Low Dose of Anisodine Hydrobromide Induced Neuroprotective Effects in Chronic Cerebral Hypoperfusion Rats.

Background: Chronic cerebral hypoperfusion is a common pathophysiological state in various cerebrovascular diseases. Anisodine has been reported to exert neuroprotective effects in cerebral ischemia/reperfusion (I/R) animal model. However, it is unclear whether anisodine hydrobromide, the hydrobromide format of anisodine, one of the tropic alkanes alkaloids, exhibits the same neuroprotective effect on chronic cerebral hypoperfusion(CCH) rats. Herein, we tried to unravel these issues. Methods: CCH model in adult male Sprague-Dawley rats was established by permanent ligation of the bilateral common carotid arteries [two-vessel occlusion (2-VO)] surgery. Rats were randomly divided into six groups: sham, 2-VO, 2-VO + Butyl phthalide and sodium chloride injection (NBP, as positive control group), 2-VO + anisodine hydrobromide (AH) 1.2mg/kg, 2-VO + AH0.6mg/kg, 2-VO + AH0.3mg/kg. Cognitive behavior was examined by Morris Water Maze Test. Neuronal survival and apoptosis were evaluated by Nissl staining and Terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL staining). The relative monoamine neurotransmitter (5-hydroxytryptamine (5-HT), norepinephrine (NA)), the content of Ach, the activity of acetylcholin esterase (AchE) were measured in cholinergic system, and the protein expressions of Bcl-2, Bax, p-Akt and p-GSK-3 beta-were detected by Western blot assay. Results: The results showed that there is significant memory impairment and a remarkable neuron necrosis and apoptosis, along with the dysfunction of the neurotransmitter systems and central cholinergic system in CCH rats. AH treatment could significantly improve cognitive deficits, while reducing neuron necrosis and apoptosis, apart from increasing the content of 5-HT and decreasing the activity of AchE markedly. Further study revealed that AH could promote the protein expression of Bcl-2, phosphorylation of Akt and GSK-3 beta, and downregulate the protein of Bax. Conclusion: AH was demonstrated to ameliorate memory deficits by revising the imbalance of the monoamine neurotransmitter and cholinergic dysfunction. Moreover, AH can attenuate neuronal cell death and apoptosis by activating the Akt/GSK-3 beta signaling pathway.