Abstract
Purpose: To investigate if ellagic acid exerts neuroprotective effects in hypoxic ischemic (HI) brain injury by inhibiting apoptosis and inflammatory responses. Methods: Separate groups of rat pups from post-natal day 4 (D4) were administered with ellagic acid (10, 20 or 40 mg/kg body weight) orally till post- natal day 10 (D10). On D10, the rats were subjected to HI brain injury. Following HI injury, infarct size, weight and volume of the brain were measured. Apoptosis was assessed by Fluoro-Jade C staining. Expression of caspases (caspase-3, 8 and 9), apoptotic pathway proteins (Bax, Bad, Bcl-2 and Bcl-xL), MAPKs, NF κB(p65) and p-IK-Bα were assessed by western blotting. mRNA levels of inflammatory mediators (TNF-α, IL-1α, IL-1β, iNOS, COX-2) were analyzed. Results: Ellagic acidmarkedly (p < 0.05) reduced infarct size, volume and tissue loss. Significant (p < 0.05) reduction in neuroapoptosis was observed on pre treatment with ellagic acid. Expression levels of caspases, apoptotic pathway proteins and MAPK proteins were down-regulated with marked (p < 0.05) suppression of inflammatory mediators, NF-κB(p65) and p-IK-Bα. Conclusion: Ellagic acid affords neuroprotection in HI brain injury by inhibiting apoptosis, inflammatory responses and modulating the proteins of apoptotic and MAPK pathways. Thus, ellagic acid may be a potent candidate for the treatment of HI injury. Keywords: Brain injury, Ellagic acid, Hypoxia, Inflammatory mediators, Mitogen activated protein kinases, Neuroprotective
Highlights
Neonatal hypoxic-ischemic (HI) brain injury is a major cause of perinatal mortality and morbidity [1]
The activated Mitogen activated protein kinases (MAPKs) principally function as mediators of cellular stress by phosphorylating various transcription factors, cytosolic proteins and intracellular enzymes that are involved in cell survival, apoptosis and in expression of inflammatory mediators [7]
Studies have reported that neonatal brain cells exhibit features of apoptosis following HI insult [21].Apoptosis has been reported as a typical mechanism of cell death in the developing brain
Summary
Neonatal hypoxic-ischemic (HI) brain injury is a major cause of perinatal mortality and morbidity [1]. HI brain injury arising in neonatal and perinatal stages damages brain cell development, resulting in long-lasting neurologic sequelae with cerebral palsy, epilepsy, learning disabilities and motor disability as complications [3]. Brain injury in perinatal stage has multifaceted aetiology involving inflammation, a major cause in the progression of HI-induced injury in neonates and in adults [4]. Inflammation is involved in sensitizing the neonatal brain to ischaemia through pro-inflammatory cytokines which are found in increased levels [5]. Mitogen activated protein kinases (MAPKs) p38s, extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs) are activated in mammalian cells in response to various growth factors, cytokines and agents that cause cell damage [6]. The activated MAPKs principally function as mediators of cellular stress by phosphorylating various transcription factors, cytosolic proteins and intracellular enzymes that are involved in cell survival, apoptosis and in expression of inflammatory mediators [7]
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