Oxidative changes in brain pyridine nucleotides and neuroprotection using nicotinamide

Klaidman, Lori K.; Mukherjee, Suman; Adams, James D.

doi:10.1016/s0304-4165(00)00181-1

Cited by 89 publications

(75 citation statements)

References 30 publications

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“…NADPH levels within the brain are low and are not directly involved with metabolism (Chance et al, 1962;Kaplan, 1985;Klaidman et al, 2001). The depth of NADH fluorescence was confirmed in previous studies by placing a slice on a net shown to be fluorescent in ultraviolet light (Foster et al, 2005).…”

Section: Nadh Imagingmentioning

confidence: 62%

“…During periods of oxidative stress, the levels of pyridine nucleotides, including NADPH, NADP + , NADH and NAD + , determine a cell's ability to continue functioning, since the levels of pyridine nucleotides determine the balance of reductive power and ATP production rate (Klaidman et al, 2001). In an oxygen-depleted environment, a decline in NAD + levels determines the onset of cell death since NAD + is required in the production of ATP.…”

Section: Nadh Reduction and Hyperoxidationmentioning

confidence: 99%

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NADH hyperoxidation correlates with enhanced susceptibility of aged rats to hypoxia

Foster¹,

Margraf²,

Turner³

2008

Neurobiology of Aging

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Aging increases mitochondrial dysfunction and susceptibility to hypoxia. Previous reports have indicated an association between post-hypoxic hyperoxidation of intra-mitochondrial enzymes and delayed neuronal injury. Therefore we investigated the relationship between NADH fluorescence and neuronal function during and after hypoxia across the lifespan. Hippocampal slices were prepared from adult (1 to >22 months) F344 rats. NADH fluorescence, extracellular voltage and tissue PO 2 were recorded from the CA1 region during hypoxia (95% N 2 ) of various lengths following onset of hypoxic spreading depression (hsd). Slices from younger rats recovered evoked neuronal responses to a greater degree and exhibited less hyperoxidation after a hypoxic episode, than slices from older rats. However, the use of Ca 2+ free-media in slices from >22 month old rats improved recovery and delayed NADH hyperoxidation (2.5 min hypoxia after hsd). Post-hypoxic decrease of NADH fluorescence (hyperoxidation) was age dependent and correlated with decreased neuronal recovery. Slices exposed to repeated hypoxic episodes yielded data suggesting depletion of the NAD + pool, which may have contributed to the deterioration of neuronal function.

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Section: Nadh Imagingmentioning

confidence: 62%

Section: Nadh Reduction and Hyperoxidationmentioning

confidence: 99%

NADH hyperoxidation correlates with enhanced susceptibility of aged rats to hypoxia

Foster¹,

Margraf²,

Turner³

2008

Neurobiology of Aging

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“…This disequilibrium implies that the glutathione pool rapidly cycles in the cell and that glutathione reductase exerts considerable control over the thiol redox potential. There is evidence that glutathione reductase is limited by the low GSSG concentration in the cell; thus, oxidation of the GSH pool by t-butyl hydroperoxide leads to a rapid and selective oxidation of NADPH both in cultured cells (47) and in vivo (48). Although it is intuitive that reductions in the GSH pool will exacerbate the rate limitation due to glutathione reductase, the distinctive thermodynamics of the glutathione couple, where two GSH molecules condense upon oxidation to form GSSG, mean that the midpoint potential becomes progressively more oxidized as the pool decreases.…”

Section: Discussionmentioning

confidence: 99%

Acute Glutathione Depletion Restricts Mitochondrial ATP Export in Cerebellar Granule Neurons

Vesce

Jekabsons

Johnson-Cadwell

et al. 2005

Journal of Biological Chemistry

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Decreases in GSH pools detected during ischemia sensitize neurons to excitotoxic damage. Thermodynamic analysis predicts that partial GSH depletion will cause an oxidative shift in the thiol redox potential. To investigate the acute bioenergetic consequences, neurons were exposed to monochlorobimane (mBCl), which depletes GSH by forming a fluorescent conjugate. Neurons transfected with redox-sensitive green fluorescent protein showed a positive shift in thiol redox potential synchronous with the formation of the conjugate. Mitochondria within neurons treated with mBCl for 1 h failed to hyperpolarize upon addition of oligomycin to inhibit their ATP synthesis. A decreased ATP turnover was confirmed by monitoring neuronal oxygen consumption in parallel with mitochondrial membrane potential (⌬ m ) and GSH-mBCl formation. mBCl progressively decreased cell respiration, with no effect on mitochondrial proton leak or maximal respiratory capacity, suggesting adequate glycolysis and a functional electron transport chain. This approach to "state 4" could be mimicked by the adenine nucleotide translocator inhibitor bongkrekic acid, which did not further decrease respiration when administered after mBCl. The cellular ATP/ADP ratio was decreased by mBCl, and consistent with mitochondrial ATP export failure, respiration could not respond to an increased cytoplasmic ATP demand by plasma membrane Na ؉ cycling; instead, mitochondria depolarized. More prolonged mBCl exposure induced mitochondrial failure, with ⌬ m collapse followed by cytoplasmic Ca 2؉ deregulation. The initial bioenergetic consequence of neuronal GSH depletion in this model is thus an inhibition of ATP export, which precedes other forms of mitochondrial dysfunction.A balance between the formation of reactive oxygen species, as normal byproducts of mitochondrial respiration (1), and the actions of antioxidants prevents oxidative stress and is crucial to neuronal survival (2). Together with the overactivation of glutamate receptors (excitotoxicity), oxidative stress is a result of the bioenergetic crisis that characterizes ischemia and plays a central role in the pathophysiology of the consequent neuronal damage (3). Neurons are particularly sensitive to oxidative damage and can be strongly sensitized to other injurious stimuli by levels of oxidative stress that are nontoxic per se (4). Similarly, Ca 2ϩ homeostasis is lost more quickly in cerebellar granule neurons (CGNs), 2 which show higher superoxide levels prior to the application of toxic concentrations of glutamate (5).The tripeptide glutathione is a key antioxidant that maintains protein thiols in a reduced state and scavenges H 2 O 2 in a reaction catalyzed by glutathione peroxidase (6, 7). In vivo, mitochondrial glutathione is partially lost during ischemia (8), and its supplementation in the form of glutathione ethyl ester can reduce the infarct size (9). Although mitochondria within cells deprived of GSH can eventually release cytochrome c and undergo opening of the permeability transition pore (PTP) (10...

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“…Nicotinamide is the precursor for the coenzyme β-nicotinamide adenine dinucleotide (NAD + ) and is considered to be an essential nutrient for cell growth and function (for review, see [26]). Recently, nicotinamide has been reported to exert a number of pharmacological effects including prevention of ATP depletion [22,24,42], inhibition of poly(ADP-ribose) polymerase (PARP) [22,23,42] and lipid peroxidation [10,23,29], antiinflammatory activity [40] and prevention of apoptosis [24,29]. In adult rats nicotinamide protects against both early necrotic cell death in the core and delayed apoptosis like cell death in the penumbra in stroke models [41].…”

Section: Introductionmentioning

confidence: 99%

“…Nicotinamide directly modulates mitochondrial membrane potential and pore formation to prevent cytochrome c release and caspase-3 and caspase-9 like activities [10]. In adult animals nicotinamide protects against free radical injury to the brain [10,23,29]. Oxidants and free radicals can initiate apoptosis by stimulating mitochondrial pore formation [35].…”

Section: Introductionmentioning

confidence: 99%

Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat

Feng¹,

Paul²,

LeBlanc³

2006

Brain Research Bulletin

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Nicotinamide reduces ischemic brain injury in adult rats. Can similar brain protection be seen in newborn animals? Seven-day-old rat pups had the right carotid artery permanently ligated followed by 2.5 h of 8% oxygen. Nicotinamide 250 or 500 mg/kg was administered i.p. 5 min after reoxygenation, with a second dose given at 6 h after the first. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Nicotinamide 500 mg/kg reduced brain weight loss from 24.6 ± 3.6% in vehicle pups (n = 28) to 11.9 ± 2.6% in the treated pups (n = 29, P < 0.01), but treatment with 250 mg/kg did not affect brain weight. Nicotinamide 500 mg/kg also improved behavior in rotarod performance. Levels of 8-isoprostaglandin F 2α measured in the cortex by enzyme immune assay 16 h after reoxygenation was 115 ± 7 pg/g in the shams (n = 6), 175 ± 17 pg/g in the 500 mg/kg nicotinamide treated (n = 7), and 320 ± 79 pg/g in the vehicle treated pups (n = 7, P < 0.05 versus sham, P < 0.05 versus nicotinamide). Nicotinamide reduced the increase in caspase-3 activity caused by hypoxic ischemia (P < 0.01). Nicotinamide reduces brain injury in the neonatal rat, possibly by reducing oxidative stress and caspase-3 activity.

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Oxidative changes in brain pyridine nucleotides and neuroprotection using nicotinamide

Cited by 89 publications

References 30 publications

NADH hyperoxidation correlates with enhanced susceptibility of aged rats to hypoxia

NADH hyperoxidation correlates with enhanced susceptibility of aged rats to hypoxia

Acute Glutathione Depletion Restricts Mitochondrial ATP Export in Cerebellar Granule Neurons

Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat

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