Matrine Alleviates Cognitive Dysfunction Induced by Chronic Cerebral Ischemia Through PTEN Regulating PI3K/AKT Signaling Pathway

JIN Na; GAO Yuanze; SHI Baoxiang; SHAN Wei

doi:10.3969/j.issn.2096-305X.2025.03.002

Abstract：Objective To investigate the influence of matrine on cognitive dysfunction and the PTEN/PI3K/AKT signaling pathway in rats with chronic cerebral ischemia(CCI).Methods SPF SD rats were used to establish the CCI rat model by the Two-vessel occlusion(2-VO)method and randomly divided into 7 groups:Sham operation group(Sham group),cerebral ischemia group(CCI group),low-dose matrine group(Matroin-L group),medium-dose matrine group(Matroin-M group),high-dose matrine group(Matroin-H group),bitter Matrine+PTEN virus overexpression group(Matrine+AAV-PTEN group)and the matrine+viral empty vector group(Matrine+AAV-NC group).On the first day after the 2-VO surgery,three different doses of matrine were intraperitoneally injected once a day for 8 consecutive weeks.The possible targets of matrine were analyzed using PPI.Molecular docking was used to verify the binding activity of matrine and PTEN.The Morris water maze experiment was used to observe the effect of matrine on the cognitive function of CCI rats.Neurological function score and Nissl staining were used to observe nerve injury.The levels of central neuron-specific protein(s-100β)and neuron-specific enolase(NSE)in the hippocampal tissue of rats were determined by ELISA.The co-localization of PTEN and neurons(NeuN)was detected by immunofluorescence.Neuronal apoptosis was detected by TUNEL staining.Results Matrine can stably bind to the PTEN protein structure through amino acid residues ARG-173,GLU-299,ILE-303 and TYR-176.Medium-dose matrine has the best therapeutic effect on CCI rats.The escape latency in the CCI group was significantly shorter than that in the Sham group(P<0.01).The escape latency of larger mice in the matrine group was significantly prolonged compared with that in the CCI group(P<0.01).The escape latency of rats in the Matrine+AAV-PTEN group was shorter than that in the matrine group(P<0.01).The neurological function score of the CCI group was worse than that of the Sham group,with cell atrophy,increased expressions of s-100β and NSE,and increased neuronal apoptosis(P<0.01).The neurological function score of matrine was higher than that of the CCI group,the cell morphology was restored,the expressions of s-100β and NSE were decreased,and the neuronal apoptosis was reduced(P<0.01).However,after administration of AAV-PTEN on the basis of the matrine group,the protective effect of matrine was reversed(P<0.01).Conclusion Matrine can significantly inhibit cognitive dysfunction in CCI rats,which may be related to the inhibition of PTEN/PI3K/AKT signaling pathway.