  22. 22.  Migdalska-Richards A, Ko WKD, Li Q, Bezard E, Schapira AHV 2017. Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate. Synapse 71:7e21967
    [Google Scholar]
  23. 23.  Wyse RK, Brundin P, Sherer TB 2016. Nilotinib—differentiating the hope from the hype. J. Parkinson's Dis. 6:519–22
    [Google Scholar]
  24. 24.  Biglan KM, Oakes D, Lang AE, Hauser RA, Hodgeman K et al. 2017. A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY-PD III). Ann. Clin. Transl. Neurol. 4:360–68
    [Google Scholar]
  25. 25.  Simuni T, Borushko E, Avram MJ, Miskevics S, Martel A et al. 2010. Tolerability of isradipine in early Parkinson's disease: a pilot dose escalation study. Mov. Disord. 25:2863–66
    [Google Scholar]
  26. 26.  Rodnitzky RL 1999. Can calcium antagonists provide a neuroprotective effect in Parkinson's disease?. Drugs 57:845–49
    [Google Scholar]
  27. 27.  Mullapudi A, Gudala K, Boya CS, Bansal D 2016. Risk of Parkinson's disease in the users of antihypertensive agents: an evidence from the meta-analysis of observational studies. J. Neurodegener. Dis. 2016:5780809
    [Google Scholar]
  28. 28.  Gudala K, Kanukula R, Bansal D 2015. Reduced risk of Parkinson's disease in users of calcium channel blockers: a meta-analysis. Int. J. Chron. Dis. 2015:697404
    [Google Scholar]
  29. 29.  Lang Y, Gong D, Fan Y 2015. Calcium channel blocker use and risk of Parkinson's disease: a meta-analysis. Pharmacoepidemiol. Drug Saf. 24:559–66
    [Google Scholar]
  30. 30.  Hou L, Li Q, Jiang L, Qiu H, Geng C et al. 2018. Hypertension and diagnosis of Parkinson's disease: a meta-analysis of cohort studies. Front. Neurol. 9:162
    [Google Scholar]
  31. 31.  Ritz B, Rhodes SL, Qian L, Schernhammer E, Olsen JH, Friis S 2010. L-type calcium channel blockers and Parkinson disease in Denmark. Ann. Neurol. 67:600–6
    [Google Scholar]
  32. 32.  Becker C, Jick SS, Meier CR 2008. Use of antihypertensives and the risk of Parkinson disease. Neurology 70:1438–44
    [Google Scholar]
  33. 33.  Lee YC, Lin CH, Wu RM, Lin JW, Chang CH, Lai MS 2014. Antihypertensive agents and risk of Parkinson's disease: a nationwide cohort study. PLOS ONE 9:e98961
    [Google Scholar]
  34. 34.  Pasternak B, Svanstrom H, Nielsen NM, Fugger L, Melbye M, Hviid A 2012. Use of calcium channel blockers and Parkinson's disease. Am. J. Epidemiol. 175:627–35
    [Google Scholar]
  35. 35.  Alexander SP, Striessnig J, Kelly E, Marrion NV, Peters JA et al. 2017. The concise guide to pharmacology 2017/18: voltage-gated ion channels. Br. J. Pharmacol. 174:Suppl. 1S160–94
    [Google Scholar]
  36. 36.  Zamponi GW, Striessnig J, Koschak A, Dolphin AC 2015. The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol. Rev. 67:821–70
    [Google Scholar]
  37. 37.  Sinnegger-Brauns MJ, Hetzenauer A, Huber IG, Renström E, Wietzorrek G et al. 2004. Isoform-specific regulation of mood behavior and pancreatic β cell and cardiovascular function by L-type Ca2+ channels. J. Clin. Investig. 113:1430–39
    [Google Scholar]
  38. 38.  Sinnegger-Brauns MJ, Huber IG, Koschak A, Wild C, Obermair GJ et al. 2009. Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. Mol. Pharmacol. 75:407–14
    [Google Scholar]
  39. 39.  Avery RB, Johnston D 1996. Multiple channel types contribute to the low-voltage-activated calcium current in hippocampal CA3 pyramidal neurons. J. Neurosci. 16:5567–82
    [Google Scholar]
  40. 40.  Power JM, Sah P 2005. Intracellular calcium store filling by an L-type calcium current in the basolateral amygdala at subthreshold membrane potentials. J. Physiol. 562:439–53
    [Google Scholar]
  41. 41.  Li Y, Bennett DJ 2003. Persistent sodium and calcium currents cause plateau potentials in motoneurons of chronic spinal rats. J. Neurophysiol. 90:857–69
    [Google Scholar]
  42. 42.  Durante P, Cardenas CG, Whittaker JA, Kitai ST, Scroggs RS 2004. Low-threshold L-type calcium channels in rat dopamine neurons. J. Neurophysiol. 91:1450–54
    [Google Scholar]
  43. 43.  Puopolo M, Raviola E, Bean BP 2007. Roles of subthreshold calcium current and sodium current in spontaneous firing of mouse midbrain dopamine neurons. J. Neurosci. 27:645–56
    [Google Scholar]
  44. 44.  Guzman JN, Ilijic E, Yang B, Sanchez-Padilla J, Wokosin D et al. 2018. Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress. J. Clin. Investig. 128:2266–80
    [Google Scholar]
  45. 45.  Lieb A, Ortner N, Striessnig J 2014. C-terminal modulatory domain controls coupling of voltage-sensing to pore opening in Cav1.3 L-type calcium channels. Biophys. J. 106:1467–75
    [Google Scholar]
  46. 46.  Striessnig J, Pinggera A, Kaur G, Bock G, Tuluc P 2014. L-type calcium channels in heart and brain. Wiley Interdiscip. Rev. Membr. Transp. Signal. 3:215–38
    [Google Scholar]
  47. 47.  Liao P, Yu D, Li G, Yong TF, Soon JL et al. 2007. A smooth muscle Cav1.2 calcium channel splice variant underlies hyperpolarized window current and enhanced state-dependent inhibition by nifedipine. J. Biol. Chem. 282:35133–42
    [Google Scholar]
  48. 48.  Rice ME, Patel JC 2015. Somatodendritic dopamine release: recent mechanistic insights. Philos. Trans. R. Soc. Lond. B Biol. Sci. 370:20140182
    [Google Scholar]
  49. 49.  Sulzer D, Cragg SJ, Rice ME 2016. Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia 6:123–48
    [Google Scholar]
  50. 50.  Gantz SC, Ford CP, Morikawa H, Williams JT 2018. The evolving understanding of dopamine neurons in the substantia nigra and ventral tegmental area. Annu. Rev. Physiol. 80:219–41
    [Google Scholar]
  51. 51.  Grace AA, Bunney BS 1984. The control of firing pattern in nigral dopamine neurons: burst firing. J. Neurosci. 4:2877–90
    [Google Scholar]
  52. 52.  Grace AA, Bunney BS 1984. The control of firing pattern in nigral dopamine neurons: single spike firing. J. Neurosci. 4:2866–76
    [Google Scholar]
  53. 53.  Blythe SN, Wokosin D, Atherton JF, Bevan MD 2009. Cellular mechanisms underlying burst firing in substantia nigra dopamine neurons. J. Neurosci. 29:15531–41
    [Google Scholar]
  54. 54.  Brown MT, Henny P, Bolam JP, Magill PJ 2009. Activity of neurochemically heterogeneous dopaminergic neurons in the substantia nigra during spontaneous and driven changes in brain state. J. Neurosci. 29:2915–25
    [Google Scholar]
  55. 55.  Paladini CA, Roeper J 2014. Generating bursts (and pauses) in the dopamine midbrain neurons. Neuroscience 282:109–21
    [Google Scholar]
  56. 56.  Dragicevic E, Schiemann J, Liss B 2015. Dopamine midbrain neurons in health and Parkinson's disease: emerging roles of voltage-gated calcium channels and ATP-sensitive potassium channels. Neuroscience 284:798–814
    [Google Scholar]
  57. 57.  Drion G, Massotte L, Sepulchre R, Seutin V 2011. How modeling can reconcile apparently discrepant experimental results: the case of pacemaking in dopaminergic neurons. PLOS Comput. Biol. 7:e1002050
    [Google Scholar]
  58. 58.  Guzman JN, Sanchez-Padilla J, Chan CS, Surmeier DJ 2009. Robust pacemaking in substantia nigra dopaminergic neurons. J. Neurosci. 29:11011–19
    [Google Scholar]
  59. 59.  Philippart F, Destreel G, Merino-Sepúlveda P, Henny P, Engel D, Seutin V 2016. differential somatic Ca2+ channel profile in midbrain dopaminergic neurons. J. Neurosci. 36:7234–45
    [Google Scholar]
  60. 60.  Cardozo DL, Bean BP 1995. Voltage-dependent calcium channels in rat midbrain dopamine neurons: modulation by dopamine and GABAB receptors. J. Neurophys. 74:1137–48
    [Google Scholar]
  61. 61.  Brimblecombe KR, Gracie CJ, Platt NJ, Cragg SJ 2015. Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains: dynamic control of striatal dopamine by calcium. J. Physiol. 593:929–46
    [Google Scholar]
  62. 62.  Branch SY, Sharma R, Beckstead MJ 2014. Aging decreases L-type calcium channel currents and pacemaker firing fidelity in substantia nigra dopamine neurons. J. Neurosci. 34:9310–18
    [Google Scholar]
  63. 63.  Evans RC, Zhu M, Khaliq ZM 2017. Dopamine inhibition differentially controls excitability of substantia nigra dopamine neuron subpopulations through T-type calcium channels. J. Neurosci. 37:3704–20
    [Google Scholar]
  64. 64.  Poetschke C, Dragicevic E, Duda J, Benkert J, Dougalis A et al. 2015. Compensatory T-type Ca2+ channel activity alters D2-autoreceptor responses of Substantia nigra dopamine neurons from Cav1.3 L-type Ca2+ channel KO mice. Sci. Rep. 5:13688
    [Google Scholar]
  65. 65.  Kimm T, Khaliq ZM, Bean BP 2015. Differential regulation of action potential shape and burst-frequency firing by BK and Kv2 channels in substantia nigra dopaminergic neurons. J. Neurosci. 35:16404–17
    [Google Scholar]
  66. 66.  Wolfart J, Roeper J 2002. Selective coupling of T-type calcium channels to SK potassium channels prevents intrinsic bursting in dopaminergic midbrain neurons. J. Neurosci. 22:3404–13
    [Google Scholar]
  67. 67.  Dragicevic E, Poetschke C, Duda J, Schlaudraff F, Lammel S et al. 2014. Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons. Brain 137:2287–302
    [Google Scholar]
  68. 68.  Iyer R, Ungless MA, Faisal AA 2017. Calcium-activated SK channels control firing regularity by modulating sodium channel availability in midbrain dopamine neurons. Sci. Rep. 7:5248
    [Google Scholar]
  69. 69.  Hallworth NE, Wilson CJ, Bevan MD 2003. Apamin-sensitive small conductance calcium-activated potassium channels, through their selective coupling to voltage-gated calcium channels, are critical determinants of the precision, pace, and pattern of action potential generation in rat subthalamic nucleus neurons in vitro. J. Neurosci. 23:7525–42
    [Google Scholar]
  70. 70.  Bergquist F, Nissbrandt H 2003. Influence of R-type (Cav2.3) and T-type (Cav3.1–3.3) antagonists on nigral somatodendritic dopamine release measured by microdialysis. Neuroscience 120:757–64
    [Google Scholar]
  71. 71.  Bonci A, Grillner P, Mercuri NB, Bernardi G 1998. L-Type calcium channels mediate a slow excitatory synaptic transmission in rat midbrain dopaminergic neurons. J. Neurosci. 18:6693–703
    [Google Scholar]
  72. 72.  Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C et al. 2007. ‘Rejuvenation’ protects neurons in mouse models of Parkinson's disease. Nature 447:1081–86
    [Google Scholar]
  73. 73.  Bean BP 2007. The action potential in mammalian central neurons. Nat. Rev. Neurosci. 8:451–65
    [Google Scholar]
  74. 74.  Ortner NJ, Bock G, Dougalis A, Kharitonova M, Duda J et al. 2017. Lower affinity of isradipine for L-type Ca2+ channels during substantia nigra dopamine neuron-like activity: implications for neuroprotection in Parkinson's disease. J. Neurosci. 37:6761–77
    [Google Scholar]
  75. 75.  Grace AA 1991. Regulation of spontaneous activity and oscillatory spike firing in rat midbrain dopamine neurons recorded in vitro. Synapse 7:221–34
    [Google Scholar]
  76. 76.  Kang Y, Kitai ST 1993. Calcium spike underlying rhythmic firing in dopaminergic neurons of the rat substantia nigra. Neurosci. Res. 18:195–207
    [Google Scholar]
  77. 77.  Wilson CJ, Callaway JC 2000. Coupled oscillator model of the dopaminergic neuron of the substantia nigra. J. Neurophysiol. 83:3084–100
    [Google Scholar]
  78. 78.  Hage TA, Khaliq ZM 2015. Tonic firing rate controls dendritic Ca2+ signaling and synaptic gain in substantia nigra dopamine neurons. J. Neurosci. 35:5823–36
    [Google Scholar]
  79. 79.  Jang J, Um KB, Jang M, Kim SH, Cho H et al. 2014. Balance between the proximal dendritic compartment and the soma determines spontaneous firing rate in midbrain dopamine neurons. J. Physiol. 592:2829–44
    [Google Scholar]
  80. 80.  Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E et al. 2010. Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468:696–700
    [Google Scholar]
  81. 81.  Carbone C, Costa A, Provensi G, Mannaioni G, Masi A 2017. The hyperpolarization-activated current determines synaptic excitability, calcium activity and specific viability of substantia nigra dopaminergic neurons. Front. Cell Neurosci. 11:187
    [Google Scholar]
  82. 82.  Schiemann J, Schlaudraff F, Klose V, Bingmer M, Seino S et al. 2012. K-ATP channels in dopamine substantia nigra neurons control bursting and novelty-induced exploration. Nat. Neurosci. 15:1272–80
    [Google Scholar]
  83. 83.  Ortner NJ, Striessnig J 2016. L-type calcium channels as drug targets in CNS disorders. Channels 10:17–13
    [Google Scholar]
  84. 84.  Kang S, Cooper G, Dunne SF, Dusel B, Luan CH et al. 2012. CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease. Nat. Commun. 3:1146
    [Google Scholar]
  85. 85.  Patel JC, Witkovsky P, Avshalumov MV, Rice ME 2009. Mobilization of calcium from intracellular stores facilitates somatodendritic dopamine release. J. Neurosci. 29:6568–79
    [Google Scholar]
  86. 86.  Dryanovski DI, Guzman JN, Xie Z, Galteri DJ, Volpicelli-Daley LA et al. 2013. Calcium entry and α-synuclein inclusions elevate dendritic mitochondrial oxidant stress in dopaminergic neurons. J. Neurosci. 33:10154–64
    [Google Scholar]
  87. 87.  Takada M, Kang Y, Imanishi M 2001. Immunohistochemical localization of voltage-gated calcium channels in substantia nigra dopamine neurons. Eur. J. Neurosci. 13:757–62
    [Google Scholar]
  88. 88.  Dufour MA, Woodhouse A, Goaillard J-M 2014. Somatodendritic ion channel expression in substantia nigra pars compacta dopaminergic neurons across postnatal development. J. Neurosci. Res. 92:981–99
    [Google Scholar]
  89. 89.  Park A, Stacy M 2015. Disease-modifying drugs in Parkinson's disease. Drugs 75:2065–71
    [Google Scholar]
  90. 90.  Przedborski S 2017. The two-century journey of Parkinson disease research. Nat. Rev. Neurosci. 18:251–59
    [Google Scholar]
  91. 91.  Mosharov EV, Larsen KE, Kanter E, Phillips KA, Wilson K et al. 2009. Interplay between cytosolic dopamine, calcium, and α-synuclein causes selective death of substantia nigra neurons. Neuron 62:218–29
    [Google Scholar]
  92. 92.  Collier TJ, Kanaan NM, Kordower JH 2011. Ageing as a primary risk factor for Parkinson's disease: evidence from studies of non-human primates. Nat. Rev. Neurosci. 12:359–66
    [Google Scholar]
  93. 93.  Post MR, Lieberman OJ, Mosharov EV 2018. Can interactions between α-synuclein, dopamine and calcium explain selective neurodegeneration in Parkinson's disease?. Front. Neurosci. 12:161
    [Google Scholar]
  94. 94.  Deng H, Wang P, Jankovic J 2018. The genetics of Parkinson disease. Ageing Res. Rev. 42:72–85
    [Google Scholar]
  95. 95.  Jansen IE, Gibbs JR, Nalls MA, Price TR, Lubbe S et al. 2017. Establishing the role of rare coding variants in known Parkinson's disease risk loci. Neurobiol. Aging 59:220.e11–18
    [Google Scholar]
  96. 96.  Hernandez DG, Reed X, Singleton AB 2016. Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J. Neurochem. 139:Suppl. 159–74
    [Google Scholar]
  97. 97.  Ammal Kaidery N, Thomas B 2018. Current perspective of mitochondrial biology in Parkinson's disease. Neurochem. Int. 117:91–113
    [Google Scholar]
  98. 98.  Chang D, Nalls MA, Hallgrimsdottir IB, Hunkapiller J, van der Brug M et al. 2017. A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci. Nat. Genet. 49:1511–16
    [Google Scholar]
  99. 99.  Schöndorf DC, Aureli M, McAllister FE, Hindley CJ, Mayer F et al. 2014. iPSC-derived neurons from GBA1-associated Parkinson's disease patients show autophagic defects and impaired calcium homeostasis. Nat. Commun. 5:4028
    [Google Scholar]
  100. 100.  Bolam JP, Pissadaki EK 2012. Living on the edge with too many mouths to feed: why dopamine neurons die. Mov. Disord. 27:1478–83
    [Google Scholar]
  101. 101.  Pacelli C, Giguère N, Bourque M-J, Lévesque M, Slack RS, Trudeau L-É 2015. Elevated mitochondrial bioenergetics and axonal arborization size are key contributors to the vulnerability of dopamine neurons. Curr. Biol. 25:2349–60
    [Google Scholar]
  102. 102.  Meiser J, Weindl D, Hiller K 2013. Complexity of dopamine metabolism. Cell Commun. Signal. 11:34
    [Google Scholar]
  103. 103.  Matsuda W, Furuta T, Nakamura KC, Hioki H, Fujiyama F et al. 2009. Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J. Neurosci. 29:444–53
    [Google Scholar]
  104. 104.  Pissadaki EK, Bolam JP 2013. The energy cost of action potential propagation in dopamine neurons: clues to susceptibility in Parkinson's disease. Front. Comput. Neurosci. 7:13
    [Google Scholar]
  105. 105.  Foehring RC, Zhang XF, Lee JCF, Callaway JC 2009. Endogenous calcium buffering capacity of substantia nigral dopamine neurons. J. Neurophysiol. 102:2326–33
    [Google Scholar]
  106. 106.  Mouatt-Prigent A, Agid Y, Hirsch EC 1994. Does the calcium binding protein calretinin protect dopaminergic neurons against degeneration in Parkinson's disease?. Brain Res 668:62–70
    [Google Scholar]
  107. 107.  Schapira AHV, Gegg M 2011. Mitochondrial contribution to Parkinson's disease pathogenesis. Parkinson's Dis 2011:159160
    [Google Scholar]
  108. 108.  Zucca FA, Segura-Aguilar J, Ferrari E, Muñoz P, Paris I et al. 2017. Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease. Prog. Neurobiol. 155:96–119
    [Google Scholar]
  109. 109.  Rivero-Rios P, Gomez-Suaga P, Fdez E, Hilfiker S 2014. Upstream deregulation of calcium signaling in Parkinson's disease. Front. Mol. Neurosci. 7:53
    [Google Scholar]
  110. 110.  Aumann T, Horne M 2012. Activity-dependent regulation of the dopamine phenotype in substantia nigra neurons. J. Neurochem. 121:497–515
    [Google Scholar]
  111. 111.  Lieberman OJ, Choi SJ, Kanter E, Saverchenko A, Frier MD et al. 2017. α-Synuclein-dependent calcium entry underlies differential sensitivity of cultured SN and VTA dopaminergic neurons to a Parkinsonian neurotoxin. eNeuro 4:6ENEURO.0167–17.2017
    [Google Scholar]
  112. 112.  Schildknecht S, Di Monte DA, Pape R, Tieu K, Leist M 2017. Tipping points and endogenous determinants of nigrostriatal degeneration by MPTP. Trends Pharmacol. Sci. 38:541–55
    [Google Scholar]
  113. 113.  Langston JW 2017. The MPTP story. J. Parkinson's Dis. 7:Suppl. 1S11–22
    [Google Scholar]
  114. 114.  Larsen SB, Hanss Z, Krüger R 2018. The genetic architecture of mitochondrial dysfunction in Parkinson's disease. Cell Tissue Res 373:21–37
    [Google Scholar]
  115. 115.  Ludtmann MHR, Abramov AY 2018. Mitochondrial calcium imbalance in Parkinson's disease. Neurosci. Lett. 663:86–90
    [Google Scholar]
  116. 116.  Zhou Q, Yen A, Rymarczyk G, Asai H, Trengrove C et al. 2016. Impairment of PARK14-dependent Ca2+ signalling is a novel determinant of Parkinson's disease. Nat. Commun. 7:10332
    [Google Scholar]
  117. 117.  Sun Y, Zhang H, Selvaraj S, Sukumaran P, Lei S et al. 2017. Inhibition of L-type Ca2+ channels by TRPC1-STIM1 complex is essential for the protection of dopaminergic neurons. J. Neurosci. 37:3364–77
    [Google Scholar]
  118. 118.  Franz O, Liss B, Neu A, Roeper J 2000. Single-cell mRNA expression of HCN1 correlates with a fast gating phenotype of hyperpolarization-activated cyclic nucleotide-gated ion channels (Ih) in central neurons. Eur. J. Neurosci. 12:2685–93
    [Google Scholar]
  119. 119.  Subramaniam M, Althof D, Gispert S, Schwenk J, Auburger G et al. 2014. Mutant α-synuclein enhances firing frequencies in dopamine substantia nigra neurons by oxidative impairment of potassium channels. J. Neurosci. 34:13586–99
    [Google Scholar]
  120. 120.  Soden ME, Jones GL, Sanford CA, Chung AS, Guler AD et al. 2013. Disruption of dopamine neuron activity pattern regulation through selective expression of a human KCNN3 mutation. Neuron 80:997–1009
    [Google Scholar]
  121. 121.  Liss B, Haeckel O, Wildmann J, Miki T, Seino S, Roeper J 2005. K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons. Nat. Neurosci. 8:1742–51
    [Google Scholar]
  122. 122.  Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC et al. 2017. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science 357:1255–61
    [Google Scholar]
  123. 123.  Striessnig J 1999. Pharmacology, structure and function of cardiac L-type calcium channels. Cell. Physiol. Biochem. 9:242–69
    [Google Scholar]
  124. 124.  Moosmang S, Schulla V, Welling A, Feil R, Feil S et al. 2003. Dominant role of smooth muscle L-type calcium channel Cav1.2 for blood pressure regulation. EMBO J 22:6027–34
    [Google Scholar]
  125. 125.  Hille B 1977. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J. Gen. Physiol. 69:497–515
    [Google Scholar]
  126. 126.  Bean BP 1984. Nitrendipine block of cardiac calcium channels: high-affinity binding to the inactivated state. PNAS 81:6388–92
    [Google Scholar]
  127. 127.  Koschak A, Reimer D, Huber I, Grabner M, Glossmann H et al. 2001. α1D (Cav1.3) subunits can form L-type Ca2+ channels activating at negative voltages. J. Biol. Chem. 276:22100–6
    [Google Scholar]
  128. 128.  Xu W, Lipscombe D 2001. Neuronal Cav1.3α1 L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines. J. Neurosci. 21:5944–51
    [Google Scholar]
  129. 129.  Huang H, Yu D, Soong TW 2013. C-terminal alternative splicing of CaV1.3 channels distinctively modulates their dihydropyridine sensitivity. Mol. Pharmacol. 84:643–53
    [Google Scholar]
  130. 130.  Parkinson Study Group 2013. Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson's disease (STEADY-PD). Mov. Disord. 28:1823–31
    [Google Scholar]
  131. 131. Drugs.com. 2018. DynaCirc CR: pharmacokinetics and metabolism. Drugs.com, https://www.drugs.com/pro/dynacirc-cr.html
  132. 132.  Shenfield GM, Boutagy J, Stokes GS, Rumble F, Dunagan F 1990. The pharmokinetics of isradipine in hypertensive subjects. Eur. J. Clin. Pharmacol. 38:209–11
    [Google Scholar]
  133. 133.  Surmeier DJ, Halliday GM, Simuni T 2017. Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease. Exp. Neurol. 298:202–9
    [Google Scholar]
  134. 134.  Ortner NJ, Bock G, Vandael DHF, Mauersberger R, Draheim HJ et al. 2014. Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca2+ channel activators. Nat. Commun. 5:3897
    [Google Scholar]
  135. 135.  Urien S, Pinquier JL, Paquette B, Chaumet-Riffaud P, Kiechel JR, Tillement JP 1987. Effect of the binding of isradipine and darodipine to different plasma proteins on their transfer through the rat blood-brain barrier. Drug binding to lipoproteins does not limit the transfer of drug. J. Pharmacol. Exp. Ther. 242:349–53
    [Google Scholar]
  136. 136.  Herbette LG, Vanterve YMH, Rhodes DG 1989. Interaction of 1,4-dihydropyridine calcium channel antagonists with biological membranes: Lipid bilayer partitioning could occur before drug binding to receptors. J. Mol. Cell Cardiol. 21:187–201
    [Google Scholar]
  137. 137.  Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SC et al. 1983. Cerebral arterial spasm—a controlled trial of nimodipine in patients with subarachnoid hemorrhage. N. Engl. J. Med. 308:619–24
    [Google Scholar]
  138. 138.  Woodward DK, Hatton J, Ensom MH, Young B, Dempsey R, Clifton GD 1998. α1-acid glyco-protein concentrations and cerebrospinal fluid drug distribution after subarachnoid hemorrhage. Pharmacotherapy 18:1062–68
    [Google Scholar]
  139. 139.  Nanou E, Catterall WA 2018. Calcium channels, synaptic plasticity, and neuropsychiatric disease. Neuron 98:466–81
    [Google Scholar]
  140. 140.  Malik ZA, Stein IS, Navedo MF, Hell JW 2014. Mission CaMKIIγ: shuttle calmodulin from membrane to nucleus. Cell 159:2235–37
    [Google Scholar]
  141. 141.  Wang X, Marks CR, Perfitt TL, Nakagawa T, Lee A et al. 2017. A novel mechanism for Ca2+/calmodulin-dependent protein kinase II targeting to L-type Ca2+ channels that initiates long-range signaling to the nucleus. J. Biol. Chem. 292:4217324–36
    [Google Scholar]
  142. 142.  Christensen HR, Antonsen K, Simonsen K, Lindekaer A, Bonde J et al. 2000. Bioavailability and pharmacokinetics of isradipine after oral and intravenous administration: half-life shorter than expected?. Pharmacol. Toxicol. 86:178–82
    [Google Scholar]
  143. 143.  Park J-H, Park Y-S, Rhim S-Y, Jhee O-H, Kim S-H et al. 2009. Quantification of isradipine in human plasma using LC-MS/MS for pharmacokinetic and bioequivalence study. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 877:59–64
    [Google Scholar]
  144. 144.  Michelson G, Wärntges S, Leidig S, Lötsch J, Geisslinger G 2006. Nimodipine plasma concentration and retinal blood flow in healthy subjects. Investig. Ophthalmol. Vis. Sci. 47:3479–86
    [Google Scholar]
  145. 145.  Blardi P, Urso R, De Lalla A, Volpi L, Perri TD, Auteri A 2002. Nimodipine: drug pharmacokinetics and plasma adenosine levels in patients affected by cerebral ischemia. Clin. Pharmacol. Ther. 72:556–61
    [Google Scholar]
  146. 146.  Uchida S, Yamada S, Nagai K, Deguchi Y, Kimura R 1997. Brain pharmacokinetics and in vivo receptor binding of 1,4-dihydropyridine calcium channel antagonists. Life Sci 61:2083–90
    [Google Scholar]
  147. 147.  Larkin JG, Thompson GG, Scobie G, Forrest G, Drennan JE, Brodie MJ 1992. Dihydropyridine calcium antagonists in mice: blood and brain pharmacokinetics and efficacy against pentylenetetrazol seizures. Epilepsia 33:760–69
    [Google Scholar]
  148. 148.  Kupsch A, Sautter J, Schwarz J, Riederer P, Gerlach M, Oertel WH 1996. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in non-human primates is antagonized by pretreatment with nimodipine at the nigral, but not at the striatal level. Brain Res 741:185–96
    [Google Scholar]
  149. 149.  Johnson BA, Javors MA, Lam Y-WF, Wells LT, Tiouririne M et al. 2005. Kinetic and cardiovascular comparison of immediate-release isradipine and sustained-release isradipine among non-treatment-seeking, cocaine-dependent individuals. Prog. Neuropsychopharmacol. Biol. Psychiatry 29:15–20
    [Google Scholar]
  150. 150.  Carrara V, Porchet H, Dayer P 1994. Influence of input rates on (±)-isradipine haemodynamics and concentration-effect relationship in healthy volunteers. Eur. J. Clin. Pharmacol. 46:29–33
    [Google Scholar]
  151. 151.  Janezic S, Threlfell S, Dodson PD, Dowie MJ, Taylor TN et al. 2013. Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model. PNAS 110:E4016–25
    [Google Scholar]
  152. 152.  Mor DE, Tsika E, Mazzulli JR, Gould NS, Kim H et al. 2017. Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration. Nat. Neurosci. 20:1560–68
    [Google Scholar]
  153. 153.  Blesa J, Przedborski S 2014. Parkinson's disease: animal models and dopaminergic cell vulnerability. Front. Neuroanat. 8:155
    [Google Scholar]
  154. 154.  Tieu K 2011. A guide to neurotoxic animal models of Parkinson's disease. Cold Spring Harb. Perspect. Med. 1:a009316
    [Google Scholar]
  155. 155.  Jackson-Lewis V, Przedborski S 2007. Protocol for the MPTP mouse model of Parkinson's disease. Nat. Protoc. 2:141–51
    [Google Scholar]
  156. 156.  Potts LF, Wu H, Singh A, Marcilla I, Luquin MR, Papa SM 2014. Modeling Parkinson's disease in monkeys for translational studies, a critical analysis. Exp. Neurol. 256:133–43
    [Google Scholar]
  157. 157.  Munoz-Manchado AB, Villadiego J, Romo-Madero S, Suarez-Luna N, Bermejo-Navas A et al. 2016. Chronic and progressive Parkinson's disease MPTP model in adult and aged mice. J. Neurochem. 136:373–87
    [Google Scholar]
  158. 158.  Meredith GE, Sonsalla PK, Chesselet M-F 2008. Animal models of Parkinson's disease progression. Acta Neuropathol. 115:385–98
    [Google Scholar]
  159. 159.  Gerlach M, Russ H, Winker J, Witzmann K, Traber J et al. 1993. Effects of nimodipine on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced depletions in the biogenic amine levels in mice. Drug Res 43:413–15
    [Google Scholar]
  160. 160.  Price CJ, Sutherland ML, Mathews JM, Fennell TR, Black SR et al. 2014. Evaluation of isradipine for neuroprotection in the MPTP/p mouse model of Parkinson's disease Poster presented at the Annual Society for Neuroscience Meeting Washington, DC: Novemb. 18
  161. 161.  Kupsch A, Gerlach M, Pupeter SC, Sautter J, Dirr A et al. 1995. Pretreatment with nimodipine prevents MPTP-induced neurotoxicity at the nigral, but not at the striatal level in mice. Neuroreport 6:621–25
    [Google Scholar]
  162. 162.  Singh A, Verma P, Balaji G, Samantaray S, Mohanakumar KP 2016. Nimodipine, an L-type calcium channel blocker attenuates mitochondrial dysfunctions to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in mice. Neurochem. Int. 99:221–32
    [Google Scholar]
  163. 163.  Wang Q-M, Xu Y-Y, Liu S, Ma Z-G 2017. Isradipine attenuates MPTP-induced dopamine neuron degeneration by inhibiting up-regulation of L-type calcium channels and iron accumulation in the substantia nigra of mice. Oncotarget 8:47284–95
    [Google Scholar]
  164. 164.  Ilijic E, Guzman JN, Surmeier DJ 2011. The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson's disease. Neurobiol. Dis. 43:364–71
    [Google Scholar]
  165. 165.  Sautter J, Kupsch A, Earl CD, Oertel WH 1997. Degeneration of pre-labelled nigral neurons induced by intrastriatal 6-hydroxydopamine in the rat: behavioural and biochemical changes and pretreatment with the calcium-entry blocker nimodipine. Exp. Brain. Res. 117:111–19
    [Google Scholar]
  166. 166.  Wang R, Ma Z, Wang J, Xie J 2012. L-type Cav1.2 calcium channel is involved in 6-hydroxydopamine-induced neurotoxicity in rats. Neurotoxicity Res 21:266–70
    [Google Scholar]
  167. 167.  Specht CG, Schoepfer R 2001. Deletion of the α-synuclein locus in a subpopulation of C57BL/6J inbred mice. BMC Neurosci 2:11
    [Google Scholar]
  168. 168.  Liron T, Raphael B, Hiram-Bab S, Bab IA, Gabet Y 2018. Bone loss in C57BL/6J-OlaHsd mice, a substrain of C57BL/6J carrying mutated α-synuclein and multimerin-1 genes. J. Cell Physiol. 233:371–77
    [Google Scholar]
  169. 169.  Simon MM, Greenaway S, White JK, Fuchs H, Gailus-Durner V et al. 2013. A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains. Genome Biol 14:R82
    [Google Scholar]
  170. 170.  Zurita E, Chagoyen M, Cantero M, Alonso R, Gonzalez-Neira A et al. 2011. Genetic polymorphisms among C57BL/6 mouse inbred strains. Transgenic Res 20:481–89
    [Google Scholar]
  171. 171.  Bryant CD, Zhang NN, Sokoloff G, Fanselow MS, Ennes HS et al. 2008. Behavioral differences among C57BL/6 substrains: implications for transgenic and knockout studies. J. Neurogenet. 22:315–31
    [Google Scholar]
  172. 172. Envigo. 2018. Research models and services. C57BL/6: substrain information Data Sheet, Envigo Madison, WI: https://www.envigo.com/assets/docs/envigo-68-c57bl6-enhanced-technical-data-sheet_screen.pdf
  173. 173.  Bendor JT, Logan TP, Edwards RH 2013. The function of α-synuclein. Neuron 79:1044–66
    [Google Scholar]
  174. 174.  Dauer W, Kholodilov N, Vila M, Trillat A-C, Goodchild R et al. 2002. Resistance of α-synuclein null mice to the parkinsonian neurotoxin MPTP. PNAS 99:14524–29
    [Google Scholar]
  175. 175.  Schluter OM, Fornai F, Alessandri MG, Takamori S, Geppert M et al. 2003. Role of α-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in mice. Neuroscience 118:985–1002
    [Google Scholar]
  176. 176.  Sellers RS 2017. Translating mouse models. Toxicol. Pathol. 45:134–45
    [Google Scholar]
  177. 177.  Slomianka L, West MJ 2005. Estimators of the precision of stereological estimates: an example based on the CA1 pyramidal cell layer of rats. Neuroscience 136:757–67
    [Google Scholar]
  178. 178.  Yiu S, Knaus EE 1996. Synthesis, biological evaluation, calcium channel antagonist activity, and anticonvulsant activity of felodipine coupled to a dihydropyridine-pyridinium salt redox chemical delivery system. J. Med. Chem. 39:4576–82
    [Google Scholar]
  179. 179.  Ji B, Wang M, Gao D, Xing S, Li L et al. 2017. Combining nanoscale magnetic nimodipine liposomes with magnetic resonance image for Parkinson's disease targeting therapy. Nanomedicine 12:237–53
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-010818-021214
Loading
/content/journals/10.1146/annurev-pharmtox-010818-021214
Loading

Data & Media loading...

Supplemental Material

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error