Tichauer Juan E, Lira Matías, Cerpa Waldo, Orellana Juan A, Sáez Juan C, Rovegno Maximiliano
Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Biol Res. 2024 Jun 12;57(1):39. doi: 10.1186/s40659-024-00519-9.
Spreading depression (SD) is an intriguing phenomenon characterized by massive slow brain depolarizations that affect neurons and glial cells. This phenomenon is repetitive and produces a metabolic overload that increases secondary damage. However, the mechanisms associated with the initiation and propagation of SD are unknown. Multiple lines of evidence indicate that persistent and uncontrolled opening of hemichannels could participate in the pathogenesis and progression of several neurological disorders including acute brain injuries. Here, we explored the contribution of astroglial hemichannels composed of connexin-43 (Cx43) or pannexin-1 (Panx1) to SD evoked by high-K stimulation in brain slices.
Focal high-K stimulation rapidly evoked a wave of SD linked to increased activity of the Cx43 and Panx1 hemichannels in the brain cortex, as measured by light transmittance and dye uptake analysis, respectively. The activation of these channels occurs mainly in astrocytes but also in neurons. More importantly, the inhibition of both the Cx43 and Panx1 hemichannels completely prevented high K-induced SD in the brain cortex. Electrophysiological recordings also revealed that Cx43 and Panx1 hemichannels critically contribute to the SD-induced decrease in synaptic transmission in the brain cortex and hippocampus.
Targeting Cx43 and Panx1 hemichannels could serve as a new therapeutic strategy to prevent the initiation and propagation of SD in several acute brain injuries.
扩散性抑制（SD）是一种有趣的现象，其特征是大脑出现大量缓慢的去极化，影响神经元和神经胶质细胞。这种现象具有重复性，并产生代谢过载，增加继发性损伤。然而，与SD起始和传播相关的机制尚不清楚。多条证据表明，半通道的持续且不受控制的开放可能参与包括急性脑损伤在内的几种神经疾病的发病机制和进展。在此，我们探讨了由连接蛋白43（Cx43）或泛连接蛋白1（Panx1）组成的星形胶质细胞半通道对脑片高钾刺激诱发的SD的作用。
通过分别测量光透射率和染料摄取分析发现，局灶性高钾刺激迅速诱发了一波与大脑皮质中Cx43和Panx1半通道活性增加相关的SD。这些通道的激活主要发生在星形胶质细胞中，但也发生在神经元中。更重要的是，抑制Cx43和Panx1半通道完全阻止了大脑皮质中高钾诱导的SD。电生理记录还显示，Cx43和Panx1半通道对SD诱导的大脑皮质和海马体突触传递减少起关键作用。
靶向Cx43和Panx1半通道可能成为预防几种急性脑损伤中SD起始和传播的一种新的治疗策略。
