Jijo Stebin Justus, Marcelo S. Rodolphi, Bruna Valdameri, Vitória G. de Oliveira, Nathan R. Strogulski, Marco A. Stefani, Luis V. Portela
{"title":"A Pharmacological Perspective on Targeting the Voltage-Gated Calcium Channel Subunit α2δ(1–2) to Mitigate Traumatic Brain Injury Sequelae","authors":"Jijo Stebin Justus, Marcelo S. Rodolphi, Bruna Valdameri, Vitória G. de Oliveira, Nathan R. Strogulski, Marco A. Stefani, Luis V. Portela","doi":"10.1007/s11064-025-04565-x","DOIUrl":null,"url":null,"abstract":"<div><p>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<sup>2+</sup> influx, membrane depolarization, and an increased vesicular release of glutamate and Ca<sup>2+</sup> into the synaptic cleft. This leads to the overactivation of NMDA receptors and the propagation of neurotoxic Ca<sup>2+</sup> signals to neighboring neurons, further spreading neurobiochemical disruptions. Given this, blocking Ca<sup>2+</sup> influx may mitigate excitotoxicity, and mitochondrial alterations caused by TBI. Among the pathways involved in Ca<sup>2+</sup> cytotoxicity, the alpha-2-delta (α<sub>2</sub>δ<sub>(1–2)</sub>) 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<sup>2+</sup> 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 α<sub>2</sub>δ<sub>(1–2)</sub> subunit, as a promising therapeutic strategy to counteract Ca<sup>2+</sup>-induced neurotoxicity following TBI.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 5","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurochemical Research","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s11064-025-04565-x","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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 Ca2+ influx, membrane depolarization, and an increased vesicular release of glutamate and Ca2+ into the synaptic cleft. This leads to the overactivation of NMDA receptors and the propagation of neurotoxic Ca2+ signals to neighboring neurons, further spreading neurobiochemical disruptions. Given this, blocking Ca2+ influx may mitigate excitotoxicity, and mitochondrial alterations caused by TBI. Among the pathways involved in Ca2+ cytotoxicity, the alpha-2-delta (α2δ(1–2)) 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 Ca2+ 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 α2δ(1–2) subunit, as a promising therapeutic strategy to counteract Ca2+-induced neurotoxicity following TBI.
期刊介绍:
Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.