2,4 Dinitrophenol Attenuates Mitochondrial Dysfunction and Improves Neurobehavioral Outcomes Postanoxia in Neonatal Rats.

Following anoxia, a rapid and marked mitochondrial-linked cell death occurs in the cerebral cortex of newborn rats which leads to insult advancement within a couple of days and causes lifelong neurobehavioral abnormalities. The present study investigated the role of 2,4 dinitrophenol (2,4 DNP) in three doses, i.e.,1, 2.5, and 5 mg/kg on anoxia-induced time-dependent mitochondrial dysfunction and associated neurobehavioral outcome using a well-established global model of anoxia. Briefly, rat pups of 30-h age (P2) were subjected to two episodes of anoxia (10 min each) at 24 h of the time interval in an enclosed chamber supplied with 100% N and immersed in a water bath (35-37 °C) to avoid hypothermia. Results demonstrated that the uncoupler 2,4 DNP, in the dose 2.5 and 5 mg/kg injected i.p. within 5 min after second anoxic episode significantly (P < 0.05) preserved mitochondrial function on day 7 preferentially by maintaining mitochondrial membrane potential (MMP) and inhibiting mitochondrial permeability transition (MPT) pore. Further, 2,4 DNP preserved mitochondrial function by improving different states of mitochondrial respiration (s2, s3, s4, s5), respiratory control ratio (RCR), antioxidant enzyme system like superoxide dismutase (SOD) and catalase (CAT), and mitochondrial complex enzymes (I, II, IV, V) after anoxia. Furthermore, a marked decrease in the levels of expression of cytochrome C (cyt C) and pro-apoptotic (Bcl-2 family) and apoptotic (caspase-9/3) proteins was observed on day 7 indicating that the treatment with 2,4 DNP prevented mitochondrial dysfunction and further insult progression (day 1 to day 7). Moreover, 2,4 DNP decreased the apoptotic cell death on day 7 and overall improved the neurobehavioral outcomes like reflex latency and hanging latency which suggests its role in treating neonatal anoxia.