ROLIPRAM TREATMENT EXACERBATES PERIVENTRICULAR WHITE MATTER LESIONS IN RAT PUPS

Objectives: No specific therapy exists for periventricular leukomalacia (PVL), a principle form of brain injury in premature infants. Diffuse injury to the developing oligodendrocytes with subsequent hypomyelination is the major neuropathological features of PVL. Cyclic adenosine monophosphate (cAMP) is important in regulating oligodendrocyte proliferation and maturation. The study tested the hypothesis that rolipram, a type IV phosphodiesterase antagonist, treatment leading to cAMP accumulation, could protect against PVL.

Methods: Rat pups were subjected to hypoxic-ischemia (HI) (right carotid artery ligation plus 1-hr 6% O2 hypoxia) on P7. They received daily injection of rolipram (0.5- or 1- mg/kg, i.p.) or vehicle for 5 days, commencing immediately after HI. Immunohistochemical analysis was performed on P11.

Results: Moderate HI induced regional injury in the ipsilateral periventricular and subcortical white matter. All vehicletreated rats showed moderate decreases of myelin basic protein (MBP) immunostaining in the ipsilateral periventricular and subcortical white matter compared with that in the contralateral hemisphere. The rolipram-treated groups had significantly less MBP immunoreactivities in the ipsilateral periventricular areas than the vehicle-treated group (p<0.05). No dose-related effect in white matter lesion was found among the rolipramtreated groups. Within the ipsilateral deep cortical layer, HE stain showed 82% of the vehicle-treated group had scattered eosinophilic neurons, while 78% of the rolipramtreated groups had more extensive eosinophilic neurons. Propidium-iodide staining revealed prominent dying cells with condensed nuclei in the deep cortical layer and periventricular white matter in the rolipram-treated groups. The rolipram-treated groups had a significantly larger right lateral ventricle than the vehicle-treated rats (p<0.05). Glial-fibrillary-acidic protein reactivity was also significantly increased in the rolipramtreated groups.

Conclusion: Moderate HI brain injury in rat pups resulted in selective white matter injury. Rolipram treatment exacerbated the white matter and deep cortical neuronal lesions.