Neuroprotective and brain edema-reducing efficacy of the novel cannabinoid receptor agonist BAY 38-7271.
BAY 38-7271 is a new high-affinity cannabinoid receptor agonist with strong neuroprotective efficacy in a rat model of traumatic brain injury (acute subdural hematoma, SDH). In the present study we investigated CB1 receptor signal transduction by [35S]GTPgammaS binding in situ and in vitro to assess changes in receptor functionality after SDH. Further, we continued to investigate the neuroprotective properties of BAY 38-7271 in the rat SDH and transient middle cerebral artery occlusion (tMCA-O) model as well as the efficacy with respect to SDH-induced brain edema. [35S]GTPgammaS binding revealed minor attenuation of CB1 receptor functionality on brain membranes from injured hemispheres when compared to non-injured hemispheres or controls. In the rat SDH model, BAY 38-7271 displayed strong neuroprotective efficacy when administered immediately after SDH either as a 1 h (65% infarct volume reduction at 0.1 microg/kg) or short-duration (15 min) infusion (53% at 10 microg/kg). When administered as a 4 h infusion with a 5 h delay after injury, significant neuroprotection was observed (49% at 1.0 microg/kg/h). This was also observed when BAY 38-7271 was administered as a 5 h delayed 15 min short-duration infusion (64% at 3 microg/kg). In addition, the neuroprotective potential of BAY 38-7271 was demonstrated in the rat tMCA-O model, displaying pronounced neuroprotective efficacy in the cerebral cortex (91% at 1 ng/kg/h) and striatum (53% at 10 ng/kg/h). BAY 38-7271 also reduced intracranial pressure (28% at 250 ng/kg/h) and brain water content (20% at 250 ng/kg/h) when determined 24 h post-SDH. Based on these data it is concluded that the neuroprotective efficacy of BAY 38-7271 is mediated by multiple mechanisms triggered by cannabinoid receptors.
D000818:Animals; D001929:Brain Edema / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006408:Hematoma, Subdural / Q000188:drug therapy* / Q000378:metabolism; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D013451:Sulfonic Acids / Q000494:pharmacology / Q000627:therapeutic use*
C459384:3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate; D007189:Indans; D018696:Neuroprotective Agents; D043884:Receptor, Cannabinoid, CB1; D013451:Sulfonic Acids