CDK5介导外泌体调节在慢性神经病理性疼痛伴快感缺失中的作用及机制研究

Patients with chronic neuropathic pain (CNP) is often associated with anhedonia, the underlying mechanism has not been fully elucidated. Our previous studies suggested that the species and level of gut microbiota has changed significantly. Meanwhile, the expression of brain derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC) was decreased in rats CNP with anhedonia. However, the pathway by which gut microbiota regulates BDNF remains to be explored. Studies have shown that exosome as carriers of hormones and neurotransmitters. At the same time, CDK5, as a periodic regulatory gene, is regulated by melatonin and plays an important role in exosome secretion and gut microbiota metabolism. Accordingly, we propose the following scientific hypothesis: CDK5-mediated exosomal regulation may work as an important mediator connecting the "gut-brain" axis, acting on the brain BDNF-TrkB signaling pathway and participating in the pathogenesis of CNP with anhedonia. Therefore, we intend to study the therapeutic effects of exosomal melatonin on CNP with anhedonia in vivo and in vitro, as well as the mechanism of CDK5-mediated exosomal regulation, and try to explore the interaction of exosomes in the gut microbiota and brain BDNF-TrkB signaling pathway. It will provide new ideas and theoretical basis for the prevention and treatment of CNP with anhedonia and broaden the field of exosome research.

慢性神经病理性疼痛(CNP)患者常伴快感缺失症状，但具体机制仍未完全阐明。我们前期研究发现CNP伴快感缺失大鼠肠道菌群种类和数量发生显著变化，且脑mPFC区脑源性神经营养因子(BDNF)表达明显降低，但肠道菌群通过何种途径调节BDNF变化仍未见报道。研究表明外泌体是传递分泌激素和神经递质的载体，CDK5作为周期调节基因除受褪黑素调控外，对外泌体分泌和肠道菌群代谢具有重要作用。据此，我们提出如下科学假说：CDK5介导外泌体调节可作为连接“肠-脑”轴的重要媒介，作用于脑BDNF-TrkB信号通路，参与到CNP伴快感缺失发病机制中。因此，我们拟通过在体及离体模型研究外泌体载褪黑素对CNP伴快感缺失的治疗作用，并明确CDK5介导外泌体调节在其中的机制，并试图阐述外泌体在肠道菌群与脑BDNF-TrkB信号通路中的交互作用。从而为防治这一疾病提供新思路和理论基础，也为外泌体研究拓宽领域。

慢性神经病理性疼痛（CNP）是临床常见的疼痛类型，而其中越来越多的患者伴有快感缺失的症状。申请者对慢性CNP伴快感缺失的发生机制进行了相关研究。我们通过坐骨神经结扎（SNI）模型模拟CNP，并通过聚类分析的方法筛选和构建更贴合临床的CNP伴快感缺失的动物模型，避免了研究过程中的混杂因素，提高了实验结果的准确性，增加了实验结果的可信度。结果发现，CNP伴快感缺失的发生与铁死亡和氧化应激的产生有密切联系，进一步地，其潜在机制可能与抑制CDK5从而抑制脑BDNF-TrkB信号通路有关。而褪黑素通过减轻抑制该信号通路，减少铁死亡和氧化应激的产生，能够有效改善CNP伴快感缺失的发生。此外，褪黑素还可通过激活SIRT1/Mfn2/PERK信号通路，减轻内质网应激有效改善吸入麻醉药所致大鼠认知功能障碍。该研究结果将为预防和治疗CNP伴致快感缺失提供新的思路和理论基础。