Master of Science - Research
School of Health Sciences
Mackovski, Nikolce, Chronic treatment with simvastatin affects cannabinoid receptor type 1 and muscarinic receptors type 2/4 in different brain regions among sham and 6-hydroxydopamine lesioned rats, Master of Science - Research thesis, School of Health Sciences, University of Wollongong, 2013. http://ro.uow.edu.au/theses/3940
Background: Simvastatin is a hypolipidemic drug belonging to the family of statins. It has been previously reported that simvastatin, among other statins, significantly prevented dopaminergic neurons from degeneration in Parkinsonism in vivo model.
Objectives: It has been well documented that there are close interactions among the cannabinoid, muscarinic, and dopaminergic systems. This study aimed to explore whether chronic simvastatin treatment prevented any perturbations in autoradiography binding expression of Cannabinoid receptor type 1 (CB1) and Muscarinic receptors type 2/4 (M2/4) from 6-hydroxydopamine (6-OHDA) lesioning in the medial forebrain bundle of rat brains.
Method: Male Sprague Dawley rats (5 to 8 per group) were randomized for receiving saline or for the 6-OHDA-lesioned Parkinsonian model. Before surgery, rats were pretreated with 1mg/kg/day simvastatin, or 10 mg/kg/day simvastatin, or saline for 5 days (sham group), and the same treatment for each group was continued for 3 weeks after surgery. Simvastatin or saline was administered via an oral gavage daily. Quantitative autoradiography was employed to investigate the binding density of CB1 receptors using [3H] SR141716A and M2/4 receptors using [3H] AF-DX 384 in rat brain sections.
Results: Rats given only 6-OHDA lesion significantly up-regulated [3H] AF-DX 384 receptor binding levels in all brain regions when compared to the sham rat group (p<0.05). 6-OHDA lesioned rats treated with simvastatin at 1 mg/kg/day significantly reversed these elevations only in the prefrontal cortex, nucleus accumbens, and substantia nigra (p<0.05). 6-OHDA lesioned only rats significantly down-regulated [3H] SR141716A receptor binding levels when compared to the sham rat group in all brain regions examined (p<0.05). 6-OHDA lesioned rats with chronic simvastatin treatment at 10 mg/kg/day significantly elevated binding levels compared to the rats given only 6-OHDA lesion in all brain regions examined (p<0.05). Treatment in 6-OHDA lesioned rats with 1 mg/kg/day of simvastatin also significantly elevated binding levels compared to rats given 6-OHDA lesions alone, in the substantia nigra and hippocampus (p<0.05).
Conclusions: Chronic simvastatin treatment restored CB1 receptor binding to normal levels, whereas M2/4 receptor binding density was only restored in a few regions compared to rats that received the 6-OHDA lesion. These findings contribute to a better understanding of the critical role of simvastatin in treating neuropsychological dysfunctions such as PD, potentially via CB1 and M2/4 receptors.