l-3-n-Butylphthalide attenuates β-amyloid-induced toxicity in neuroblastoma SH-SY5Y cells through regulating mitochondrion-mediated apoptosis and MAPK signaling

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Amyloid-β protein (Aβ), the hallmark of AD, invokes a cascade of mitochondrial dysfunction and eventually leads to neuronal death. l-3-n-Butylphthalide (l-NBP) has shown the potent neuroprotective effects in stroke and AD animal models. The present study is to evaluate the neuroprotective effect of l-NBP on Aβ_25–35-induced neuronal injury and the possible mechanism in the human neuroblastoma SH-SY5Y cells. Our results showed that l-NBP significantly attenuated Aβ_25–35-induced cell death and reduced neuronal apoptosis. l-NBP significantly inhibited Aβ_25–35-induced mitochondrial dysfunction, including mitochondrial membrane potential reduction, and reactive oxygen species production. Furthermore, l-NBP could partially reverse the elevations of Aβ_25–35-induced active caspase-3, caspase-9, and cytochrome c expressions, and the downregulation of anti-apoptosis protein Bcl-2. Moreover, l-NBP markedly inhibited the activations of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase/stress-activated protein kinase signaling pathway. These results demonstrated that l-NBP was capable of protecting neuronal cells from Aβ_25–35-induced toxicity through a mitochondrial-dependent apoptotic pathway. Thus, l-NBP shows promising candidate of multi-target neuronal protective agent for the treatment of AD.

Keywords::

• Alzheimer's disease
• Aβ
• l-3-n-butylphthalide
• apoptosis
• mitochondria

Acknowledgments

This study was financially supported by the grants from National Natural Sciences Foundation of China (Nos 30973511 and 81373387), National Science and Technology Major Special Project on Major New Drug Innovation of China (2009ZX09303-003), and 2010 Program for New Century Excellent Talents in University (NCET-10-0961). We appreciated Dr Rui Liu and Mr Jinze Li from National Center of Pharmacological Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College for the technical guidance.