Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis

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 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.

Prenatal pregabalin is associated with sex‐dependent alterations in some behavioral parameters in valproic acid‐induced autism in rat offspring

“…However, the analgesic mechanism of PGB was explained by inhibition of excitatory neurotransmitter release in the pain pathway, facilitation in synaptic inhibition, decreasing glutamate cytotoxicity, and improvement of neuroinflammation. All occurred through Inhibition of alpha‐2‐delta‐1 subunit of voltage‐gated calcium channels (Hundehege et al., 2018; Joshi & Taylor, 2006).…”

“…Coordination impairment in VPA groups might occur through decreasing the dimension of the purkinje cells and decreasing the expression of calcium‐binding protein (Main & Kulesza, 2017). Since, some of the PGB effects are mediated through its effects on calcium channels (Hundehege et al., 2018; Joshi & Taylor, 2006), so maternal exposure to PGB can minimize prenatal VPA‐induced sex differences in beam balance test.…”

Ion Channels as New Attractive Targets to Improve Re-Myelination Processes in the Brain

“…Pregabalin (Lyrica ® ) is prescribed to MS patients to treat neuropathic pain by targeting Cav [ 62 ] and, in addition, it could provide neuroprotection by inhibiting exaggerated Cav currents during excitotoxicity and neuroinflammation. Indeed, it has been demonstrated that Pregabalin treatment alleviates EAE symptoms in mice possibly by reverting, at neuronal level, intracellular Ca 2+ overload in EAE lesions [ 63 ]. However, in the same paper, the authors pointed to a significant reduction of hippocampal long-term potentiation in pregabalin-treated EAE mice, thus warning of potential side effects on memory and learning processes [ 58 , 63 ].…”

High-Dose Vitamin D-Mediated Hypercalcemia as a Potential Risk Factor in Central Nervous System Demyelinating Disease

“…Consequently, this inhibition of voltage-gated calciumchannels diminishes the amount of available neurotransmitters in the synaptic cleft. When tested in an animal model of MS, pregabalin reduced the calcium-mediated neuronal cytotoxicity and neuronal damage (82). A similar attenuation of EAE was observed when mice were treated with the calcium antagonist nimodipine.…”