Intracerebroventricular infusion of secretoneurin inhibits neuronal NLRP3-Apoptosis pathway and preserves learning and memory after cerebral ischemia

IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemistry international Pub Date : 2024-05-16 DOI:10.1016/j.neuint.2024.105770
Caihong Gu , Xiuwen Kang , Xiaobing Chen , Yan Sun , Xiaomin Li
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Abstract

Transient global cerebral ischemia (GCI) results in delayed neuronal death, primarily apoptosis, in the hippocampal CA1 subregion, which leads to severe cognitive deficits. While therapeutic hypothermia is an approved treatment for patients following cardiac arrest, it is associated with various adverse effects. Secretoneurin (SN) is an evolutionarily conserved neuropeptide generated in the brain, adrenal medulla and other endocrine tissues. In this study, SN was infused into the rat brain by intracerebroventricular injection 1 day after GCI, and we demonstrated that SN could significantly preserve spatial learning and memory in the Barnes maze tasks examined on days 14–17 after GCI. To further investigate underlying pathways involved, we demonstrated that, on day 5 after GCI, SN could significantly inhibit GCI-induced expression levels of Apoptosis Inducing Factor (AIF) and cleaved-PARP1, as well as neuronal apoptosis and synaptic loss in the hippocampal CA1 region. Additionally, SN could attenuate GCI-induced activation of both caspase-1 and caspase-3, and the levels of pro-inflammatory cytokines IL-1β and IL-18 in the CA1 region. Mechanically, we observed that treatment with SN effectively inhibited NLRP3 protein elevation and the bindings of NLRP3-ASC and ASC-caspase-1 in hippocampal neurons after GCI. In summary, our data indicate that SN could effectively attenuate NLRP3 inflammasome formation, as well as the activation of caspase-1 and -3, the production of pro-inflammatory cytokines, and ultimately the neuronal apoptotic loss induced by GCI. Potential neuronal pyroptosis, or caspase-1-dependent cell death, could also be involved in ischemic neuronal death, which needs further investigation.

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脑室内灌注 Secretoneurin 可抑制神经元 NLRP3-Apoptosis 通路并保护脑缺血后的学习和记忆。
短暂性全脑缺血(GCI)会导致海马 CA1 亚区神经元延迟死亡,主要是细胞凋亡,从而导致严重的认知障碍。虽然治疗性低温是一种获准用于心脏骤停患者的治疗方法,但它与各种不良反应有关。分泌神经肽(SN)是一种进化保守的神经肽,产生于大脑、肾上腺髓质和其他内分泌组织。在本研究中,我们在大鼠GCI后1天通过脑室内注射将SN注入大鼠大脑,结果表明SN能显著保护大鼠在GCI后第14至17天进行的巴恩斯迷宫任务中的空间学习和记忆。为了进一步研究其中的潜在途径,我们证实,在 GCI 后的第 5 天,SN 可以显著抑制 GCI 诱导的凋亡诱导因子(AIF)和裂解-PARP1 的表达水平,以及海马 CA1 区的神经元凋亡和突触丢失。此外,SN还能减轻GCI诱导的caspase-1和caspase-3的激活,以及CA1区促炎细胞因子IL-1β和IL-18的水平。在机制上,我们观察到 SN 能有效抑制 GCI 后海马神经元中 NLRP3 蛋白的升高以及 NLRP3-ASC 和 ASC-caspase-1 的结合。总之,我们的数据表明,SN 能有效抑制 NLRP3 炎性体的形成,以及 Caspase-1 和 -3 的激活、促炎性细胞因子的产生,并最终抑制 GCI 诱导的神经元凋亡。潜在的神经元热凋亡或依赖于 caspase-1 的细胞死亡也可能参与缺血性神经元死亡,这还需要进一步研究。
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来源期刊
Neurochemistry international
Neurochemistry international 医学-神经科学
CiteScore
8.40
自引率
2.40%
发文量
128
审稿时长
37 days
期刊介绍: Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.
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