2,4 Dinitrophenol Attenuates Mitochondrial Dysfunction and Improves Neurobehavioral Outcomes Postanoxia in Neonatal Rats
Authors: Gopeshwar Narayan
Puneet K Samaiya
Sairam Krishnamurthy
Ashok Kumar
Journal: Neurotoxicity Research (2018)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: 2,4 Dinitrophenol; Animal model; Anoxia; Apoptosis; Mitochondrial function
Affiliations: Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India., Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, 221005, India., Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India., Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India. .

Abstract:  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% N2 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 &lt; 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. 

Retracted: No

PubPeer comments:
 Figure 5A. Some bands appear to be visible multiple times within the same panel, albeit sometimes in mirror image. Arrows of the same color show similarities and orientation. Image contrast slightly adjusted to bring out details. ![file] , 
 Figures 6A and 7A. * Pink arrows highlight an unexpected similarity between lanes in panels depicting Bcl-2 at day 1 in the cytoplasm vs day 7 in mitochondria. ![file] , 
 Figure 8 and 9 show flow cytometry panels that bear an unexpected resemblance to panels in an older paper by the same group, i.e. : * Debapriya Garabadu Ausaf Ahmad Sairam Krishnamurthy - Risperidone Attenuates Modified Stressu2013Re-stress Paradigm-Induced Mitochondrial Dysfunction and Apoptosis in Rats Exhibiting Post-traumatic Stress Disorder-Like Symptoms - J Mol Neurosci (2015) - DOI: 10.1007 s12031-015-0532-7 - see: https: pubpeer.com publications 9C8B8FC2B51B8E25BD3CEF905769B9 Using the same color coding as in the older Garabadu paper, here is a comparison of panels from this paper. Boxes of the same color show quadrants that look similar across different panels, while arrows show their orientation. ![file] Garabadu D et al. J Mol Neurosci (2015): Panels represent different brain regions from adult rats exposed to stressful situations, treated with risperidone. Samaiya P et al. Neurotoxicity Research (2018) (this paper): Panels represent cerebral cortex of newborn rats exposed to anoxia, treated with 2,4 Dinitrophenol. Could the authors please comment how a very different set of rats, exposed to different experiments and treated with different compounds could result in flow cytometry panels that look so similar? ,