Rolipram, a phosphodiesterase type IV inhibitor, exacerbates periventricular white matter lesions in rat pups.
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.
Chang
Ying-Chao
YC
Department of Pediatrics, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. ycchao@adm.cgmh.org.tw
Huang
Chao-Ching
CC
Hung
Pi-Lien
PL
Huang
Hsiu-Mei
HM
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002552:Cerebral Ventricles; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D058988:Phosphodiesterase 4 Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D058988:Phosphodiesterase 4 Inhibitors; D020889:Rolipram