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.