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Beta-amyloid peptide (Aβ), a major protein component of senile plaques, has been considered as a critical cause in the pathogenesis of Alzheimer's disease (AD). Modulation of the Aβ-induced neurotoxicity has emerged as a possible therapeutic approach to ameliorate the onset and progression of AD. The present study aimed to evaluate the protective effect of isorhynchophylline, an oxindole alkaloid isolated from a Chinese herb Uncaria rhynchophylla, on Aβ-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. The results showed that pretreatment with isorhynchophylline significantly elevated cell viability, decreased the levels of intracellular reactive oxygen species and malondialdehyde, increased the level of glutathione, and stabilized mitochondrial membrane potential in Aβ(25-35)-treated PC12 cells. In addition, isorhynchophylline significantly suppressed the formation of DNA fragmentation and the activity of caspase-3 and moderated the ratio of Bcl-2/Bax. These results indicate that isorhynchophylline exerts a neuroprotective effect against Aβ(25-35)-induced neurotoxicity in PC12 cells, at least in part, via inhibiting oxidative stress and suppressing the mitochondrial pathway of cellular apoptosis.

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The progressive accumulation of amyloid-β (Aβ) 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 Aβ 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 Aβ25-35-treated rats and to elucidate its action mechanisms. We showed that Aβ25-35 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 Aβ25-35 in the rats. In addition, IRN attenuated the Aβ25-35-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 3β (GSK-3β) activity, and activate the phosphorylation of phosphatidylinositol 3-kinase (PI3K) substrate Akt. These results indicate that down-regulation of GSK-3β 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.

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Preclinical and clinical investigations have shown hippocampal neuronal atrophy and destruction were observed in patients with depression, which could be ameliorated by the treatment with antidepressants. Therefore, neuroprotection has been proposed to be one of the acting mechanisms of antidepressant. Paeoniflorin, a monoterpene glycoside, has been reported to display antidepressant-like effects in animal models of behavioral despair. The present study aimed to examine the protective effect of paeoniflorin on glutamate-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. The results showed that pretreatment with paeoniflorin elevated cell viability, inhibited apoptosis, decreased levels of intracellular reactive oxygen species and malondialdehyde, and enhanced activity of superoxide dismutase in glutamate-treated PC12 cells. Pretreatment with paeoniflorin also reversed the increased intracellular Ca(2+) concentration and the reduced Calbindin-D28K mRNA level caused by glutamate in PC12 cells. The results suggest that paeoniflorin exerts a neuroprotective effect on glutamate-induced neurotoxicity in PC12 cells, at least in part, via inhibiting oxidative stress and Ca(2+) overload. This neuroprotective effect may be one of the action pathways accounting for the in vivo antidepressant activity of paeoniflorin.