Neuroprotective effects of Tongmai Yizhi Decoction () against Alzheimer's disease through attenuating cyclin-dependent kinase-5 expression.

OBJECTIVES: To explore the protective effects of Tongmai Yizhi Decoction (, TYD), a Chinese herb complex prescription against the impairment of cognitive functions and memory loss in amyloid beta 1-40 (Aß1-40) peptide and ibotenic (IBO)-induced Alzheimer's disease (AD) model rats. METHODS: The in vivo model was established by injecting Aß1-40 and IBO into left hippocampal CA1 area of Sprague-Dawley (SD) rat to mimic AD. Totally 32 SD rats were divided into 4 groups, including sham operation group, AD model group, TYD group [AD rats treated with TYD at the dosage of 19.44 g/(kg•d) for 4 weeks] and huperzine A group [AD rats treated with huperzine A at the dosage of 40.5 µg/(kg•d) for 4 weeks]. Spatial learning and memory level was detected by Morris Water Maze test. Histological morphology in the hippocampus was tested by hematoxylin-eosin (HE) staining. Cyclin-dependent kinase-5 (Cdk5) protein and gene expression level were investigated by Western blot analysis and real-time quantitative polymerase chain reaction (RT-qPCR), respectively. RESULTS: Aß1-40 and IBO treatment induced longer escape latency of rats, compared with sham operation group from day 25 (P<0.01). However, TYD and huperzine A obviously shortened the escape latency from day 26 (P<0.01). Moreover, the effect of TYD was similar to huperzine A (P>0.05). Furthermore, HE staining also showed that TYD and huperzine A reversed the neuropathological changes in the hippocampus triggered by Aß1-40 and IBO. TYD and huperzine A effectively reduced the expression levels of Cdk5 protein and gene located in rat hippocampus, compared with the AD model group (P<0.01). CONCLUSION: TYD could be a promising neuroprotective agent for protecting neuron from AD injury through inhibiting Cdk5 expression.

Peroxynitrite Decomposition Catalyst Reduces Delayed Thrombolysis-induced Hemorrhagic Transformation in Ischemia-reperfused Rat Brains.

AIM: Hemorrhagic transformation (HT) is a major complication of delayed tissue plasminogen activator (t-PA) treatment in ischemic stroke. We aimed to explore whether peroxynitrite decomposition catalyst (PDC) could prevent such complication. METHODS: Male Sprague-Dawley (SD) rats were subjected to middle cerebral artery occlusion (MCAO) with t-PA (10 mg/kg) or t-PA plus FeTMPyP (3 mg/kg, a representative PDC) at MCAO for 2 or 5 h and reperfusion for 22 or 19 h, respectively. HT was assessed with hemoglobin assay. Neurological deficit was evaluated with Modified Neurological Severity Score (mNSS). Peroxynitrite formation was examined by detecting 3-nitrotyrosine (3-NT) formation. The expression and activity of MMP-9/MMP-2 were assessed by Western blotting and gelatin zymography. RESULTS: t-PA treatment at 2 h of MCAO did not induce HT but attenuated neurological deficit, whereas treatment at 5 h significantly induced HT and worsened the neurological outcome. Such complications were prevented by FeTMPyP cotreatment. Early t-PA treatment inhibited 3-NT and MMP-9/MMP-2 expression, whereas delayed treatment induced 3-NT and MMP-9/MMP-2 expression and activity. FeTMPyP cotreatment downregulated 3-NT and inhibited MMP-9/MMP-2 in both time points. CONCLUSION: Peroxynitrite decomposition catalyst could prevent hemorrhagic transformation and improve neurological outcome ischemic rat brains with delayed t-PA treatment via inhibiting peroxynitrite-mediated MMP activation.