Cerebral palsy (CP) is defined as permanent disorders of movement and posture. Prematurity and hypoxia-ischemia (HI) are risk factors of CP, and boys display a greater vulnerability to develop CP. Magnesium sulfate (MgSO4) is administered to mothers at risk of preterm delivery as a neuroprotective agent. However, its effectiveness is only partial at long term. To prolong MgSO4 effects, it was combined with 4-phenylbutyrate (4-PBA). A mouse model of neonatal HI, generating lesions similar to those reported in preterms, was realized. At short term, at the behavioral and cellular levels, and in both sexes, the MgSO4/4-PBA association did not alter the total prevention induced by MgSO4 alone. At long term, the association extended the MgSO4 preventive effects on HI-induced motor and cognitive deficits. This might be sustained by the promotion of oligodendrocyte precursor differentiation after HI at short term, which led to improvement of white matter integrity at long term. Interestingly, at long term, at a behavioral level, sex-dependent responses to HI were observed. This might partly be explained by early sex-dependent pathological processes that occur after HI. Indeed, at short term, apoptosis through mitochondrial pathways seemed to be activated in females but not in males, and only the MgSO4/4-PBA association seemed to counter this apoptotic process.
Keywords: 4-phenylbutyrate; behavior; hypoxic–ischemic lesion; magnesium sulfate; sex; white matter oligodendrocyte differentiation.