Astrocytes are the first responders to noxious stimuli by undergoing cellular and functional transition referred as reactive gliosis. Every acute or chronic disorder is accompanied by reactive gliosis, which could be categorized as detrimental (A1) of beneficial (A2) for nervous tissue. Another signature of pathological astrocyte activation is disturbed Ca²⁺ homeostasis, a common denominator of neurodegenerative diseases. Deregulation of Ca⁺ signaling further contributes to production of pro-inflammatory cytokines and reactive oxygen species. Trimethyltin (TMT) intoxication is a widely used model of hippocampal degeneration, sharing behavioral and molecular hallmarks of Alzheimer’s disease (AD), thus representing a useful model of AD-like pathology. However, the role of astrocyte in the etiopathology of TMT-induced degeneration as well as in AD is not fully understood. In an effort to elucidate the role of astrocytes in such pathological processes, we examined in vitro effects of TMT on primary cortical astrocytes. The application of a range of TMT concentrations (5, 10, 50, and 100 μM) revealed changes in [Ca²⁺]_i in a dose-dependent manner. Specifically, TMT-induced Ca²⁺ transients were due to L-type voltage-gated calcium channels (VGCC). Additionally, TMT induced mitochondrial depolarization independent of extracellular Ca²⁺ and disturbed antioxidative defense of astrocyte in several time points (4, 6, and 24 h) after 10 μM TMT intoxication, inducing oxidative and nitrosative stress. Chronic exposure (24 h) to 10 μM TMT induced strong upregulation of main pro-inflammatory factors, components of signaling pathways in astrocyte activation, A1 markers, and VGCC. Taken together, our results provide an insight into cellular and molecular events of astrocyte activation in chronic neuroinflammation.

星形胶质细胞是对有害刺激的第一反应者，通过经历称为反应性神经胶质增生的细胞和功能转变。每种急性或慢性疾病都伴有反应性神经胶质增生，可将其归类为对神经组织有害（A1）或有益（A2）。病理性星形胶质细胞激活的另一个特征是 Ca ²⁺稳态紊乱，这是神经退行性疾病的一个共同点。 Ca ⁺信号传导的失调进一步促进促炎细胞因子和活性氧的产生。三甲基锡 (TMT) 中毒是一种广泛使用的海马变性模型，具有阿尔茨海默病 (AD) 的行为和分子特征，因此代表了 AD 样病理学的有用模型。然而，星形胶质细胞在 TMT 诱导的变性以及 AD 的病因病理学中的作用尚不完全清楚。为了阐明星形胶质细胞在此类病理过程中的作用，我们研究了 TMT 对原代皮质星形胶质细胞的体外影响。应用一系列 TMT 浓度（5、10、50 和 100 μM）揭示了 [Ca ^{2 +} ] _i以剂量依赖性方式发生的变化。具体来说，TMT 诱导的 Ca ^{2 +}瞬变是由于 L 型电压门控钙通道 (VGCC) 造成的。此外，TMT 诱导独立于细胞外 Ca ²⁺的线粒体去极化，并在 10 μM TMT 中毒后的几个时间点（4、6 和 24 小时）扰乱星形胶质细胞的抗氧化防御，诱导氧化和亚硝化应激。 长期暴露（24 小时）10 μM TMT 会诱导主要促炎因子、星形胶质细胞激活信号通路成分、A1 标记物和 VGCC 的强烈上调。总而言之，我们的结果提供了对慢性神经炎症中星形胶质细胞激活的细胞和分子事件的深入了解。