精准医学杂志 (Feb 2025)
Effect of minocycline on cognitive dysfunction in mice with intracerebral hemorrhage and its mechanism
Abstract
Objective To investigate the effect of minocycline (Mcy) on cognitive dysfunction in mice with intracerebral hemorrhage (ICH) and its mechanism. Methods Male C57BL/6J mice were randomly divided into groups A, B, C, D, and E, with 20 mice in each group. The mice in group A were given injection of normal saline via the caudal vein, those in group B were given injection of autologous blood via the caudal vein to establish a model of ICH, those in groups C and D were given Mcy by gavage every day at a dose of 20 mg/kg and 50 mg/kg, respectively, in addition to the treatment in group B, and those in group E were given intraperitoneal injection of 5 μL DMSO solution containing 12 μg MK-2206 in addition to the treatment in group D; the course of treatment was 14 days for all groups. After treatment, modified Neurological Severity Score (mNSS) was used to assess nerve injury of mice in each group; the water maze test was used to evaluate the cognitive ability of mice in each group; brain water content was calculated for mice in each group; HE staining was used to observe the pathological morphology of hippocampal tissue; the TUNEL method was used to measure neuronal apoptosis in hippocampal tissue of mice in each group; ELISA was used to measure the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) in hippocampal tissue of mice, and Western blot was used to measure the protein expression levels of Bax, Bcl-2, phosphatase and tensin ho-molog (PTEN), protein kinase B (Akt), and phosphorylated Akt (p-Akt) in hippocampal tissue. Results Nerve injury assessment showed that groups C and D had a significantly lower mNSS score than group B (q=22.925,55.457,P<0.05), and group E had a significantly higher mNSS score than group D (q=44.448,P<0.05). The water maze test showed that compared with group B, groups C and D had significantly longer escape latency and exploration time (q=22.169-91.845,P<0.05) and a significantly higher number of crossings (q=18.347,41.936,P<0.05), and compared with group D, group E had significantly longer escape latency and exploration time (q=30.765,85.881,P<0.05) and a significantly lower number of crossings (q=39.315,P<0.05). The results of brain water content and TUNEL staining showed that compared with group B, groups C and D had significantly lower brain water content and neuronal apoptosis rate in hippocampal tissue (q=7.269-33.327,P<0.05), and compared with group D, group E had significantly higher brain water content and neuronal apoptosis rate (q=9.957,31.004,P<0.05). ELISA and Western blot showed that compared with group B, groups C and D had significantly lower content of MDA and relative expression levels of Bax and PTEN in hippocampal tissue (q=10.734-22.978,P<0.05) and significantly higher activities of SOD and GSH-Px, relative expression level of Bcl-2, and p-Akt/Akt ratio (q=11.862-31.997,P<0.05), and compared with group D, group E had significantly higher content of MDA and relative expression levels of Bax and PTEN in hippocampal tissue (q=14.766-20.400,P<0.05) and significantly lower activities of SOD and GSH-Px, relative expression level of Bcl-2, and p-Akt/Akt ratio (q=24.007-30.370,P<0.05). Conclusion Mcy can inhibit neuronal apoptosis in the hippocampus of ICH mice, thereby alleviating hippocampal injury and improving learning and memory abilities and cognitive dysfunction, possibly by activating the PI3K/Akt signaling pathway after inhibiting PTEN.
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