A Pharmacological Perspective on Targeting the Voltage-Gated Calcium Channel Subunit α2δ(1–2) to Mitigate Traumatic Brain Injury Sequelae

IF 3.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jijo Stebin Justus, Marcelo S. Rodolphi, Bruna Valdameri, Vitória G. de Oliveira, Nathan R. Strogulski, Marco A. Stefani, Luis V. Portela
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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.

靶向电压门控钙通道亚基α2δ(1-2)减轻创伤性脑损伤后遗症的药理学研究
创伤性脑损伤(TBI)是一个重大的全球公共卫生问题,每年影响数百万人。过多的钙流入神经元和星形胶质细胞会引发一系列神经毒性事件,包括线粒体功能障碍、活性氧产生增加和代谢降低,所有这些都会导致神经功能受损。脑外伤后,突触前电压门控钙通道(VGCCs)的改变和质膜孔的形成促进了Ca2+内流、膜去极化以及谷氨酸和Ca2+进入突触间隙的囊泡释放增加。这导致NMDA受体的过度激活和神经毒性Ca2+信号向邻近神经元的传播,进一步传播神经生化破坏。鉴于此,阻断Ca2+内流可能会减轻脑外伤引起的兴奋性毒性和线粒体改变。在参与Ca2+细胞毒性的途径中,位于突触前末端的VGCCs的α -2- δ(α2δ(1-2))亚基仍然是研究最少的。在这篇综述中,我们简要地研究了TBI的病理生理特征及其与Ca2+失调的联系,同时探索了VGCC亚型在大脑中的分布。此外,我们强调普瑞巴林,加巴喷丁的类似物和α2δ(1-2)亚基的选择性拮抗剂,作为一种有希望的治疗策略,以抵消Ca2+诱导的TBI后神经毒性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
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.
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