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Karger AG, Basel Published Online: November 26, 2018 by S Neurosignals 2018;26:77-93 DOI: 10.1159/000495425 © 2018 The Author(s).© 2018 Published The Author(s) by S. Karger AG, Basel Published online: November 26, 2018 www.karger.com/nsgPublished by S. Karger AG, Basel 77 www.karger.com/nsg Accepted:Hundehege November et al.: Pregabalin 08, 2018 in Experimental Autoimmune Encephalitis This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 Interna- tional License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Original Paper Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis Petra Hundehegea Juncal Fernandez-Ortha Pia Römera Tobias Rucka Thomas Münteferinga Susann Eichlera Manuela Cerinaa Lisa Eppinga Sarah Albrechta Amélie F. Menkea Katharina Birknerb Kerstin Göbela Thomas Buddec Frauke Zippb Heinz Wiendla Ali Gorjid Stefan Bittnerb Sven G. Meutha aNeurology Department with Institute of Translational Neurology, University of Münster, bDepartment of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, cInstitute of Physiology I, University of Münster, dNeurology Department with Institute of Translational Neurology and Neurosurgery Department, University of Münster, Germany Key Words Multiple sclerosis • Pregabalin • Experimental autoimmune encephalomyelitis • Neuroprotection Abstract Background/Aims: Multiple sclerosis (MS) is a prototypical autoimmune central nervous system (CNS) disease. Particularly progressive forms of MS (PMS) show significant neuroaxonal damage as consequence of demyelination and neuronal hyperexcitation. Immuno-modulatory treatment strategies are beneficial in relapsing MS (RMS), but mostly fail in PMS. Pregabalin (Lyrica®) is prescribed to MS patients to treat neuropathic pain. Mechanistically, it targets voltage-dependent Ca2+ channels and reduces harmful neuronal hyperexcitation in mouse epilepsy models. Studies suggest that GABA analogues like pregabalin exert neuroprotective effects in animal models of ischemia and trauma. Methods: We tested the impact of pregabalin in a mouse model of MS (experimental autoimmune encephalomyelitis, EAE) and performed histological and immunological evaluations as well as intravital two-photon-microscopy of brainstem EAE lesions. Results: Both prophylactic and therapeutic treatments ameliorated the clinical symptoms of EAE and reduced immune cell infiltration into the CNS. On neuronal level, pregabalin reduced long-term potentiation in hippocampal brain slices indicating an impact on mechanisms of learning and memory. In contrast, T cells, microglia and brain endothelial cells were unaffected by pregabalin. However, we found a direct impact of pregabalin on neurons P. Hundehege, J. Fernandez-Orth, S. Bittner and S.G. Meuth contributed equally to this paper. P. Hundehege and J. Fernandez-Orth share first authorship; S. Bittner and S. G. Meuth share last authorship. Dr. Petra Hundehege Department of Neurology with Institute of Translational Neurology, Westfälische Wilhelms-Universität Münster, ICB, Mendelstraße 7, 48149 Münster (Germany) E-Mail [email protected] Neurosignals 2018;26:77-93 DOI: 10.1159/000495425 © 2018 The Author(s). Published by S. Karger AG, Basel Published online: November 26, 2018 www.karger.com/nsg 78 Hundehege et al.: Pregabalin in Experimental Autoimmune Encephalitis during CNS inflammation as it reversed the pathological elevation of neuronal intracellular Ca2+ levels in EAE lesions. Conclusion: The presented data suggest that pregabalin primarily acts on neuronal Ca2+ channel trafficking thereby reducing Ca2+-mediated cytotoxicity and neuronal damage in an animal model of MS. Future clinical trials need to assess the benefit for neuronal survival by expanding the indication for pregabalin administration to MS patients in further disease phases. © 2018 The Author(s) Published by S. Karger AG, Basel Introduction Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) representing the primary cause of neurological disability in young adults in the Western world [1, 2]. The initiation of the pathogenesis is characterized by the consequently inducing extensive demyelination and neurodegeneration [1]. Treatment infiltration of auto-reactive immune cells into the CNS leading to inflammatory lesions strategiesneurodegeneration modifying and the thereby immune disability system progression response were in PMS found [3, 4]. beneficial, Suitable drugs but with that an exception of the B-cell depleting drug Ocrelizumab, these drugs fail to ameliorate In this regard, ion channels are known to be interesting targets for the treatment of promote neuronal survival in autoimmune inflammatory disorders are urgently needed. channels have been considered potential therapeutic targets for the treatment of MS, MSas they and wereother shownimmunological to exert diseases.a neuroprotective Among them, effect blockers and a reduction of voltage-gated of the immune sodium like symptoms in rodents [6, 7]. However, as the other treatment strategies, these drugs cell infiltration in mice [5] as well as an improved motor coordination and cerebellar- animal model of MS [8]. wereGlutamate unsuccessful excitotoxicity, as they showed a phenomenon worsen clinical due to deficitsan excessive and harmful amount effectsof glutamate in the resulting in cell death, could be a link between inflammatory and neurodegenerative processes(Lyrica®) evidentcould be in the MS key [9]. to Inhibition overcome of autoimmune voltage-gated neurodegeneration calcium channels in(VGCCs) diseases is alike potential MS. Chemically, neuroprotective pregabalin mechanism belongs against to the excitotoxicitygroup of gabapentinoids, [10-12], and pregabalinwhich are analogues of the inhibitory neurotransmitter γ-aminobutyric acid2 (GABA) subunits [13], play and an instead of binding to GABA receptors it binds to two isoforms of the auxiliary α2δ subunit (gene names: Cacna2d1 and Cacna2d2) of VGCCs [14].2 α δ important role in channel folding and consequently in2+ inwardthe trafficking current. of In channels neurons, to thisthe plasmasubsequently membrane induces [15, a reduction16]. The binding of neurotransmitter of pregabalin release to the fromα δ subunit the presynapse of the VGCC [17, inhibits18]. Under channel pathological trafficking conditions leading in to animal a reduced seizure Ca models, this effect reduces neuronal hyperexcitability and abnormal synchronization [18]. Nowadays gabapentinoids are not only used as antiepileptics but also for the treatment of other indications, including neuropathic pain in MS patients. Due to the 1 subunit, as well as its auxiliary and 2 existencethree different of numerous subfamilies variants [Cav1 of (Ca itsv pore-formingv1.4), Ca vα2 (Cav v2.3) and Cav3 (Cav βCav3.3)].α Caδ vsubunits,1 and Cav 2VGCCs channels are are organized capable ofin forming complex functional protein assemblieschannels together [19, 20] with in one of the four different auxiliary 2 1.1-Ca subunits [21, 22]. These2.1-Ca subfamilies are known3.1- to α δ be expressed in the plasma membrane of excitable and non-excitable cells (e.g. neurons, muscle,[27]. glial cells) [23-26] while there is a debate in the literature concerning their functional expression in various types of immune cells, including B- and T-lymphocytes Neurosignals 2018;26:77-93 DOI: 10.1159/000495425 © 2018 The Author(s). Published by S. Karger AG, Basel Published online: November 26, 2018 www.karger.com/nsg 79 Hundehege et al.: Pregabalin in Experimental Autoimmune Encephalitis gabapentinInterestingly, was found besides to effectively its well-known reduce acute therapeutic seizures spectrum,and injury afterthere ischemia are hints in pointingmice [29, to31]. a Furthermore,direct neuroprotective gabapentin effect demonstrated of pregabalin similar [28-31]. neuroprotective In this regard,effects as methylprednisolone in the early phase of spinal cord injury [28]. In a rat model of facial nerve avulsion, pregabalin administration led to better neuronal survival [30]. If spectrum to autoimmune neurodegeneration diseases, like MS. Here, we make use of thesean animal findings model hold of true, MS, they the mightexperimental argue for autoimmune an expansion encephalomyelitis of pregabalin’s therapeutic (EAE), to examine whether pregabalin exerts an effect apart from neuropathic pain reduction in MS pathophysiology. Material and Methods Mice Male and female C57BL/6J WT mice were purchased from Charles River Laboratories (Sulzfeld, Germany).Induction Mice and were evaluation kept under of activeIVC (Individually experimental Ventilated autoimmune Cages) encephalomyelitis animal housing conditions. ) peptide (Charité, Berlin, Germany). The Active EAE was induced by immunization of 8 – 10-week-old female wild type (WT; C57BL/6J) mice with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55 35–55 Mycobacterium tuberculosisanimals were subcutaneously immunized with 200 μg of mouse MOG peptide emulsified in 200 μl complete Freund’s adjuvant (Sigma-Aldrich GmbH, Steinheim, Germany) containing 200 μg day of immunization(strain H37 (day Ra; 0) Becton, and 2 Dickinsondays after and immunization. Company (BD), The Sparks,animals MD, belonging
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