title: Analysis of the protective effects of the α2/δ subunit of voltage-gated Ca2+channels in brain injury.
abstract: 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 100mg/kg Gabapentin exhibited a decrease in lesion size, while the 40mg/kg Gabapentin injection was effective in rol/+ mice but not +/+ mice. The administration of 100mg/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.
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: taeyeonkim@brain.riken.jp.
authors.forename: Tae Yeon
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Kimie
authors.initials: K
authors.lastname: Niimi
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Eiki
authors.initials: E
authors.lastname: Takahashi
mesh_terms: D000588:Amines / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D003080:Cold Temperature; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D000077206:Gabapentin; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000588:Amines; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D003509:Cyclohexanecarboxylic Acids; D000077206:Gabapentin; D018696:Neuroprotective Agents; D005680:gamma-Aminobutyric Acid; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Brain injury; Cav.2.1; Cav.2.1α1 subunit; Cav.2.1α2/δ subunit; Gabapentin; Rolling Nagoya