Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.
Department of Neuroscience, Mashhad University of Medical Sciences, Mashhad, Iran.
Mol Neurobiol. 2018 May;55(5):4225-4239. doi: 10.1007/s12035-017-0642-z. Epub 2017 Jun 13.
Repetitive cortical spreading depression (CSD) can lead to cell death in immature brain tissue. Caspases are involved in neuronal cell death in several CSD-related neurological disorders, such as stroke and epilepsy. Yet, whether repetitive CSD itself can induce caspase activation in adult or juvenile tissue remains unknown. Inducing repetitive CSD in somatosensory cortices of juvenile and adult rats in vivo, we thus aimed to investigate the effect of repetitive CSD on the expression caspase-3, caspase-8, caspase-9, and caspase-12 in different brain regions using immunohistochemistry and western blotting techniques. Higher numbers of dark neurons and TUNEL-positive cells were observed in the hippocampal CA1 and CA3 regions as well as in the entorhinal and somatosensory cortices after CSD in juvenile rats. This was accompanied by higher expressions of caspase-3, caspase-8, and caspase-9. Caspase-12 levels remained unchanged after CSD, suggesting that endoplasmic reticulum stress is not involved in CSD-triggered apoptosis. Changes in caspase expression were paralleled by a decrease of procaspase-3, procaspase-8, and procaspase-9 in juvenile rat brain tissue subjected to CSD. In contrast, repetitive CSD in adult rats did not result in the upregulation of caspase signaling. Our data points to a maturation-dependent vulnerability of brain tissue to repetitive CSD with a higher degree of apoptotic damage and caspase upregulation observed in juvenile tissue. Findings suggest a key role of caspase signaling in CSD-induced cell death in the immature brain. This implies that anti-apoptotic treatment may prevent CSD-related functional deficits in the immature brain.
重复的皮质扩散性抑制（CSD）可导致未成熟脑组织中的细胞死亡。半胱天冬酶参与了几种与 CSD 相关的神经疾病中的神经元细胞死亡，如中风和癫痫。然而，重复的 CSD 是否本身可以在成年或幼年组织中诱导半胱天冬酶的激活仍然未知。在体内诱导幼年和成年大鼠体感皮层中的重复 CSD，我们因此旨在使用免疫组织化学和 Western blot 技术研究重复 CSD 对不同脑区中 caspase-3、caspase-8、caspase-9 和 caspase-12 的表达的影响。在 CSD 后，幼年大鼠的海马 CA1 和 CA3 区以及内嗅皮层和体感皮层中观察到更多的暗神经元和 TUNEL 阳性细胞。这伴随着 caspase-3、caspase-8 和 caspase-9 的表达增加。CSD 后 caspase-12 水平保持不变，表明内质网应激不参与 CSD 触发的细胞凋亡。CSD 后，幼鼠脑组织中 procaspase-3、procasapse-8 和 procasapse-9 的减少与 caspase 表达的变化平行。相比之下，成年大鼠的重复 CSD 不会导致 caspase 信号通路的上调。我们的数据表明，脑组织对重复 CSD 的成熟依赖性易感性增加，与幼年组织中观察到的凋亡损伤和 caspase 上调程度更高。研究结果表明，caspase 信号在 CSD 诱导的未成熟脑的细胞死亡中起着关键作用。这意味着抗凋亡治疗可能防止未成熟大脑中与 CSD 相关的功能缺陷。
