探索星形胶质细胞参与和谷氨酸诱导的神经炎症在毒死蜱诱导的自闭症谱系障碍(ASD)范例中的作用

IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemical Research Pub Date : 2024-06-19 DOI:10.1007/s11064-024-04191-z
Manasi Varma, Ranjana Bhandari PhD, Ankan Sarkar, Manish Jain, Jyoti K. Paliwal, Bikash Medhi, Anurag Kuhad
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引用次数: 0

摘要

自闭症谱系障碍(ASD)是一种主要表现为儿童的神经发育障碍,症状包括社交/沟通障碍和刻板印象,以及焦虑、抑郁和多动症等相关行为异常。虽然病理机制尚不十分清楚,但神经炎症的作用已被提出。尽管如此,以前并没有详细探讨过引起这种神经炎症的诱因,因此本研究旨在探讨谷氨酸在这些过程中的作用,谷氨酸可能通过增加炎症细胞(如星形胶质细胞)的活性和降低神经元的健康水平来发挥作用。本研究采用了毒死蜱诱导幼鼠 ASD 的新范例。这些动物接受了评估其新生儿发育和青春期行为(社交技能、刻板行为、感觉运动缺陷、焦虑、抑郁、嗅觉和痛觉)的测试。此外,还测量了炎症标志物以及谷氨酸兴奋毒性和神经炎症相关分子的水平。此外,还评估了活性氧的表达、神经元炎症标志物(GFAP)和功能标志物(c-Fos),以及组织病理学改变。根据这些评估结果发现,在新生儿期和青少年期,产后服用氯化石蜡会对神经行为产生负面影响,尤其是对发育标志物,并导致类似 ASD 的症状产生。谷氨酸和下游钙以及某些细胞因子和神经炎症标志物的表达升高进一步证实了这一点,组织病理学和免疫组化结果也验证了这一点,这些结果显示神经元健康状况的下降是由星形胶质细胞介导的细胞因子依赖型方式造成的。通过我们的研究结果,我们获得了确凿的证据,证明谷氨酸参与了牵涉到 ASD 类症状发展的神经炎症通路,并能进一步激活与神经元损伤相关的下游过程。此外,还总结了星形胶质细胞的作用及其对神经元健康的不利影响。我们的研究及其发现的意义在于评估毒死蜱诱导的神经毒性参与 ASD 的发展,特别是与谷氨酸能功能障碍和神经元损伤有关的神经毒性。
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Exploring Astrocytes Involvement and Glutamate Induced Neuroinflammation in Chlorpyrifos-Induced Paradigm Of Autism Spectrum Disorders (ASD)

Autism spectrum disorders (ASD) are neurodevelopmental disorders manifested mainly in children, with symptoms ranging from social/communication deficits and stereotypies to associated behavioral anomalies like anxiety, depression, and ADHD. While the patho-mechanism is not well understood, the role of neuroinflammation has been suggested. Nevertheless, the triggers giving rise to this neuroinflammation have not previously been explored in detail, so the present study was aimed at exploring the role of glutamate on these processes, potentially carried out through increased activity of inflammatory cells like astrocytes, and a decline in neuronal health. A novel chlorpyrifos-induced paradigm of ASD in rat pups was used for the present study. The animals were subjected to tests assessing their neonatal development and adolescent behaviors (social skills, stereotypies, sensorimotor deficits, anxiety, depression, olfactory, and pain perception). Markers for inflammation and the levels of molecules involved in glutamate excitotoxicity, and neuroinflammation were also measured. Additionally, the expression of reactive oxygen species and markers of neuronal inflammation (GFAP) and function (c-Fos) were evaluated, along with an assessment of histopathological alterations. Based on these evaluations, it was found that postnatal administration of CPF had a negative impact on neurobehavior during both the neonatal and adolescent phases, especially on developmental markers, and brought about the generation of ASD-like symptoms. This was further corroborated by elevations in the expression of glutamate and downstream calcium, as well as certain cytokines and neuroinflammatory markers, and validated through histopathological and immunohistochemical results showing a decline in neuronal health in an astrocyte-mediated cytokine-dependent fashion. Through our findings, conclusive evidence regarding the involvement of glutamate in neuroinflammatory pathways implicated in the development of ASD-like symptoms, as well as its ability to activate further downstream processes linked to neuronal damage has been obtained. The role of astrocytes and the detrimental effect on neuronal health are also concluded. The significance of our study and its findings lies in the evaluation of the involvement of chlorpyrifos-induced neurotoxicity in the development of ASD, particularly in relation to glutamatergic dysfunction and neuronal damage.

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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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