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Isorhynchophylline treatment improves the amyloid-ß-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylation.

J Alzheimers Dis; 39(2): 331-46, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24164737
The progressive accumulation of amyloid-ß (Aß) in the form of senile plaques has been recognized as a key causative factor leading to the cognitive deficits seen in Alzheimer's disease (AD). Recent evidence indicates that Aß induces neurotoxicity in the primary neuronal cultures as well as in the brain. Previously, we have demonstrated that isorhynchophylline (IRN), the major chemical ingredient of Uncaria rhynchophylla, possessed potent neuroprotective effects. In the present study, we aimed to investigate the effect of IRN on cognitive function, neuronal apoptosis, and tau protein hyperphosphorylation in the hippocampus of the Aß25-35-treated rats and to elucidate its action mechanisms. We showed that Aß25-35 injection caused spatial memory impairment, neuronal apoptosis, and tau protein hyperphosphorylation. Treatment with IRN (20 or 40 mg/kg) for 21 days could significantly ameliorate the cognitive deficits induced by Aß25-35 in the rats. In addition, IRN attenuated the Aß25-35-induced neuronal apoptosis in hippocampus by down-regulating the protein and mRNA levels of the ratio of Bcl-2/Bax, cleaved caspase-3 and caspase-9, as well as suppressing the tau protein hyperphosphorylation at the Ser396, Ser404, and Thr205 sites. Mechanistic study showed that IRN could inhibit the glycogen synthase kinase 3ß (GSK-3ß) activity, and activate the phosphorylation of phosphatidylinositol 3-kinase (PI3K) substrate Akt. These results indicate that down-regulation of GSK-3ß activity and activation of PI3K/Akt signaling pathway are intimately involved in the neuroprotection of IRN. The experimental findings provide further evidence to affirm the potential of IRN as a worthy candidate for further development into a therapeutic agent for AD and other tau pathology-related neurodegenerative diseases.