ligustilide and Neurodegenerative-Diseases

Radix Angelica Sinensis (RAS) has beneficial effects in patients suffering from cognitive impairment associated with chronic cerebral hypoperfusion. It has previously been demonstrated that RAS prevents the neurotoxic effects of β-amyloid (Aβ) in vitro, protects from injuries due to oxidative stress, inflammation and apoptosis and ameliorates scopolamine-induced amnesia in rats. Here, we studied the effects of RAS on cognitive improvement and neurogenic enhancement and examined the possible underlying mechanisms in a rat model with permanent bilateral common carotid artery occlusion, which serves as a model of chronic cerebral hypoperfusion-related neurodegenerative diseases. RAS enhances adult neurogenesis in the hippocampus following chronic cerebral hypoperfusion and improves the cognitive decline associated with hypoperfusion. Long-term ablation of adult hippocampal neurogenesis through cranial irradiation abolishes the protective effects of RAS on cognition. Furthermore, administration of RAS restores the decrease of brain-derived neurotrophic factor (BDNF) expression, the phosphorylation of cAMP-responsive element binding protein (CREB) and the glutamic acid decarboxylase 65 (GAD65) staining intensity in rats with chronic cerebral hypoperfusion. The present study supports the hypothesis that adult neurogenesis is required for RAS to facilitate recovery from the cognitive impairment induced by chronic cerebral hypoperfusion, while neurogenic enhancement secondary to RAS treatment may be due to increased BDNF and phosphorylated cAMP-responsive element binding protein (p-CREB) levels and increased γ-aminobutyric acid (GABA) expression. Based on the possible mechanisms suggested by the present study, this well-known traditional medicine may represent a candidate therapeutic agent for the treatment of dementia associated with vascular injury.

Topics: 4-Butyrolactone; Adult Stem Cells; Angelica sinensis; Animals; Blotting, Western; Cell Differentiation; Cognition Disorders; Cranial Irradiation; Disease Models, Animal; Drugs, Chinese Herbal; Hippocampus; Immunohistochemistry; Male; Neural Stem Cells; Neurodegenerative Diseases; Neurogenesis; Rats; Rats, Wistar

Z-ligustilide (Z-LIG) is the primary lipophilic compound of the Chinese medicine Danggui (Radix Angelica sinensis). Previous studies demonstrated that Z-LIG had significant neuroprotective potential in both transient and permanent cerebral ischemia, possibly through antioxidant and anti-apoptotic mechanisms. The present study examined the mechanisms of Z-LIG on hydrogen peroxide (H(2)O(2))-induced injury in PC12 cells. Following exposure of the cells to H(2)O(2 )(500 microM), a significant reduction in cell survival and total antioxidant capacity (TAC), as well as increased intracellular reactive oxygen species (ROS), were observed. In addition, H(2)O(2 )treatment significantly upregulated Bax expression, cleaved-caspase 3, and cytosolic cytochrome-c, and decreased Bcl-2 protein levels. Pretreatment of the cells with Z-LIG (0.1, 1.0, 2.5, or 5.0 microg/ml) significantly attenuated H(2)O(2)-induced cell death, attenuated increased intracellular ROS levels, and decreased Bax expression, cleaved-caspase 3, and cytochrome-c. Further, Z-LIG improved cellular TAC and concentration-dependently upregulated Bcl-2 expression. These results demonstrate that Z-LIG has a pronounced protective effect against H(2)O(2)-induced cytotoxicity, at least partly through improving cellular antioxidant defense and inhibiting the mitochondrial apoptotic pathway. These findings suggest that Z-LIG may be useful in the treatment of neurodegenerative disorders in which oxidative stress and apoptosis are mainly implicated.

Topics: 4-Butyrolactone; Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Cytoprotection; Cytotoxins; Dose-Response Relationship, Drug; Free Radical Scavengers; Hydrogen Peroxide; Mitochondria; Nerve Degeneration; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Rats; Reactive Oxygen Species; Up-Regulation