Periventricular white matter injury is the leading cause of
cerebral palsy in premature infants for which no effective treatments are available. Our previous studies have demonstrated that pharmacological activation of the
cAMP response element-binding protein (CREB) signaling pathway, before hypoxic-
ischemia protected against neuronal injury in neonatal rats. We examined whether
rolipram, a
phosphodiesterase type IV inhibitor, treatment after hypoxic-
ischemia is protective against white matter injury in neonatal rats. Rats were exposed to
hypoxia-
ischemia (HI) on P7 and then treated with daily
injections of various doses of
rolipram (P7-P11). Immunohistochemical staining for
myelin basic protein, ED1,
glial fibrillary acidic protein, CREB and O1 were examined on P11. We found that the periventricular white matter and deep cortical lesions were exacerbated by
rolipram administration after HI injury. The lesions in the
rolipram-treated group also showed increased
astrogliosis and increased CREB phosphorylation in the activated microglia and astrocytes. Furthermore, the
rolipram-posttreated HI group had markedly depleted preoligodendrocytes in the ipsilateral hemisphere, which may be related to decreased preoligodendrocytes proliferation after
rolipram treatment per se. These data suggest that
rolipram treatment after hypoxic-
ischemia is not protective; in contrast,
rolipram may exacerbate hypoxic-ischemic white matter injury in neonatal rat brains.