Abstract
Neonatal hypoxic-ischemic (HI) injury still remains an important issue as it is a major cause of neonatal death and neurological dysfunctions. Currently, there are no well-established treatments to reduce brain damage and its long-term sequel in infants. Recently, reported data show that histone deacetylase inhibitors provide neuroprotection in adult stroke models. However, the proof of their relevance in vivo after neonatal HI brain injury remains particularly limited. In the present study, we show neuroprotective/neurogenic effect of sodium butyrate (SB), one of histone deacetylase inhibitors (HDACis), in the dentate gyrus of HI-injured immature rats. Postnatal day 7 (P7) rats underwent left carotid artery ligation followed by 7.6 % O2 exposure for 1 h. SB (300 mg/kg) was administered in a 5-day regime with the first injection given immediately after the onset of HI. The damage of the ipsilateral hemisphere was evaluated by weight deficit. Newly produced cells were labeled with BrdU, at 50 mg/kg, injected twice daily for 3 consecutive days. Subsequent differentiation of the newborn cells was investigated 2 and 4 weeks after the insult by immunohistochemistry using neuronal and glial cell-lineage markers and BrdU incorporation. Finally, we performed several behavioral tests to evaluate functional outcome. In summary, SB led to a remarkable reduction of the brain damage caused by HI. Moreover, the application of this HDACi protected against HI-induced loss of neuroblasts and oligodendrocyte precursor cells, as well as against neuroinflammation. The observed neuroprotective action suggests that SB may serve as a potential candidate for future treatment of HI-evoked injury in neonates.
Highlights
Neonatal hypoxic-ischemic encephalopathy (HIE) remains one of the most important causes of neonatal mortality and long-term neurological sequelae such as cerebral palsy, mental retardation, epilepsy, and spastic paresis [1,2,3,4]
In order to evaluate the effect of sodium butyrate on brain damage caused by neonatal hypoxia-ischemia, we compared the wet weight of ipsilateral hemispheres to the contralateral ones
The present study showed that treatment with histone deacetylase inhibitor-sodium butyrate after HI provides neuroprotection
Summary
Neonatal hypoxic-ischemic encephalopathy (HIE) remains one of the most important causes of neonatal mortality and long-term neurological sequelae such as cerebral palsy, mental retardation, epilepsy, and spastic paresis [1,2,3,4]. Encephalopathy due to hypoxic-ischemic (HI) events derives from acute and unpredictable episodes of perinatal asphyxia. The interruption of blood supply to the brain leads to insufficient oxygen and glucose delivery and triggers a cascade of biochemical events including loss of energy, acidosis, excitotoxicity, elevation of intracellular calcium, induction of oxidative stress, inflammation, and apoptosis, culminating in extensive brain damage [2, 5]. Despite the significant progress in knowledge relating the mechanism(s) underlying evolving brain injury, there are no well-established effective therapies to reduce brain damage and its long-term sequel in infants. The clinical application of promising neuroprotective agents has been truly restricted due either to inefficient or adverse effects
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