Recent developments on the role of mitochondria in poly(ADP-ribose) polymerase inhibition.

Numerous pathophysiological disorders involve some element of oxidative stress and bioenergetic deficit. Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been used recently as a promising new therapeutic strategy aimed at halting the bioenergetic decline associated with oxidative brain insults and other conditions. PARP-1 uses NAD+ as a substrate and is activated during stressful circumstances, mainly in the nucleus.

Nicotinamide offers multiple protective mechanisms in stroke as a precursor for NAD+, as a PARP inhibitor and by partial restoration of mitochondrial function.

The purpose of the current study was to investigate aspects of improved bioenergetic function using nicotinamide during stroke. Using a global ischemia-reperfusion mouse model, ATP was depleted by 50% in the brain. The use of nicotinamide to provide a large reserve of brain NAD+ restored ATP levels to 61% of control levels.

Alterations in brain glutathione homeostasis induced by the nerve gas soman.

Public awareness of the dangers of chemical and biological warfare has been heightened in recent times. In particular, chemical nerve agents such as soman and its analogs have been developed and used in war as well as recent incidents, such as in Iraq and Japan. Soman, a rapid acting acetylcholinesterase inhibitor, produces a status epilepticus that leads to extensive neuropathology in vulnerable brain regions (eg, piriform cortex and hippocampus).

The effects of nicotinamide on energy metabolism following transient focal cerebral ischemia in Wistar rats.

This study examined the effects of nicotinamide on adenosine triphosphate (ATP) and nicotinamide adenine (NAD) levels and poly(adenosine diphosphate-ribose) (poly(ADP-ribose)) polymerase activity following ischemia and reperfusion in ketamine pretreated rats. Nicotinamide was administered at the end of the ischemic period. Nicotinamide protected against the depletion of ATP and NAD at 6 and 24 h of reperfusion.

Medicinal chemistry of nicotinamide in the treatment of ischemia and reperfusion.

Nicotinamide can facilitate DNA repair by inhibiting poly(ADP-ribose) polymerase, increasing NAD levels and adjusting other related enzyme activities. This review will summarize recent work on the design of poly(ADP-ribose) polymerase inhibitors, poly(ADP-ribose) glycohydrolase inhibitors and will discuss the possible use of drugs that interact with NAD synthetic enzymes.

Nicotinamide therapy protects against both necrosis and apoptosis in a stroke model.

Background And Purpose: Nicotinamide protects against brain damage in ischemia-reperfusion. However, the dosage and time of treatment require clarification. It is also not clear if nicotinamide can protect against both necrosis and apoptosis.

Nicotinamide and ketamine reduce infarct volume and DNA fragmentation in rats after brain ischemia and reperfusion.

The possible ability of nicotinamide and ketamine to decrease infarction volume and DNA fragmentation was investigated in a middle cerebral artery occlusion rat model. DNA fragmentation was measured with an enzyme linked immunoassay. Control infarct volume was 223.

Brain oxidative stress--analytical chemistry and thermodynamics of glutathione and NADPH.

Oxidative stress occurs in the brain due to stroke, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, trauma, aging and other conditions. Analysis of the effects of oxidative stress can involve quantitation of brain GSH, GSSG, NADPH and NADP. Reliable and rapid assays have been developed for these compounds and will be presented in detail.

Parkinson's disease--redox mechanisms.

Parkinson's disease occurs in 1% of people over the age of 65 when about 60% of the dopaminergic neurons in the substantia nigra of the midbrain are lost. Dopaminergic neurons appear to die by a process of apoptosis that is induced by oxidative stress. Oxygen radicals abstract hydrogen from DNA forming DNA radicals that lead to DNA fragmentation, activation of DNA protective mechanisms, NAD depletion and apoptosis.

Oxidative changes in brain pyridine nucleotides and neuroprotection using nicotinamide.

Pyridine nucleotides are critical during oxidative stress due to their roles in reductive reactions and energetics. The aim of the present study was to examine pyridine nucleotide changes in six brain regions of mice after an intracerebroventricular injection of the oxidative stress inducing agent, t-butyl hydroperoxide (t-BuOOH). A secondary aim was to investigate the correlation between NAD+ levels and DNA fragmentation.

Tyrosine hydroxylase: mechanisms of oxygen radical formation.

A new mechanism of oxygen radical formation in dopaminergic neurons is proposed, based on the oxidative mechanism of tyrosine hydroxylase. The cofactor (6R,6S)-5,6,7,8-tetrahydrobiopterin can rearrange in solution which allows an autoxidation reaction producing O2.-, H2O2 and HO.

Increased stress response and beta-phenylethylamine in MAOB-deficient mice.

MAOA and MAOB are key iso-enzymes that degrade biogenic and dietary amines. MAOA preferentially oxidizes serotonin (5-hydroxytryptamine, or 5-HT) and norepinephrine (NE), whereas MAOB preferentially oxidizes beta-phenylethylamine (PEA). Both forms can oxidize dopamine (DA).

Increased brain NAD prevents neuronal apoptosis in vivo.

Apoptosis is a characteristic form of cell death which has been implicated in neurodegeneration. In this study we document the induction of apoptosis and DNA fragmentation in vivo by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin. MPTP selectively damages dopaminergic neurons in the substantia nigra of the midbrain.

The effects of oxidative stress on in vivo brain GSH turnover in young and mature mice.

Glutathione (GSH) synthetase activities and GSH turnover rates were examined during severe oxidative stress in the mouse brain as induced by t-butylhydroperoxide (t-BuOOH). Brain GSH synthetase activities in 8-mo-old mice in the cortex, striatum, thalamus, hippocampus, midbrain, and cerebellum were found to increase following t-BuOOH treatment. The effect of GSH synthesis on brain GSH turnover rates for 2- and 8-mo-old mice were determined after intracerebroventricular (icv) injection of [35S]cysteine.

Apoptosis and oxidative stress in the aging brain.

DNA is a primary site of damage during oxidative stress in the brain. DNA fragmentation occurs within minutes of induction of oxidative stress. This DNA fragmentation probably results from the attack of free radicals on DNA and from the activation of endonucleases.

Nicotinamide as a precursor for NAD+ prevents apoptosis in the mouse brain induced by tertiary-butylhydroperoxide.

The vitamin nicotinamide can protect against oxidative stress-induced apoptosis in the brain when used as a precursor for nicotinamide adenine dinucleotide (NAD+). The intracerebroventricular administration of tertiary-butylhydroperoxide (t-buOOH) to mice was used to simulate physiologic oxidative stress and apoptosis which may occur in some neurodegenerative conditions. t-buOOH produced characteristic apoptotic nuclear degeneration in neurons with extensive fragmentation of DNA.

Dietary α-tocopherol content modulates responses to moderate ethanol consumption.

Rats were fed with diets containing differing amounts of α-tocopherol for 21 days. For the latter 14 days of this period, one half of the rats also received ethanol (7% v/v) in the drinking water. Treatments did not alter the rate of weight gain between groups.

Age-dependent effects of t-BuOOH on glutathione disulfide reductase, glutathione peroxidase, and malondialdehyde in the brain.

Intracerebroventricular t-butyl hydroperoxide has been reported to induce damage to many types of brain cells. t-Butyl hydroperoxide administration increases glutathione disulfide levels and decreases levels of glutathione. Young adult mice may be more protected from t-butyl hydroperoxide than mature mice due to their higher glutathione levels, even after the administration of t-butyl hydroperoxide.

High-performance liquid chromatography analysis of oxidized and reduced pyridine dinucleotides in specific brain regions.

An ultrasensitive HPLC method has been developed for measuring NADP+, NADPH, NAD+, and NADH. A simple, rapid reaction of the oxidized nucleotides with cyanide in basic solution leads to two stable fluorescent products and allows all four nucleotides to be separated and quantitated on one chromatogram. Furthermore, only one extraction is needed, rather than prior procedures which require one acid extraction (for oxidized species) and one basic extraction (for reduced species).

Apoptosis and DNA fragmentation as induced by tertiary butylhydroperoxide in the brain.

In this study, the effect of intracerebroventricular administration of the free radical generator, tertiary butylhydroperoxide, on DNA, was quantitated. Previous studies had established DNA as a very important site of free radical attack. The purpose of the study was to detect whether DNA was one of the primary targets of the toxin as well as to detect any apoptosis that may have been induced by the toxin.

The neuropathology of intracerebroventricular t-butylhydroperoxide.

t-Butylhydroperoxide can be used as a model oxidative stress-inducing agent in the brain following intracerebroventricular administration. Mice were treated with saline, t-butanol, or t-butylhydroperoxide. t-Butanol is the major metabolite of t-butylhydroperoxide.

Acrolein-induced oxygen radical formation.

The mechanism of acrolein-induced lipid peroxidation is unknown. This study found that acrolein and its glutathione adduct, glutathionylpropionaldehyde, induce oxygen radical formation. These oxygen radicals may be responsible for the induction of lipid peroxidation by acrolein.

MPP+ and MPDP+ induced oxygen radical formation with mitochondrial enzymes.

MPP+ has been reported to inhibit reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase in mitochondria, which results in the formation of O2(.-). The current report demonstrates that H2O2 and HO.

Redox cycling of MPP+: evidence for a new mechanism involving hydride transfer with xanthine oxidase, aldehyde dehydrogenase, and lipoamide dehydrogenase.

MPP+ is redox active in the presence of cytochrome P450 reductase and induces the formation of O2.- and HO(.).