Periventricular leukomalacia is a major cause of cerebral palsy. Perinatal white matter lesions associated with cerebral palsy appears to involve glutamate excitotoxicity. When injected intracerebrally into newborn mice, the glutamatergic analog, ibotenate, induces white matter cysts mimicking human periventricular leukomalacia. Intraperitoneal injection of melatonin was previously shown to be neuroprotective in this mouse model. The goal of the present study was to compare in this model the protective effects of agomelatine (S 20098), a melatonin derivative, with melatonin. Mice that received intraperitoneal S 20098 or melatonin had significant reductions in size of ibotenate-induced white matter cysts when compared with controls. Although agomelatine and melatonin did not prevent the initial appearance of white matter lesions, they did promote secondary lesion repair. Interestingly, while melatonin effects were only observed when given within the first two hours following the excitotoxic insult, agomelatine was still significantly neuroprotective when administered eight hours after the insult. The protective effects of agomelatine and melatonin were counter-acted by co-administration of luzindole or S 20928, two melatonin receptor antagonists. Agomelatine, acting through melatonin receptors, could represent a promising new drug for treating human periventricular leukomalacia and have beneficial effects on neuroplasticity.