TY - JOUR
T1 - Age-Dependent Effects of ALK5 Inhibition and Mechanism of Neuroprotection in Neonatal Hypoxic-Ischemic Brain Injury
AU - Kim, Brian H.
AU - Guardia Clausi, Mariano
AU - Frondelli, Michelle
AU - Nnah, Israel C.
AU - Saqcena, Chaitali
AU - Dobrowolski, Radek
AU - Levison, Steven W.
N1 - Funding Information: This work was supported by grants from the National Institutes of Health HD052064 and the Leducq Foundation awarded to S.W.L. and by The International Alzheimer's Association (NIRG-305325) and the New Jersey Commission on Brain Injury (CBIR14PIL001) awarded to R.D. The authors would like to thank Ms. Clare Ongera for assisting with the MWM experiments. Publisher Copyright: © 2017 S. Karger AG, Basel. Copyright: All rights reserved.
PY - 2017/7/1
Y1 - 2017/7/1
N2 - Neonatal encephalopathy due to hypoxic-ischemic (HI) brain injury triggers a wave of neuroinflammatory events attributed to causing the progressive degeneration and functional deficits seen weeks after the initial insult. In a recent set of studies, we evaluated the therapeutic efficacy of a small molecule antagonist for ALK5 (activin-like kinase 5), TGF-β receptor in a rat model of moderate perinatal HI and found significant improvements in neurologic outcomes. Here, we have extended those studies to evaluate the efficacy of delayed TGF-β receptor antagonism on postnatal day (P) 6 and P9 HI rat pups with and without hypothermia. The ALK5 receptor antagonist SB505124 was administered systemically by osmotic pump beginning 3 days following HI. Extending our earlier data set that showed protection of the hippocampus in P6 pups treated with SB505124, these animals sustained less damage to their hippocampi and had improved performance on the Morris water maze (MWM) when tested on P60 versus vehicle-treated HI animals. By contrast, SB505124 did not improve sensorimotor deficits and exacerbated hippocampal and thalamic volume loss when administered 3 days after HI to P9 pups. SB505124-treated rats injured on P9 tended to perform worse than their vehicle-treated counterparts on MWM, and SB505124 treatment did not preserve hippocampal or thalamic neurons in P9 pups when combined with hypothermia. To elucidate the mechanism whereby ALK5 inhibition reduced neuronal death in the P6 HI model, we assessed levels of autophagy markers in neurons of the neocortex, hippocampus, and thalamus, and in the subcortical white matter, and found that SB505124 increased numbers of autophagosomes and levels of lipidated LC3 (light chain 3), a key protein known to mediate autophagy. Altogether, our results demonstrate that there is a dynamic switch in the CNS response to TGF-β1 that occurs around P9 in rats where TGF-β signaling inhibition worsens functional outcomes. This response is similar to the outcome of antagonizing TGF-β signaling in adult stroke and other CNS disease models. We conclude that attenuating TGF-β1 signaling will likely be an effective treatment for HI-related encephalopathy in moderately preterm infants, offering protection of the neocortex, hippocampus, and thalamus with enhanced cerebral autophagy contributing to the decrease in the extent of progressive neuronal cell death.
AB - Neonatal encephalopathy due to hypoxic-ischemic (HI) brain injury triggers a wave of neuroinflammatory events attributed to causing the progressive degeneration and functional deficits seen weeks after the initial insult. In a recent set of studies, we evaluated the therapeutic efficacy of a small molecule antagonist for ALK5 (activin-like kinase 5), TGF-β receptor in a rat model of moderate perinatal HI and found significant improvements in neurologic outcomes. Here, we have extended those studies to evaluate the efficacy of delayed TGF-β receptor antagonism on postnatal day (P) 6 and P9 HI rat pups with and without hypothermia. The ALK5 receptor antagonist SB505124 was administered systemically by osmotic pump beginning 3 days following HI. Extending our earlier data set that showed protection of the hippocampus in P6 pups treated with SB505124, these animals sustained less damage to their hippocampi and had improved performance on the Morris water maze (MWM) when tested on P60 versus vehicle-treated HI animals. By contrast, SB505124 did not improve sensorimotor deficits and exacerbated hippocampal and thalamic volume loss when administered 3 days after HI to P9 pups. SB505124-treated rats injured on P9 tended to perform worse than their vehicle-treated counterparts on MWM, and SB505124 treatment did not preserve hippocampal or thalamic neurons in P9 pups when combined with hypothermia. To elucidate the mechanism whereby ALK5 inhibition reduced neuronal death in the P6 HI model, we assessed levels of autophagy markers in neurons of the neocortex, hippocampus, and thalamus, and in the subcortical white matter, and found that SB505124 increased numbers of autophagosomes and levels of lipidated LC3 (light chain 3), a key protein known to mediate autophagy. Altogether, our results demonstrate that there is a dynamic switch in the CNS response to TGF-β1 that occurs around P9 in rats where TGF-β signaling inhibition worsens functional outcomes. This response is similar to the outcome of antagonizing TGF-β signaling in adult stroke and other CNS disease models. We conclude that attenuating TGF-β1 signaling will likely be an effective treatment for HI-related encephalopathy in moderately preterm infants, offering protection of the neocortex, hippocampus, and thalamus with enhanced cerebral autophagy contributing to the decrease in the extent of progressive neuronal cell death.
KW - Autophagy
KW - Birth asphyxia
KW - Cell death
KW - Encephalopathy
KW - Neuroprotection
KW - Premature birth
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U2 - https://doi.org/10.1159/000477490
DO - https://doi.org/10.1159/000477490
M3 - Article
C2 - 28628913
SN - 0378-5866
VL - 39
SP - 338
EP - 351
JO - Developmental Neuroscience
JF - Developmental Neuroscience
IS - 1-4
ER -