RRC ID 47308
Author Kim TY, Niimi K, Takahashi E.
Title Analysis of the protective effects of the α2/δ subunit of voltage-gated Ca2+ channels in brain injury.
Journal Brain Res
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.
Volume 1655
Pages 138-144
Published 2017-1-15
DOI 10.1016/j.brainres.2016.11.009
PII S0006-8993(16)30746-6
PMID 27840189
MeSH Amines / pharmacology* Animals Astrocytes / drug effects Astrocytes / metabolism Astrocytes / pathology Brain / drug effects Brain / metabolism Brain / pathology Brain Injuries / drug therapy* Brain Injuries / metabolism Brain Injuries / pathology Calcium Channel Blockers / pharmacology* Calcium Channels, N-Type / genetics Calcium Channels, N-Type / metabolism* Cell Proliferation / drug effects Cell Proliferation / physiology Cold Temperature Cyclohexanecarboxylic Acids / pharmacology* Disease Models, Animal Gabapentin MAP Kinase Signaling System / drug effects MAP Kinase Signaling System / physiology Male Mice, Inbred C57BL Mice, Mutant Strains Neurodegenerative Diseases / drug therapy Neurodegenerative Diseases / metabolism Neurodegenerative Diseases / pathology Neuroprotective Agents / pharmacology* gamma-Aminobutyric Acid / pharmacology* p38 Mitogen-Activated Protein Kinases / metabolism
IF 2.733
Times Cited 2
Mice RBRC00388