Isorhynchophylline Treatment Improves the Amyloid-β-Induced Cognitive Impairment in Rats via Inhibition of Neuronal Apoptosis and Tau Protein Hyperphosphorylation

Article type: Research Article

Authors: Xian, Yan-Fang^a | Mao, Qing-Qiu^a | Wu, Justin CY^b | Su, Zi-Ren^c | Chen, Jian-Nan^c | Lai, Xiao-Ping^c | Ip, Siu-Po^{a; *} | Lin, Zhi-Xiu^{a; *}

Affiliations: [a] School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China | [b] Institute of Integrative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China | [c] College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou, China

Correspondence: [*] Correspondence to: Dr. Zhi-Xiu Lin, School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China. Tel.: +852 3943 6347; Fax: +852 2603 7203; E-mail: [email protected]; Dr. Siu-Po Ip, Tel.: +852 3943 4457; Fax: +852 3943 4459; E-mail: [email protected].

Abstract: 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.

Keywords: Amyloid-β, apoptosis, isorhynchophylline, PI3K/Akt signaling pathway, spatial memory, tau protein hyperphosphorylation

DOI: 10.3233/JAD-131457

Journal: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 331-346, 2014