The cannabinoid agonist WIN55212 reduces brain damage in an in vivo model of hypoxic-ischemic encephalopathy in newborn rats

Neonatal hypoxic-ischemic encephalopathy (NHIE) is a devastating condition for which effective therapeutic treatments are still unavailable. Cannabinoids emerge as neuroprotective substances in adult animal studies; therefore, we aimed herein to test whether cannabinoids might reduce brain damage induced by hypoxiaischemia (HI) in newborn rats. Thus, 7-d-old Wistar rats (P7) were exposed to 8% 0, for 120 min after left carotid artery ligature, then received s.c. vehicle (VEH) (HI+VEH), the cannabinoid agonist WIN55212 (WIN) (0.1 mg/kg), or WIN with the CB, or CB, receptor antagonist SR141617 (SR1) 3 mg/kg) or SR141588 (SR2) (2 mg/kcg). Brain damage was assessed by magnetic resonance imaging (MRI) at 1, 3. and 7 d after the insult. At the end of the experiment. MRI findings were corroborated by histology (Nissl staining.). HI+VEH showed an area of cytotoxic and vasogenic edema at 24 h after the insult, then evolving to necrosis. HI+WIN showed a similar damaged area at 24 h after the insult, but the final necrotic area was reduced by 66%. Coadministration of either SR1 or SR2 reversed the effects of WIN. In conclusion, likely by activating CB, and CB, receptors. WIN afforded robust neuroprotection in newborn rats after HI.