β-Asarone Inhibits Neuronal Apoptosis via the CaMKII/CREB/Bcl-2 Signaling Pathway in an in vitro Model and AβPP/PS1 Mice

Article type: Research Article

Authors: Wei, Gang^{a; 1} | Chen, Yun-bo^{d; 1} | Chen, Dong-Feng^{b; *} | Lai, Xiao-Ping^{a; c; *} | Liu, Dong-Hui^a | Deng, Ru-Dong^b | Zhou, Jian-Hong^b | Zhang, Sai-Xia^b | Li, Yi-Wei^b | Lii, Hui^b | Liu, Liu-Fang^a | Wang, Qi^d | Nie, Hui^d

Affiliations: [a] Research & Development of New Drugs, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China | [b] Department of Anatomy, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China | [c] Mathematical Engineering Academy of Chinese Medicine of Dongguan, Guangzhou University of Traditional Chinese Medicine, Dongguan, China | [d] Institute of Clinical Pharmacology, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China

Correspondence: [*] Correspondence to: Dong-Feng Chen, Department of Anatomy, Guangzhou University of Traditional Chinese Medicine, No. 12, Jichang Road, Guangzhou 510405, China. Tel.: +86 20 39358211; Fax: +86 20 36588581; E-mail: [email protected] or Xiao-Ping Lai, Tel.: +86 20 39358045; Fax: +86 20 39358045; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: β-Asarone, an active component of the Acori graminei rhizome that has been used as traditional Chinese herb, has been reported to be capable of inhibiting neuronal apoptosis. However, the signaling mechanism underlying the inhibitory effect of β-asarone has remained elusive. This study was aimed to investigate whether the CaMKII signaling pathway is involved in the β-asarone mediated neuroprotection. Using PC12 cells and primary cultures of cortical neurons treated with amyloid-β (Aβ)1-40 or Aβ1-42 peptide, we demonstrated that β-asarone can protect PC12 cells and cortical neurons and inhibit neuronal apoptosis by activating the CaMKII-α/p-CREB/Bcl-2 pathway. Moreover, CaMKII-α overexpression enhanced the β-asarone-induced p-CREB-Bcl-2 expression and anti-apoptotic effects. Interestingly, suppression of CaMKII-α by siRNA or a specific inhibitor can significantly reduce the β-asarone-induced p-CREB and Bcl-2 expression and Aβ1-40 induced neuronal apoptosis in PC12 cells. AβPP/PS1 mice at the age of 3 months and age-matched wild-type mice were intragastrically administered β-asarone (7 mg/kg/day, 21 mg/kg/day) or a vehicle daily for 4 months. β-asarone improved cognitive function of the AβPP/PS1 mice and reduced neuronal apoptosis in the cortex of the AβPP/PS1 mice. A significant increase in CaMKII/CREB/Bcl-2 expression was observed in the cortex of the AβPP/PS1 mice treated with β-asarone. In summary, our observations demonstrated that β-asarone can inhibit neuronal apoptosis via the CaMKII/CREB/Bcl-2 signaling pathway in in vitro models and in AβPP/PS1 mice. Therefore, β-asarone can be used as a potential therapeutic agent in the long-term treatment of Alzheimer's disease.

Keywords: Alzheimer's disease, β-asarone, Bcl-2, CaMKII, neuronal apoptosis, phospho-CREB-binding protein

DOI: 10.3233/JAD-2012-120865

Journal: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 863-880, 2013