Rolipram, a Phosphodiesterase Type IV Inhibitor, Exacerbates Periventricular White Matter Lesions in Rat Pups

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. N early 90% of low-birth weight infants now survive with the advances in neonatal intensive care. Of the survivors, however, 10 -15% have cerebral palsy, and 25-50% have manifest cognitive and behavioral deficits (1). Periventricular white matter injury, or leukomalacia (PVL), is the major form of brain injury in preterm babies. The neuropatholgical findings are characterized by distinct cystic white matter lesions and, commonly, a more diffuse loss of white matter volume and secondary ventriculomegaly (2). Notably, despite the significant long-term morbidity, there is currently no specific treatment for these disorders.Although, the exact cause of PVL in human infants is currently unknown, hypoxia-ischemia (HI) is believed to be a significant cause (3). Cell-type specific factors are also likely to underlie the mechanisms of PVL. Data from a recent study demonstrated that PVL in humans was related to oxidative damage that particularly targeted cells of the oligodendrocyte lineage; whereas neuronal and glial cells were markedly more resistant (4). The timing of appearance of preoligodendrocytes (preOLs) coincides with the high-risk period for PVL (5). Considerable data demonstrate that preOLs are highly susceptible to oxidative stress and hypoxic-ischemia injury (6 -9). Compared with mature oligodendrocytes, preOLs express lower levels of antioxidant enzymes (6). These data suggest that acceleration of preOLs maturation might be a feasible strategy to reduce the severity of PVL.cAMP plays an important role in inducing oligodendrocyte differentiation and myeli...

JNK signaling is the shared pathway linking neuroinflammation, blood–brain barrier disruption, and oligodendroglial apoptosis in the white matter injury of the immature brain

“…To avoid LPS-induced body temperature changes, the rat pups were returned to their dams after injection, and housed in an incubator to maintain body temperature at 33 to 34 °C before HI. HI was then induced by ligation of the right carotid artery followed by hypoxia [36]. The right common carotid artery was permanently ligated under 2.5% halothane anesthesia.…”

Baby STEPS: A Giant Leap for Cell Therapy in Neonatal Brain Injury

“…Interestingly, postnatal day 1-2 rats show more damage to the ipsilateral subcortical developing white matter than the older rats (28). That these distinct neurodevelopmental pathological manifestations resulting from HI injury are dictated by age is exemplified by the observation of localized subplate neuronal death which occurs concomitantly with increased oligodendrocyte progenitor cell proliferation following subcortical damage in young neonates (32-36). However, this limited extent of neurodegeneration and the compensatory endogenous cell repair mechanism appear to wane in older neonates when the HI insult encompasses both cortex and white matter (32-36).…”

“…That these distinct neurodevelopmental pathological manifestations resulting from HI injury are dictated by age is exemplified by the observation of localized subplate neuronal death which occurs concomitantly with increased oligodendrocyte progenitor cell proliferation following subcortical damage in young neonates (32-36). However, this limited extent of neurodegeneration and the compensatory endogenous cell repair mechanism appear to wane in older neonates when the HI insult encompasses both cortex and white matter (32-36). Accordingly, if cell therapy is initiated in HI injured rats of various postnatal ages, data interpretation should consider these dynamic levels of age-dependent neurodegeneration and neural repair.…”

Stem Cell Therapy for Neonatal Hypoxic-Ischemic Encephalopathy

“…Another important fact to note is that younger animals experience worse white matter injury than older rats (35). Therefore in HIE modeling, age is a critical factor and is further verified by a focal subcortical cell loss paired with a surge in proliferating oligodendrocyte progenitor cells following HIE in young neonates, but rather modest in older models (41–45). Age-related changes following HIE need to become standardized in order to better evaluate the therapeutic benefits of experimental treatments.…”