Delayed ALK5 inhibition improves functional recovery in neonatal brain injury

Abstract

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-1a, 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.

Age-Dependent Effects of ALK5 Inhibition and Mechanism of Neuroprotection in Neonatal Hypoxic-Ischemic Brain Injury

“…In an earlier study we showed that volumes of ipsilateral hippocampi were significantly preserved in SB505124-treated HI pups comparted to vehicle-treated HI pups when the injury was induced at P6 [11]. To determine whether the observed structural preservation translated to retained hippocampal function and whether the neuroprotection was long-lived, we tested HI injured rats in the Morris water maze task at two months of age to assess spatial learning and memory (Fig.…”

“…Cerebral HI in 6-day-old rat pups (P6, day of birth = P0; mean body mass = 15g) as a model of late pre-term injury was performed as previously described [9, 11]. Briefly, rats were anesthetized with isoflurane (3–4% induction, 1–2% maintenance) prior to right common carotid artery cauterization.…”

“…The 1007D model osmotic pump can continuously deliver solutions for 7 days and was left implanted until animal euthanization, or removed 10 days following implantation. Animals subjected to behavioral testing and volumetric analyses were treated with SB505124 for 7 days, following the same dosing schedule as in our previous study [11]. Animals used for Western blot and immunofluorescence analyses were treated with SB505124 for 4 days.…”

“…Three weeks following HI injury, rats were subjected to a comprehensive battery of sensorimotor function tests aggregated into a modified neurological severity score (mNSS) as described in detail previously [11]. Tests were conducted by an investigator blinded to the experimental groups.…”

“…In the CNS, TGF-β1 has been shown to modulate microgliosis and astrogliosis [10]. Most recently, we showed that inhibiting the type I TGFβ receptor, activin-like kinase 5 (ALK5) using the small molecule SB505124 significantly improved neurological outcome, even when administered as late as 3 days after injury in a rat model of perinatal HI [11]. Given the efficacy of ALK5 inhibition in preterm injury, we sought to validate this therapeutic for use in a near-term infant model as a standalone drug and as combinatorial therapy with hypothermia.…”