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Updated: Jul 5, 2026
Modeling Posthemorrhagic Hydrocephalus of Prematurity in Rats
Published on: March 28, 2025
Rolipram, a phosphodiesterase type IV inhibitor, exacerbates periventricular white matter lesions in rat pups
Ying-Chao Chang1, Chao-Ching Huang, Pi-Lien Hung
1Department of Pediatrics, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. ycchao@adm.cgmh.org.tw
Insights
Rolipram treatment after hypoxic-ischemia exacerbates white matter injury in neonatal rats, contrary to expectations. This finding suggests rolipram is not protective and may worsen brain damage in premature infants.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Neonatal Research
Background:
- Periventricular white matter injury is a primary cause of cerebral palsy in premature infants.
- No effective treatments currently exist for this condition.
- Previous research indicated that activating the cAMP response element-binding protein (CREB) pathway before injury is neuroprotective.
Purpose of the Study:
- To investigate if rolipram, a phosphodiesterase type IV inhibitor, administered after hypoxic-ischemia (HI) protects against white matter injury in neonatal rats.
- To evaluate the effects of post-HI rolipram treatment on CREB signaling and oligodendrocyte development.
Main Methods:
- Neonatal rats were subjected to HI on postnatal day 7 (P7).
- Rats received daily rolipram injections from P7 to P11.
- Immunohistochemical staining was performed on P11 to assess myelin basic protein, ED1, glial fibrillary acidic protein, CREB phosphorylation, and O1 expression.
Main Results:
- Rolipram treatment post-HI exacerbated periventricular white matter and deep cortical lesions.
- Increased astrogliosis and CREB phosphorylation were observed in activated microglia and astrocytes in rolipram-treated groups.
- Marked depletion of pre-oligodendrocytes was noted in the ipsilateral hemisphere, potentially due to reduced proliferation.
Conclusions:
- Rolipram treatment administered after hypoxic-ischemia does not protect against white matter injury in neonatal rat brains.
- Instead, rolipram appears to worsen hypoxic-ischemic white matter injury.
- These findings suggest that targeting CREB signaling with rolipram post-injury may be detrimental.
Abstract:
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.
