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Differential Neuroprotective and Anti-Inflammatory Effects of L-Type Voltage Dependent Calcium Channel and Ryanodine Receptor Antagonists in the Substantia Nigra and Locus Coeruleus

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Abstract

Neuroinflammation and degeneration of catecholaminergic brainstem nuclei occur early in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Neuroinflammation increases levels of pro-inflammatory cytokines and reactive oxygen species which can alter neuronal calcium (Ca+2) homoeostasis via L-type voltage dependent calcium channels (L-VDCCs) and ryanodine receptors (RyRs). Alterations in Ca+2 channel activity in the SN and LC can lead to disruption of normal pacemaking activity in these areas, contributing to behavioral deficits. Here, we utilized an in vivo model of chronic neuroinflammation: rats were infused intraventricularly with a continuous small dose (0.25 μg/h) of lipopolysaccharide (LPS) or artificial cerebrospinal fluid (aCSF) for 28 days. Rats were treated with either the L-VDCC antagonist nimodipine or the RyR antagonist dantrolene. LPS-infused rats had significant motor deficits in the accelerating rotarod task as well as abnormal behavioral agitation in the forced swim task and open field. Corresponding with these behavioral deficits, LPS-infused rats also had significant increases in microglia activation and loss of tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra pars compacta (SNpc) and locus coeruleus (LC). Treatment with nimodipine or dantrolene normalized LPS-induced abnormalities in the rotarod and forced swim, restored the number of TH-immunoreactive cells in the LC, and significantly reduced microglia activation in the SNpc. Only nimodipine significantly reduced microglia activation in the LC, and neither drug increased TH immunoreactivity in the SNpc. These findings demonstrate that the Ca+2 dysregulation in the LC and SN brainstem nuclei is differentially altered by chronic neuroinflammation. Overall, targeting Ca + 2 dysregulation may be an important target for ameliorating neurodegeneration in the SNpc and LC.

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References

  • Bardou I, Brothers HM, Kaercher RM, Hopp SC, Wenk GL (2013) Differential effects of duration and age on the consequences of neuroinflammation in the hippocampus. Neurobiol Aging 34(10):2293–2301

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bardou I, Kaercher RM, Brothers HM, Hopp SC, Royer S, Wenk GL (2014) Age and duration of inflammatory environment differentially affect the neuroimmune response and catecholaminergic neurons in the midbrain and brainstem. Neurobiol Aging 35(5):1065–1073

    Article  CAS  PubMed  Google Scholar 

  • Beach TG, Sue LI, Walker DG, Lue LF, Connor DJ, Caviness JN, Sabbagh MN, Adler CH (2007) Marked microglial reaction in normal aging human substantia nigra: correlation with extraneuronal neuromelanin pigment deposits. Acta Neuropathol 114(4):419–424

    Article  PubMed  Google Scholar 

  • Borde M, Bonansco C, Fernández de Sevilla D, Le Ray D, Buño W (2000) Voltage-clamp analysis of the potentiation of the slow Ca2 + −activated K + current in hippocampal pyramidal neurons. Hippocampus 10(2):198–206

    Article  CAS  PubMed  Google Scholar 

  • Borsody MK, Weiss JM (2004) The effects of endogenous interleukin-1 bioactivity on locus coeruleus neurons in response to bacterial and viral substances. Brain Res 1007(1–2):39–56

    Article  CAS  PubMed  Google Scholar 

  • Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318(1):121–134

    Article  PubMed  Google Scholar 

  • Brothers HM, Bardou I, Hopp SC, Marchalant Y, Kaercher RM, Turner SM, Mitchem MR, Kigerl K, Wenk GL (2013) Time-dependent compensatory responses to chronic neuroinflammation in hippocampus and brainstem: the potential role of glutamate neurotransmission. J Alzheimers Dis Parkinsonism 3:110

    Article  PubMed Central  PubMed  Google Scholar 

  • Cebrián C, Zucca FA, Mauri P, Steinbeck JA, Studer L, Scherzer CR, Kanter E, Budhu S, Mandelbaum J, Vonsattel JP, Zecca L, Loike JD, Sulzer D (2014) MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat Commun 5:3633

    Article  PubMed Central  PubMed  Google Scholar 

  • Chavis P, Fagni L, Lansman JB, Bockaert J (1996) Functional coupling between ryanodine receptors and L-type calcium channels in neurons. Nature 382(6593):719–722

    Article  CAS  PubMed  Google Scholar 

  • Custódio CS, Mello BSF, Cordeiro RC, de Araújo FYR, Chaves JH, Vasconcelos SMM, Macêdo DS (2013) Time course of the effects of lipopolysaccharide on prepulse inhibition and brain nitrite content in mice. Eur J Pharmacol 713(1–3):31–38

    Article  PubMed  Google Scholar 

  • Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9(1):46–56. doi:10.1038/nrn2297

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Daubner SC, Le T, Wang S (2011) Tyrosine hydroxylase and regulation of dopamine synthesis. Arch Biochem Biophys 508(1):1–12

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Del Tredici K, Rüb U, De Vos RAI, Bohl JRE, Braak H (2002) Where does parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61(5):413–426

    PubMed  Google Scholar 

  • Foster TC (2012) Dissecting the age-related decline on spatial learning and memory tasks in rodent models: N-methyl-D-aspartate receptors and voltage-dependent Ca2+ channels in senescent synaptic plasticity. Prog Neurobiol 96(3):283–303

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Friedrich O, Yi B, Edwards JN, Reischl B, Wirth-Hücking A, Buttgereit A, Lang R, Weber C, Polyak F, Liu I, von Wegner F, Cully TR, Lee A, Most P, Völkers M (2014) Interleukin-1α reversibly inhibits skeletal muscle ryanodine receptor: a novel mechanism for critical illness myopathy? Am J Respir Cell Mol Biol 50(6):1096–1106

    Article  PubMed  Google Scholar 

  • Furukawa K, Mattson MP (1998) The transcription factor NF-kappaB mediates increases in calcium currents and decreases in NMDA- and AMPA/kainate-induced currents induced by tumor necrosis factor-alpha in hippocampal neurons. J Neurochem 70(5):1876–1886

    Article  CAS  PubMed  Google Scholar 

  • Harro J, Pähkla R, Modiri A-R, Harro M, Kask A, Oreland L (1999) Dose-dependent effects of noradrenergic denervation by DSP-4 treatment on forced swimming and beta-adrenoceptor binding in the rat. J Neural Transm 106(7–8):619–629

    Article  CAS  PubMed  Google Scholar 

  • Hashioka S, Klegeris A, McGeer PL (2012) Inhibition of human astrocyte and microglia neurotoxicity by calcium channel blockers. Neuropharmacology 63(4):685–691

    Article  CAS  PubMed  Google Scholar 

  • Hauss-Wegrzyniak B, Dobrzanski P, Stoehr JD, Wenk GL (1998a) Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer’s disease. Brain Res 780(2):294–303

    Article  CAS  PubMed  Google Scholar 

  • Hauss-Wegrzyniak B, Lukovic L, Bigaud M, Stoeckel ME (1998b) Brain inflammatory response induced by intracerebroventricular infusion of lipopolysaccharide: an immunohistochemical study. Brain Res 794(2):211–224

    Article  CAS  PubMed  Google Scholar 

  • Horvath J, Burkhard PR, Herrmann FR, Bouras C, Kövari E (2014) Neuropathology of parkinsonism in patients with pure Alzheimer’s disease. J Alzheimers Dis 39(1):115–120

    PubMed  Google Scholar 

  • Iannaccone S, Cerami C, Alessio M, Garibotto V, Panzacchi A, Olivieri S, Gelsomino G, Moresco RM, Perani D (2013) In vivo microglia activation in very early dementia with Lewy bodies, comparison with Parkinson’s disease. Parkinsonism Relat Disord 19(1):47–52

    Article  CAS  PubMed  Google Scholar 

  • Jost BC, Grossberg GT (1996) The evolution of psychiatric symptoms in Alzheimer’s disease: a natural history study. J Am Geriatr Soc 44(9):1078–1081

    CAS  PubMed  Google Scholar 

  • Klegeris A, Choi HB, McLarnon JG, McGeer PL (2007) Functional ryanodine receptors are expressed by human microglia and THP-1 cells: Their possible involvement in modulation of neurotoxicity. J Neurosci Res 85(10):2207–2215

    Article  CAS  PubMed  Google Scholar 

  • Leverenz JB, Miller MA, Dobie DJ, Peskind ER, Raskind MA (2001) Increased alpha 2-adrenergic receptor binding in locus coeruleus projection areas in dementia with Lewy bodies. Neurobiol Aging 22(4):555–561

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Hu X, Liu Y, Bao Y, An L (2009) Nimodipine protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. Neuropharmacology 56(3):580–589

    Article  CAS  PubMed  Google Scholar 

  • Lin Y, Sarfraz Y, Jensen A, Dunn AJ, Stone EA (2011) Participation of brainstem monoaminergic nuclei in behavioral depression. Pharmacol Biochem Behav 100(2):330–339. doi:10.1016/j.pbb.2011.08.021

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Liu M, Bing G (2011) Lipopolysaccharide animal models for Parkinson’s disease. Parkinsonism Dis 2011:327089

    Google Scholar 

  • Mattson MP (2012) Parkinson’s disease: don’t mess with calcium. J Clin Invest 122(4):1195–1198

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38(8):1285–1291

    Article  CAS  PubMed  Google Scholar 

  • Monville C, Torres EM, Dunnett SB (2006) Comparison of incremental and accelerating protocols of the rotarod test for the assessment of motor deficits in the 6-OHDA model. J Neurosci Methods 158(2):219–223

    Article  PubMed  Google Scholar 

  • Muñoz P, Huenchuguala S, Paris I, Segura-Aguilar J (2012) Dopamine oxidation and autophagy. Parkinsonism Dis 20:920–953

    Google Scholar 

  • Murrough J, Boss-Williams K, Emery M, Bonsall R, Weiss J (2000) Depletion of brain norepinephrine does not reduce spontaneous ambulatory activity of rats in the home cage. Brain Res 883:125–130

    Article  CAS  PubMed  Google Scholar 

  • Palmi M, Meini A (2002) Role of the nitric oxide/cyclic GMP/Ca2+ signaling pathway in the pyrogenic effect of interleukin-1beta. Mol Neurobiol 25(2):133–147

    Article  CAS  PubMed  Google Scholar 

  • 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 Dis 28(13):1823–1831

    Article  Google Scholar 

  • Ravina B, Camicioli R, Como PG, Marsh L, Jankovic J, Weintraub D, Elm J (2007) The impact of depressive symptoms in early Parkinson disease. Neurology 69(4):342–347

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Salazar A, Gonzalez-Rivera BL, Redus L, Parrott JM, O’Connor JC (2012) Indoleamine 2,3-dioxygenase mediates anhedonia and anxiety-like behaviors caused by peripheral lipopolysaccharide immune challenge. Horm Behav 62(3):202–209

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schrempf W, Brandt MD, Storch A, Reichmann H (2014) Sleep disorders in Parkinson’s disease. J Parkinsonism Dis 4(2):211–221

    Google Scholar 

  • Simic G, Stanic G, Mladinov M, Jovanov-Milosevic N, Kostovic I, Hof PR (2009) Does Alzheimer’s disease begin in the brainstem? Neuropathol Appl Neurobiol 35(6):532–554

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Starkstein SE, Mizrahi R (2006) Depression in Alzheimer’s disease. Expert Rev Neurother 6(6):887–895

    Article  CAS  PubMed  Google Scholar 

  • Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85(3):367–370

    Article  CAS  PubMed  Google Scholar 

  • Stone EA, Lin Y, Sarfraz Y, Quartermain D (2011) The role of the central noradrenergic system in behavioral inhibition. Brain Res Rev 67(1–2):193–208

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Surmeier DJ, Schumacker PT (2013) Calcium, bioenergetics, and neuronal vulnerability in Parkinson’s disease. J Biol Chem 288(15):10736–10741

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Swiergiel AH, Dunn AJ (2007) Effects of interleukin-1beta and lipopolysaccharide on behavior of mice in the elevated plus-maze and open field tests. Pharmacol Biochem Behav 86(4):651–659

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37(3):510–518

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Thierry B, Steru L, Chermat R, Simon P (1984) Searching-waiting strategy: a candidate for an evolutionary model of depression? Behav Neural Biol 41(2):180–189

    Article  CAS  PubMed  Google Scholar 

  • Tomlinson BE, Irving D, Blessed G (1981) Cell loss in the locus coeruleus in senile dementia of Alzheimer type. J Neurol Sci 49(3):419–428

    Article  CAS  PubMed  Google Scholar 

  • Williams JT, North RA, Shefner SA, Nishi S, Egan TM (1984) Membrane properties of rat locus coeruleus neurones. Neuroscience 13(1):137–156

    Article  CAS  PubMed  Google Scholar 

  • Yasuno F, Kosaka J, Ota M, Higuchi M, Ito H, Fujimura Y, Nozaki S, Takahashi S, Mizukami K, Asada T, Suhara T (2012) Increased binding of peripheral benzodiazepine receptor in mild cognitive impairment-dementia converters measured by positron emission tomography with [11C]DAA1106. Psychiatry Res 203(1):67–74

    Article  CAS  PubMed  Google Scholar 

  • Zhang W, Yan Z, Gao J, Sun L, Huang X, Liu Z, Yu S, Cao C-J, Zuo L, Chen Z-J, Hu Y, Wang F, Hong J, Wang X (2014) Role and mechanism of microglial activation in iron-induced selective and progressive dopaminergic neurodegeneration. Mol Neurobiol 49(3):1153–1165

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Supported by U.S. Public Health Service, RO1 AG030331, RO1 AG037320, The Ohio State University Women and Philanthropy Program to GLW, and Howard Hughes Medical Institute Med-into-Grad fellowship to SCH.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Neuroscience, Ohio State University, Columbus, OH, 43210, USA

    Sarah C. Hopp, Sarah E. Royer & Gary L. Wenk

  2. Department of Psychology, Ohio State University, Columbus, OH, 43210, USA

    Heather M. D’Angelo, Roxanne M. Kaercher & Gary L. Wenk

  3. Artisan’s Asylum, Somerville, MA, 02143, USA

    David A. Fisher

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  1. Sarah C. Hopp
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  2. Sarah E. Royer
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  3. Heather M. D’Angelo
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  4. Roxanne M. Kaercher
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  5. David A. Fisher
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  6. Gary L. Wenk
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Correspondence to Gary L. Wenk.

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Hopp, S.C., Royer, S.E., D’Angelo, H.M. et al. Differential Neuroprotective and Anti-Inflammatory Effects of L-Type Voltage Dependent Calcium Channel and Ryanodine Receptor Antagonists in the Substantia Nigra and Locus Coeruleus. J Neuroimmune Pharmacol 10, 35–44 (2015). https://doi.org/10.1007/s11481-014-9568-7

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