Browsing by Author "Puneet K. Samaiya"

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2,4 Dinitrophenol Attenuates Mitochondrial Dysfunction and Improves Neurobehavioral Outcomes Postanoxia in Neonatal Rats
(Springer New York LLC, 2018) Puneet K. Samaiya; Gopeshwar Narayan; Ashok Kumar; Sairam Krishnamurthy
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 < 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. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.
Elevated levels of caspase-3 in cerebrospinal fluid of newborns with perinatal asphyxia: A biomarker of failing mitochondrial bioenergetics
(Nova Science Publishers, Inc., 2022) Puneet K. Samaiya; Ashok Kumar; Sairam Krishnamurthy
Mitochondria act as metabolic hubs within the cell, which are essential for energy production to fulfill the bioenergetic and biosynthetic demands of the developing brain. Failing mitochondrial bioenergetics can play a central role in neuronal cell death in pathological conditions like perinatal asphyxia (PA), which can be associated with insult progression over days and the development of a more severe condition hypoxic-ischemic encephalopathy (HIE) in the neonates. Therefore, to evaluate the role of mitochondrial bioenergetics in PA/HIE, we estimated apoptotic markers like caspase-3 in cerebrospinal fluid (CSF) of newborns with asphyxia (n = 42) and control (n =17) at birth. Apgar scores < 7 at 5 min were considered as asphyxic. Further, through sarnat scoring, the asphyxic neonates were divided into different stages of HIE. CSF sample was collected as sample-1 on day-1 and sample-2 on day-7 after asphyxia. We observed a significant (p < 0.05) increase in the levels of caspase-3 in the HIE stage (s)-III compared to s-II and s-I and a marked increase in the control group in sample-1. Further, the levels of caspase-3 were markedly elevated in HIE s-III compared to s-II and s-I in sample-2, which depicts the persistence of neuronal insult. The increased levels of caspase-3 in the CSF of neonates with different stages of HIE after asphyxia indicate activation of apoptosis in the developing brain of neonates, which can lead to neurological abnormalities in the later stage of life. © 2022 Nova Science Publishers, Inc.
Mitochondrial dysfunction in perinatal asphyxia: role in pathogenesis and potential therapeutic interventions
(Springer, 2021) Puneet K. Samaiya; Sairam Krishnamurthy; Ashok Kumar
Perinatal asphyxia (PA)-induced brain injury may present as hypoxic-ischemic encephalopathy in the neonatal period, and long-term sequelae such as spastic motor deficits, intellectual disability, seizure disorders and learning disabilities. The brain injury is secondary to both the hypoxic-ischemic event and oxygenation–reperfusion following resuscitation. Following PA, a time-dependent progression of neuronal insult takes place in terms of transition of cell death from necrosis to apoptosis. This transition is the result of time-dependent progression of pathomechanisms which involve excitotoxicity, oxidative stress, and ultimately mitochondrial dysfunction in developing brain. More precisely mitochondrial respiration is suppressed and calcium signalling is dysregulated. Consequently, Bax-dependent mitochondrial permeabilization occurs leading to release of cytochrome c and activation of caspases leading to transition of cell death in developing brain. The therapeutic window lies within this transition process. At present, therapeutic hypothermia (TH) is the only clinical treatment available for treating moderate as well as severe asphyxia in new-born as it attenuates secondary loss of high-energy phosphates (ATP) (Solevåg et al. in Free Radic Biol Med 142:113–122, 2019; Gunn et al. in Pediatr Res 81:202–209, 2017), improving both short- and long-term outcomes. Mitoprotective therapies can offer a new avenue of intervention alone or in combination with therapeutic hypothermia for babies with birth asphyxia. This review will explore these mitochondrial pathways, and finally will summarize past and current efforts in targeting these pathways after PA, as a means of identifying new avenues of therapeutic intervention. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Tempol (4 hydroxy-tempo) inhibits anoxia-induced progression of mitochondrial dysfunction and associated neurobehavioral impairment in neonatal rats
(Elsevier B.V., 2017) Puneet K. Samaiya; Gopeshwar Narayan; Ashok Kumar; Sairam Krishnamurthy
Background Anoxia leads to a robust generation of reactive oxygen species/nitrogen species which can result in mitochondrial dysfunction and associated cell death in the cerebral cortex of neonates. Aim The present study investigated the pharmacological role of tempol in the treatment of rat neonatal cortical mitochondrial dysfunction induced insult progression (day-1 to day-7) and associated neurobehavioral alterations post-anoxia. Methods Rat pups of 30 h age or postnatal day 2 (PND2) were randomly divided into 5 groups (n = 5 per group): (1) Control; (2) Anoxia; (3) Anoxia + Tempol 75 mg/kg; (4) Anoxia + Tempol 150 mg/kg; and (5) Anoxia + Tempol 300 mg/kg, and subjected to two episode of anoxia (10 min each) at 24 h of time interval in an enclosed chamber supplied with 100% N2. Results Tempol significantly decreased nitric oxide ([rad]NO) formation and simultaneously improved superoxide dismutase (SOD) and catalase (CAT) activities. Further, we observed a significantly (P < 0.05) improvement in mitochondrial respiration, complex enzyme activities, mitochondrial membrane potential (MMP) along with attenuation of transition pore opening (MPT) after treatment with tempol. Furthermore, tempol decreased expression of mitochondrial Bax, cytochrome-C, caspase-9 and caspase-3 while the increase in expression of cytoplasmic Bax, mitochondrial Bcl-2 on day-7 in cortical region indicating regulation of intrinsic pathway of apoptosis. Further, it improved anoxia-induced neurobehavioral outcome (hanging and reflex latencies). Conclusion Biochemical, molecular and behavioral studies suggest the role of tempol in preserving mitochondrial function and associated neurobehavioral outcomes after neonatal anoxia. © 2017 Elsevier B.V.