Analysis of the protective effects of the α₂/δ subunit of voltage-gated Ca²⁺ channels in brain injury

Voltage-gated Ca²⁺ channels (VGCCs) are comprised of α1, α₂/δ, β, and γ subunits. The pore-forming α1 subunit is essential for the proper functioning of Ca²⁺ channels, while the α₂/δ subunit interacts with components of the extracellular matrix. The α₂/δ subunit is related in many neuropathological symptoms, including epilepsy and cerebellar ataxia. We previously reported that the mutant Cav.2.1α1 subunit has protective effects following brain injury. The present study aimed to investigate the effects of the α₂/δ subunit inhibition alone and in combination with the inhibition of the Cav.2.1α1 subunit following brain injury by injecting Gabapentin using Cav.2.1α1 mutant heterozygous rolling Nagoya (rol/+) and wild-type (+/+) mice. Gabapentin binds to the α₂/δ subunit and leads to Ca²⁺ flow disturbance. A cryogenic method was used to induce brain injury. The mice pretreated with 100 mg/kg Gabapentin exhibited a decrease in lesion size, while the 40 mg/kg Gabapentin injection was effective in rol/+ mice but not +/+ mice. The administration of 100 mg/kg Gabapentin also attenuated reactive astrocyte activity and neuronal degeneration; the pattern of results was similar to that for lesion size. An analysis of phosphorylated p38 (pp38) expression revealed that Gabapentin suppressed the p38 mitogen-activated protein kinase (MAPK) signaling cascade by interrupting glutamate-signaling induced by the inhibition of VGCCs. The present findings demonstrated that the administration of the α₂/δ subunit inhibitor, Gabapentin, had neuroprotective effects following brain injury.