SIRT1 Attenuates Neuropathic Pain via CDK5-Kalirin-7 Signaling Pathway in Type 2 Diabetic Rats

Evidence has continually accumulated to illustrate that sirtuin 1 (SIRT1) is a major factor in multiple animal models of neuropathic pain, encompassing those due to drug-induced peripheral nerves, diabetes-induced neuropathy, and chronic constriction injury. This investigation sought to examine if upregulating SIRT1 expression through the CDK5-Kalirin-7 signaling pathway can reduce pain in type 2 diabetic rats. A rat model simulating peripheral nerve injury as an imitation of type 2 diabetes was integrated into the investigation. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were utilized to evaluate pain-related behavior. Our findings revealed spinal SIRT1 expression is diminished in DNP (diabetic neuropathic pain) rats, and SRT1720 (SIRT1 agonist) can alleviate pain behavior. The expression of Kalirin-7 and P-NR2B was markedly increased, while the expression of t-NR2B had no statistical difference in DNP rats. The acetylation level of CDK5 in the DNP cohort was notably elevated, and after intrathecal injection of SRT1720, Ac-CDK5 in the SRT cohort was markedly diminished in contrast to the DNP cohort, and pain behavior was improved. Roscovitine (CDK5 antagonist) was validated to be significantly decreased in CDK5, p35, Kalirin-7, and p-NR2B protein on STZ 17, 21, and 28 days, and there was no difference in t-NR2B among all cohorts. Meanwhile, the thermal hyperalgesia and mechanical allodynia were markedly diminished in cohort Ros (the cohorts were administered Roscovitine). In vitro, the protein levels of CDK5 and p35 were elevated in BV2 cells, and the expression of Kalirin-7, PSD95, and p-NR2B was increased in co-cultured PC12 cells under high-glucose conditions. All of these in vitro effects were significantly attenuated following treatment with Roscovitine. These findings indicate that SIRT1 serves a crucial function in DNP advancement via CDK5-Kalirin-7 signaling pathway.