CB1-ANTAGONISM/CB2-AGONISM PROVIDES NEUROPROTECTION IN BOTH MALE AND FEMALE RATS AFTER INFECTION-SENSITIZED NEONATAL HYPOXIC-ISCHEMIC BRAIN INJURY

Often exacerbated by inflammation, perinatal hypoxia-ischemia (HI) can result in severe brain damage, with male sex recognized as a risk factor for the development of permanent neurological sequelae. Using a rat model of infection-sensitized neonatal HI, our aim was to evaluate the neuroprotective potential of URB447, a cannabinoid receptor-1 (CB1) antagonist and CB2 agonist, considering a possible sex dimorphic response to injury and/or treatment.
Sprague-Dawley rats at postnatal day 7 (P7) were exposed to 0.1 mg/kg lipopolysaccharide (LPS) injection 4h prior to unilateral HI (50 minutes). Male and female pups were assigned to LPS+HI (6 males; 6 females) or LPS+HI+URB447 (single dose of 1 mg/kg, i.p. 2h after HI; 8 males; 9 females). At P14, brains were collected and sliced to histologically evaluate brain infarct, neuropathological score and severity of damage. Data were analyzed using GraphPad v9, and p<0.05 was considered statistically significant.
Evidenced by higher neuropathological scores and greater brain area loss, non-treated males exhibited greater histopathological vulnerability compared to females, who displayed a milder form of injury. URB447 treatment reduced LPS+HI-induced brain damage in both sexes: in males, the cannabinoid was able to significantly reduce hemispheric (p<0.001) and hippocampal (p<0.001) infarct and damage severity (p<0.01); in females, URB447 treatment also showed a neuroprotective effect on theses parameters, with values similar to those observed in males.
Following infection-sensitized neonatal HI injury, the CB1-antagonis/CB2-agonist URB447 reduced brain infarction despite sex-related differences in injury severity, highlighting its therapeutic potential independent of sex.
Acknowledgments: Grant PID2023-153191OB-I00 funded by MCIN/AEI/10.13039/501100011033 and by ERDF/EU.