Delayed ALK5 inhibition improves functional recovery in neonatal brain injury

Neuroinflammation subsequent to developmental brain injury contributes to a wave of secondary neurodegeneration and to reactive astrogliosis that can inhibit oligodendrocyte progenitor differentiation and subsequent myelination. Here we evaluated the therapeutic efficacy of a small molecule antagonist for a TGFß receptor in a model of moderate perinatal hypoxia-ischemia (H-I). Osmotic pumps containing SB505124, an antagonist of the type 1 TGFß1 receptor ALK5, or vehicle, were implanted three days after H-I induced at postnatal day 6. Perinatal H-I induced selective neuronal death, ventriculomegaly, elevated CNS levels of IL-6 and IL-1α, astrogliosis, and fewer proliferating oligodendrocyte progenitors. Myelination was reduced by ∼50%. Anterograde tracing revealed extensive axonal loss in the corticospinal tract. These alterations correlated with functional impairments across a battery of behavioral tests. All of these parameters were brought back towards normal levels with SB505124 treatment. Notably, SB505124 preserved neurons in the hippocampus and thalamus. Our results indicate that inhibiting ALK5 signaling, even as late as three days after injury, creates an environment that is more permissive for oligodendrocyte maturation and myelination producing significant improvements in neurological outcome. This new therapeutic would be especially appropriate for moderately preterm asphyxiated infants, for whom there is presently no FDA approved neuroprotective therapeutic.

Abstract TP43: Transient Global Brain Ischemia Induces Striatal Neuronal Death of T1-Hyperintensity without Hemorrhage: Susceptibility-Weighted Imaging Study on Cardiac Arrest Survivors

Background: Global brain ischemia-reperfusion leads to selective neuronal death in the hippocampal CA1 area, cerebellar cortex, dorsolateral striatum, and/or neocortical layers 3, 5, and 6 in animal models and in humans. We have reported a delayed neurodegeneration of late-onset neuroimaging change in such brain areas vulnerable to ischemia (Stroke.1994;25:2091-95., Stroke.1999;30:1038-42., Stroke.1999;30:1043-46., Cerebrovasc Dis.2000;10:2-7., Ann Neurol.2003;54:732-7.). The magnetic resonance imaging (MRI) studies on patients after cardiac arrest showed 1) bilateral neurodegeneration with hyperintensity on T1-weighted MRI in the striatum, thalamus, and/or substantia nigra (Stroke.1994;25:2091-5., Neuroradiology.1994;36:605-7.), and 2) specific hippocampal atrophy in the chronic stage (MRI volumetry) (Cerebrovascular Dis.2000;10:2-7.). In the current study with susceptibility-weighted MRI (SWI), we investigated if the delayed T1-hyperintensity in the dorsolateral striatum consistently observed in cardiac arrest survivors represents minor hemorrhage (methemoglobin) or signifies selective neuronal death without bleeding reported as a specific type of ischemic neurodegeneration (Ann Neurol.2003;54:732-47.). Methods: We studied 11 patients in a vegetative state after unexpected out-of-hospital cardiac arrest who were able to undergo multiple brain MRI. We performed SWI to evaluate if the late-onset striatal T1-hyperintensity represents iron accumulation derived from hemoglobin degradation products or not. Results: In the 11 patients, serial MR images demonstrated delayed T1-hyperintesity in the bilateral striatum from one to two weeks after the onset. The SWI study showed no hypointense change in the striatal T1-hyperintensity. Conclusion: The striatal T1-hyperintensity after cardiac arrest seems to correspond to selective neuronal death and glial proliferation with paramagnetic effects but not hemoglobin degradation due to erythrocyte-extravasation.

Amelioration of Hippocampal Neuronal Damage after Transient Forebrain Ischemia in Cyclooxygenase-2—Deficient Mice*

Several studies have suggested that cyclooxygenase-2 (COX-2) plays a role in ischemic neuronal death. Genetic disruption of COX-2 has been shown to reduce susceptibility to focal ischemic injury and N-methyl-D-aspartate-mediated neurotoxicity. The purpose of this study was to examine the effects of COX-2 deficiency on neuronal vulnerability after transient forebrain ischemia. Marked upregulation of COX-2 immunostaining in neurons was observed at the early stage and prominent COX-2 staining persisted in the CA1 medial sector and CA2 sector over 3 days after ischemia. The immunohistologic pattern of COX-2 staining in these sectors gradually condensed to a perinuclear location. The degree of hippocampal neuronal injury produced by global ischemia in COX-2–deficient mice was less than that in wild-type mice, coincident with attenuation of DNA fragmentation in the hippocampus. Also, treatment with a selective COX-2 inhibitor, nimesulide, after ischemia decreased hippocampal neuronal damages. These results of genetic disruption and chemical inhibition of cyclooxygenase-2 show that inhibition of COX-2 ameliorates selective neuronal death after transient forebrain ischemia in mice.