γ-氨基丁酸(GABA)是中枢神经系统中一种关键的抑制性神经递质,在调节神经元兴奋性中起着至关重要的作用。GABA能信号调节异常,特别是涉及共同转运蛋白NKCC1和KCC2,涉及各种病理,包括癫痫,精神分裂症,自闭症谱系障碍,唐氏综合症,和缺血。NKCC1促进氯化物流入,而KCC2通过钾梯度介导氯化物流出。这些协同转运蛋白的表达和功能的改变与兴奋性毒性有关,炎症,以减少的脑血流量为特征的缺血事件中的细胞死亡,导致组织代谢受损和随后的细胞死亡。NKCC1抑制已成为在缺血事件期间减弱细胞内氯化物积累和减轻神经元损伤的潜在治疗方法。同样,靶向调节氯化物流出的KCC2,有望改善缺血条件下的预后和减少神经元损伤。这篇综述强调了GABA的关键作用,缺血性病变中的NKCC1和KCC2及其作为治疗靶标的潜力。抑制或调节这些协同转运蛋白的活性代表了减少神经元损伤的有希望的策略。防止兴奋性毒性,改善缺血事件后的神经系统预后。此外,探索天然化合物与NKCC1/KCC2之间的相互作用为缺血性损伤的潜在治疗干预提供了额外的途径.
Gamma aminobutyric acid (GABA) is a critical inhibitory neurotransmitter in the central nervous system that plays a vital role in modulating neuronal excitability. Dysregulation of GABAergic signaling, particularly involving the cotransporters NKCC1 and
KCC2, has been implicated in various pathologies, including epilepsy, schizophrenia, autism spectrum disorder, Down syndrome, and ischemia. NKCC1 facilitates chloride influx, whereas
KCC2 mediates chloride efflux via potassium gradient. Altered expression and function of these cotransporters have been associated with excitotoxicity, inflammation, and cellular death in ischemic events characterized by reduced cerebral blood flow, leading to compromised tissue metabolism and subsequent cell death. NKCC1 inhibition has emerged as a potential therapeutic approach to attenuate intracellular chloride accumulation and mitigate neuronal damage during ischemic events. Similarly, targeting
KCC2, which regulates chloride efflux, holds promise for improving outcomes and reducing neuronal damage under ischemic conditions. This review emphasizes the critical roles of GABA, NKCC1, and
KCC2 in ischemic pathologies and their potential as therapeutic targets. Inhibiting or modulating the activity of these cotransporters represents a promising strategy for reducing neuronal damage, preventing excitotoxicity, and improving neurological outcomes following ischemic events. Furthermore, exploring the interactions between natural compounds and NKCC1/
KCC2 provides additional avenues for potential therapeutic interventions for ischemic injury.