Pharmacological effects of medicinal herbs on oxidative stress related neurodegenerative diseases

Abstract

Neurodegenerative diseases are characterized by progressive loss and altered functions of neurons. They include Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). Although there are approved drugs to treat neurodegenerative diseases, most of them only provide symptomatic improvement and have little or no impact on disease progression. Recent findings show that oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases. It could cause apoptosis of neurons. Therefore, rescuing neuronal cell death from oxidative stress challenges could be one of the important therapeutic strategies. Moreover, neural regeneration by neural stem cells is believed to be a potential method for functional recovery after neural damage. The first essential step of neural stem cell therapy is to allow the neural stem cells to survive and grow. Therefore, another aspect of treating neurodegenerative diseases is to search for agents which enhance proliferation of neural stem cells. Herbal medicine is increasingly being used in recent decades to enhance general health and well-being. In this project, three medicinal herbs including Ligusticum chuanxiong (LCX), Ganoderma lucidum (LCZ) and Cimicifuga racemosa (BC) were studied. In the first part of the study, the neuroprotective effects of the three medicinal herbs were tested. Among them, BC and LCX extracts were found to rescue PC12 cells from neuronal cell death induced by hydrogen peroxide (H2O2), as measured by MTT assays. Cim A and Z-lig, bioactive compounds of BC and LCX, respectively, also exerted the neuroprotective effects on PC12 and neuro-2a cells. Both compounds rescued the neuronal cell death via inhibition of apoptosis as measured by caspase-3 activity assays. As for the mechanisms involved, Cim A and Z-lig were found to increase H2O2-suppressed bcl-2 protein expression. Furthermore, Cim A and Z-lig suppressed the phosphorylation of p-38 but had no effect on phosphorylations of JNK, ERK and Akt in H2O2-stimulated neuronal cells. In the second part of the study, the effects of three medicinal herbs on proliferation of human H9-derived neural stem cells were tested. Only LCZ extracts could promote the proliferation of neural stem cells, as measured by MTT assays. It was further shown that LCZ extract enhanced the recovery after oxidative stress damage by H2O2 and nitric oxide. By a series of chemical separations, including solvent partition, column chromatography, and high performance liquid chromatography, a bioactive compound was isolated. It enhanced the proliferation of neural stem cells as measured by MTT and BrdU assays. The underlying mechanisms were investigated. It was found that Compound LCZ could induce the mRNA levels of CYP1B1 and HDAC9. However, these proteins did not play a role in enhanced proliferation of neural stem cells induced by Compound LCZ. Additionally, compound LCZ increased the phosphorylation of ERK but had no effect on phosphorylations of JNK, Akt and PI3K kinases. This activation of ERK correlated with the promotion of proliferation, as confirmed by an MEK inhibitor. Taken together, the study reveals that medicinal herbs LCX, BC and LCZ are potential drug candidates for treating oxidative stress related neurodegenerative diseases.