title: Neonatal anoxia leads to time dependent progression of mitochondrial linked apoptosis in rat cortex and associated long term sensorimotor deficits.
abstract: Neonatal anoxia arises due to oxygen deprivation at the time of birth and results in life long neurodevelopmental deficits and sometimes may lead to death. The present study investigated the time dependent cortical mitochondrial dysfunction linked apoptosis and related sensorimotor deficits in neonates. Neonates after 30h to birth (P2) were subjected to anoxia of two episodes (10min in each) at a time interval of 24h by passing 100% N2 into an enclosed chamber as confirmed by pulse oximetry. Sensorimotor activities like reflex latency and hanging latency were carried out 24h after last anoxic episode i.e. from P4 (day-1) and continued up to P10 (day-7). Mitochondrial dysfunction after anoxia was evident by the decrease in respiration states, respiratory control ratio (RCR), antioxidant enzyme activity but an increase in oxidative stress and lipid peroxidation and alteration in mitochondrial membrane potential (MMP) at different time points (30min, 24h and day-7). A change in expression of Bcl-2 family proteins and opening of mitochondrial transition pore (mPTP) in terms of mitochondrial swelling was observed resulting in release of cytochrome-C which further activated intrinsic (mitochondrial) pathway of apoptosis through increased expression of caspase-9/3 as confirmed by flow cytometry. In conclusion, anoxia injury leads to progressive activation of mitochondrial events leading to increase in apoptotic cell death following secondary pathological insult. Therefore, strategies in limiting mitochondrial-linked apoptosis during the secondary insult input process may be useful in treatment of long term sensorimotor deficits following anoxia.
authors.affiliation: Neurotherapeutics lab, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India.
authors.forename: Puneet K
authors.initials: PK
authors.lastname: Samaiya
authors.affiliation: Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Gopeshwar
authors.initials: G
authors.lastname: Narayan
authors.affiliation: Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Neurotherapeutics lab, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India. Electronic address: saibliss@hotmail.com.
authors.forename: Sairam
authors.initials: S
authors.lastname: Krishnamurthy
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017302:Annexins / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002540:Cerebral Cortex / Q000473:pathology / Q000648:ultrastructure*; D004195:Disease Models, Animal; D005260:Female; D020233:Gait Disorders, Neurologic / Q000209:etiology*; D000860:Hypoxia / Q000150:complications* / Q000473:pathology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D053580:Muscle Strength / Q000502:physiology; D009573:Nitrites / Q000378:metabolism; D001678:Organelle Biogenesis; D010101:Oxygen Consumption; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D012018:Reflex / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D017302:Annexins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009573:Nitrites; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D020169:Caspases
keywords: Anoxia; Apoptosis; Flow cytometry; Mitochondrial respiration; Neurobehavioral changes; Respiratory control ratio