Modulation of cannabinoid receptor activation as a neuroprotective strategy for EAE and stroke.
Recognition of the importance of the endocannabinoid system in both homeostasis and pathologic responses raised interest recently in the development of therapeutic agents based on this system. The CB(2) receptor, a component of the endocannabinoid system, has significant influence on immune function and inflammatory responses. Inflammatory responses are major contributors to central nervous system (CNS) injury in a variety of diseases. In this report, we present evidence that activation of CB(2) receptors, by selective CB(2) agonists, reduces inflammatory responses that contribute to CNS injury. The studies demonstrate neuroprotective effects in experimental autoimmune encephalomyelitis, a model of multiple sclerosis, and in a murine model of cerebral ischemia/reperfusion injury. In both cases, CB(2) receptor activation results in reduced white cell rolling and adhesion to cerebral microvessels, a reduction in immune cell invasion, and improved neurologic function after insult. In addition, administration of the CB(1) antagonist SR141716A reduces infarct size following ischemia/reperfusion injury. Administration of both a selective CB(2) agonist and a CB(1) antagonist has the unique property of increasing blood flow to the brain during the occlusion period, suggesting an effect on collateral blood flow. In summary, selective CB(2) receptor agonists and CB(1) receptor antagonists have significant potential for neuroprotection in animal models of two devastating diseases that currently lack effective treatment options.
Zhang
Ming
M
Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Martin
Billy R
BR
Adler
Martin W
MW
Razdan
Raj J
RJ
Kong
Weimin
W
Ganea
Doina
D
Tuma
Ronald F
RF
D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000517:prevention & control; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D043882:Receptors, Cannabinoid / Q000187:drug effects / Q000378:metabolism*; D020521:Stroke / Q000378:metabolism* / Q000517:prevention & control
D018696:Neuroprotective Agents; D043882:Receptors, Cannabinoid