A Pharmacological Perspective on Targeting the Voltage-Gated Calcium Channel Subunit αδ to Mitigate Traumatic Brain Injury Sequelae.

Traumatic brain injury (TBI) is a significant global public health issue, affecting millions annually. Excessive calcium influx in neurons and astrocytes triggers a cascade of neurotoxic events, including mitochondrial dysfunction, increased production of reactive oxygen species, and hypometabolism, all of which contribute to impaired neurological function. Following TBI, alterations in presynaptic voltage-gated calcium channels (VGCCs) and the formation of plasma membrane pores facilitate Ca influx, membrane depolarization, and an increased vesicular release of glutamate and Ca into the synaptic cleft. This leads to the overactivation of NMDA receptors and the propagation of neurotoxic Ca signals to neighboring neurons, further spreading neurobiochemical disruptions. Given this, blocking Ca influx may mitigate excitotoxicity, and mitochondrial alterations caused by TBI. Among the pathways involved in Ca cytotoxicity, the alpha-2-delta (αδ) subunit of VGCCs, located at the presynaptic terminal, remains the least explored. In this review, we briefly examine the pathophysiological hallmarks of TBI and their connection to Ca dysregulation, while exploring the distribution of VGCC subtypes in the brain. Additionally, we highlight pregabalin, an analog of gabapentin and a selective antagonist of the αδ subunit, as a promising therapeutic strategy to counteract Ca-induced neurotoxicity following TBI.