The cannabinoid CB2 receptor agonist GW405833 does not ameliorate brain damage induced by hypoxia-ischemia in rats.
The cannabinoid CB2 receptor has been under investigation as a potential target for neuroprotection with the suppression of neuroinflammation as the proposed mechanism of action. Several studies have now reported that CB2 agonists are neuroprotective in models of cerebral ischemia. However, these studies have tended to measure brain infarctions in rodents 1-3 days after drug administration and have not assessed behavioral outcomes. As it has been shown that apparent protection soon after injury is not necessarily correlated with improved outcome after several weeks, we tested the CB2 selective agonist GW405833 in a model of cerebral hypoxia-ischemia, and assessed histological and behavioral outcomes 15 days after injury. Many putatively neuroprotective drugs have failed to translate from promising preclinical results to clinical success. We designed our experiments to not only stringently test CB2 mediated neuroprotection, but also to test several drug administration regimens to maximize the chance of detecting any therapeutic effect. However, GW405833 failed to provide neuroprotection in any of our experiments. These results challenge how far the results of earlier studies into CB2 mediated neuroprotection as measured at early time points may be extrapolated to later time points or to other models.
Department of Pharmacology and Toxicology, School of Medical Sciences, and the Brain Health Research Centre, University of Otago, P.O. Box 913, Dunedin, New Zealand.
J R
JR
Rivers-Auty
Department of Pharmacology and Toxicology, School of Medical Sciences, and the Brain Health Research Centre, University of Otago, P.O. Box 913, Dunedin, New Zealand.
P F
PF
Smith
Department of Pharmacology and Toxicology, School of Medical Sciences, and the Brain Health Research Centre, University of Otago, P.O. Box 913, Dunedin, New Zealand. Electronic address: john.ashton@otago.ac.nz.
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JC
Ashton
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D020520:Brain Infarction / Q000188:drug therapy / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*
C463040:1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-(2-(mopholin-4-yl)ethyl)-1H-indole; C469526:Cnr2 protein, rat; D007211:Indoles; D009025:Morpholines; D018696:Neuroprotective Agents; D043885:Receptor, Cannabinoid, CB2
Brain damage; CB(2) receptor; Cannabinoid; GW405833; Hypoxia-ischemia