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The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is a key component of molecular mechanisms leading to cell death or survival after an ischemic insult. Oxidative stress damages DNA, and breaks in the DNA strands activate PARP enzyme, leading to poly(ADP-ribosyl)ation of nuclear proteins. In this study, we investigated PARP activation using immunodetection of PAR polymers in the brain of neonatal rat pups subjected to unilateral focal ischemia with reperfusion. PARP activation was detected in the ischemic core between 2 and 18 h, and in the penumbra between 24 and 48 h in the middle cerebral artery (MCA) territory but also in territories of the anterior and posterior cerebral artery, and in white matter tracts. The intranuclear accumulation of PAR in cells preceded a positive terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling, suggesting that PARP activation may actually contribute to delayed cell death. Pretreatment with 3-aminobenzamide (3-AB, 10 mg/kg) strongly reduced PARP activation and cell death. These data suggest that PARP activation represents, in the immature brain, the early sign of ischemic cell death. This raises the possibility of the use of PARP inhibitors not only immediately postischemia but perhaps also later to reduce ischemic lesion in the MCA territory and its connected structures.

Poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30) is known as a nuclear enzyme that is activated by DNA strand breaks to participate in DNA repair. It is also called poly(ADP-ribose) synthase (PARS) or poly(ADP-ribose) transferase (PADRT). In physiological conditions, PARP plays an important role in maintaining genomic stability. However, for several pathological situations, which include massive DNA injury (brain ischemia for example), excessive activation of PARP can deplete stores of nicotinamide adenine dinucleotide (NAD+), the PARP substrate, which, with the subsequent ATP depletion, leads to cell death. PARP activation appears to play a major role in neuronal death induced by cerebral ischemia, traumatic brain injury, Parkinson disease and other pathologies. PARP inhibitors (3-aminobenzamide and other compounds) and PARP gene deletion induced dramatic neuroprotection in experimental animals (rats, mice). Accordingly, these data suggest that PARP inhibitors could provide a novel therapeutic approach in a wide range of neurodegenerative disorders including cerebral ischemia and traumatic brain injury.

Most pharmacologic studies on brain trauma in animals are performed while the animals are under general anesthesia, which can interfere with brain metabolism and modify the experimental results. This study investigates the effects of three anesthetic drugs (halothane 2% and 4%, propofol at 10 mg/kg, and chloral hydrate at 400 mg/kg) on the traumatic brain injury-induced neurologic deficit in mice. Trauma was induced with a weight-drop device. For each drug, animals were divided into four groups; the first did not receive either anesthesia or trauma, the second received anesthesia but no trauma, the third received a trauma without anesthesia, and the fourth received anesthesia before the trauma. A neurologic examination using two different scorings (string and grip test) was performed 1 hour and 24 hours after the trauma. Mortality after trauma was increased for halothane 4% (48% versus 20% in unanesthetized mice), propofol (80% versus 30%), and chloral hydrate (70% versus 44%). Halothane 2% did not increase the mortality in traumatized mice. Halothane 2% or 4% anesthesia did not modify the string score after the trauma. Grip score after the trauma was better in mice anesthetized with halothane at either 2% or 4%. Mice injured under anesthesia with chloral hydrate had worse grip and string scores (P < .05) than unanesthetized mice. These results lead us to question the influence of anesthesia on the results obtained in experimental neuropharmacologic studies, particularly when there are discrepancies between two studies on the same pharmacologic treatment, which differ in their anesthesia protocols.

Nitric oxide (NO) is a recently discovered endogenous molecule considered as an unconventional biological messenger. Experimental evidence indicates that, in the brain, NO is produced enzymatically (calcium-dependent mechanism) in response to stimulation of postsynaptic excitatory amino cid receptors. NO activates soluble guanylate cyclase, that results in increases of cGMP levels in target cells. NO is physiologically involved in synaptic plasticity mechanisms. In situation of excessive production, NO can exert neurotoxic effects, suggesting a role in neurodegenerative disorders, including post-ischemic damage.