A nitric oxide donor reduces brain injury and enhances recovery of cerebral blood flow after hypoxia-ischemia in the newborn rat

Abstract

Nitric oxide (NO) released in response to hypoxia-ischemia (HI) in the newborn brain may mediate both protective and pathologic responses. We sought to determine whether pharmacologic increase of NO using an NO donor would reduce neurologic injury resulting from HI in the postnatal day 7 rat. We measured NO levels and CBF in the presence of either a NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME) or an NO donor (. Both inhibition of NOS and administration of an NO donor reduced neuropathologic injury after 7-day recovery. NO levels decreased in both ischemic and contralateral hemispheres during HI. This response was prevented by treatment with DETANONOate. Despite the decrease in NO, CBF increased during ischemia in the contralateral hemisphere but decreased when combined with brief hypoxia. Treatment with L-NAME abolished these increases, which were not altered by DETANONOate. Reduction of cellular metabolism by mild hypothermia also reduced both NO and CBF. Following prolonged HI, CBF remained decreased in the ischemic hemisphere up to 24-hour recovery. This decrease was prevented by treatment with DETANONOate. These data show that administration of an NO donor reduces neurologic injury following HI in the newborn rat. This mechanism of this protection, in part, is due to an increase in the rate of recovery of CBF compared to vehicle-treated animals. Augmentation of NO-dependent increases in CBF may serve to improve neurologic outcome after perinatal asphyxia.

Neurogenesis and neuronal commitment following ischemia in a new mouse model for neonatal stroke

“…Also establishment of efficient collateral circulation after the initial edema of the excitotoxic injury subsides is akin to human stroke conditions. Similar trends have been reported (Wainwright et al, 2007) after quantification of cerebral blood flow (CBF) using laser doppler after an HI insult in rat pups induced by permanent unilateral carotid ligation and 70 min of hypoxia. CBF in the ipsilateral hemispheres showed a gradual improvement in the first 12 h after the insult that was associated with increased CBF levels on the contralateral side and at 7 days there was no difference between the ischemic and contralateral hemispheres.…”

Pathophysiological role of inflammatory molecules in paediatric ischaemic brain injury

“…As the majority of basic research studies have been focused on inflammation in perinatal HI model, a stronger scientific effort should be N-acetylcysteine Oxygen radical scavenger Reduction in cerebral oxidative stress and cerebral injury; improvement in myelin expression and neurological outcome in neonatal rats (combined with hypothermia) (HI model) [83] Melatonin Oxygen radical scavenger Reduction in white matter damage and promotion of repair by induction of axonal regrowth or sprouting in newborn mice (ibotenate-mediated excitotoxic brain injury) [84] Decrease in oxidative damage mediators in 7-day-old rats (HI model) [85] 2-iminobiotin Selective nNOS and iNOS inhibitor Improvement in cerebral energy state, reduction in vasogenic oedema and neuronal death (HI model) [60] 7-nitroindazole Selective nNOS inhibitor Suppression of both two peaks of NO metabolites (during hypoxia and during the re-oxygenation period) (HI model) [82] Aminoguanidine Selective iNOS inhibitor Suppression only the NO metabolites peak in the re-oxygenation period. Reduction in cerebral injury in a neonatal rats (HI model) [61,62] DETANONOate (Z)-1-[N-(2-amino-ethyl)-N-(2-ammonio-ethyl)amino] diazen-1-ium-1,2-diolate NO donor Reduction in neuropathologic injury score in newborn rats (HI model) [79] Hypothermia Nonselective anti-inflammatory effects Improvement in survival and neurologic outcomes in human neonates [89][90][91] More benefit in combined pharmacological hypothermia treatment (HI model) [92,93] Simvastatin Nonselective antioxidant and anti-inflammatory effects Reduction in cerebral damage in neonatal rats (HI model) [94] *HI, Hypoxia-ischaemia.…”

DETA/NONOate, a nitric oxide donor, produces antidepressant effects by promoting hippocampal neurogenesis

“…Sildenafil, a drug that improves cerebral blood flow, induces neurogenesis after stroke . Administration of DETA/NONOate increases the rate of recovery of cerebral blood flow following hypoxia-ischemia in the newborn rat, thus reducing neurologic injury (Wainwright et al 2007). Moreover, DETA/NONOate significantly increases expression of angiopoietin Ang1/Tie2, which plays a role in regulating angiogenesis and vascular integrity after stroke .…”