Anti-inflammatory property of the cannabinoid agonist WIN-55212- 2 in a neuroinflammation rat model of Alzheimer disease.

Y.MARCHALANT*; S. ROSI; G.L. WENK.

NSMA, University of Arizona, Tucson AZ 85724

Ohio State University, Columbus, OH 43201

Cannabinoid receptor (CBr) stimulation induces numerous central (psychoactive, anti-nociceptive) and peripheral (cardiovascular, immunosuppressive) effects. A growing interest in the beneficial properties of the endocannabinoid system raised the possible implication of CBr in the control of inflammatory process in the brain. We investigated the effect of a CBr agonist, WIN-55212-2, on multiple biomarkers of neuroinflammation induced by a chronic intracerebroventricular lipolysaccharide (LPS) infusion and its consequence on performance in a spatial memory task.

Daily treatment (3 weeks) with WIN-55212-2 (0.5 or 1.0 mg/kg, intraperitoneal) were given to three months old male rats implanted into the 4 th ventricle with a chronic indwelling cannula connected to an osmotic minipump, infusing LPS (250 ng/hr) or vehicle. On the third week of treatment, the rats were tested for impairment in the Morris water-maze task. Rats were then perfused transcardially, their brains removed, and processed for immunostaining of neuroinflammation biomarkers.

Our preliminary data indicate a dramatic anti-inflammatory effect of the WIN-55212-2 compound upon microglia activation at a dose that was not associated with performance impairment in rats infused with aCSF. Nonetheless LPS-infused animal injected with WIN-55212-2 didn’t present any enhancement of performance in the Morris water-maze task as compared to the LPS-infused rats without WIN-55212-2 injections. These results highlight the possible role of CBr in the regulation of inflammatory processes within the brain. Investigations are currently being conducted to determine whether this anti-inflammatory effect is region-specific and the nature of the neural mechanisms involved.

These results reveal a promising new role of the endocannabinoid system that may lead to the use of CBr agonists in the treatment of neurodegenerative diseases associated with chronic neuroinflammation, such as Alzheimer disease.

Supported by RO1 AG10546.