Nitric Oxide Synthase Inhibition as a Neuroprotective Strategy Following Hypoxic–Ischemic Encephalopathy: Evidence From Animal Studies

Abstract

BackgroundHypoxic–ischemic encephalopathy following perinatal asphyxia is a leading cause of neonatal death and disability worldwide. Treatment with therapeutic hypothermia reduced adverse outcomes from 60 to 45%. Additional strategies are urgently needed to further improve the outcome for these neonates. Inhibition of nitric oxide synthase (NOS) is a potential neuroprotective target. This article reviews the evidence of neuroprotection by nitric oxide (NO) synthesis inhibition in animal models.MethodsLiterature search using the EMBASE, Medline, Cochrane, and PubMed databases. Studies comparing NOS inhibition to placebo, with neuroprotective outcome measures, in relevant animal models were included. Methodologic quality of the included studies was assessed.Results26 studies were included using non-selective or selective NOS inhibition in rat, piglet, sheep, or rabbit animal models. A large variety in outcome measures was reported. Outcome measures were grouped as histological, biological, or neurobehavioral. Both non-selective and selective inhibitors show neuroprotective properties in one or more outcome measures. Methodologic quality was either low or moderate for all studies.ConclusionInhibition of NO synthesis is a promising strategy for additional neuroprotection. In humans, intervention can only take place after the onset of the hypoxic–ischemic event. Therefore, combined inhibition of neuronal and inducible NOS seems the most likely candidate for human clinical trials. Future studies should determine its safety and effectiveness in neonates, as well as a potential sex-specific neuroprotective effect. Researchers should strive to improve methodologic quality of animal intervention studies by using a systematic approach in conducting and reporting of these studies.

Prediction of Drug Exposure in Critically Ill Encephalopathic Neonates Treated With Therapeutic Hypothermia Based on a Pooled Population Pharmacokinetic Analysis of Seven Drugs and Five Metabolites

“…42,43 The same prediction can be made for 2-iminobiotin and allopurinol, high-clearance drugs that are currently being investigated for additional neuroprotection in combination with TH. [44][45][46][47] Drug dosing is highly challenging in neonates in general, and may be even more difficult in critically ill encephalopathic neonates treated with TH. Studies in this populations are difficult to perform and, therefore, it is of importance to elucidate and quantify the processes that influence the pharmacokinetics of drugs used in this population.…”

Efecto de la oxitocina en los niveles de malondialdehído, óxido nítrico y proteína S100B en el recién nacido

“…En relación a los niveles de ON, no hay estudios anteriores que evalúen ambos grupos; sin embargo, se conoce que la inhibición de la sintasa de óxido nítrico tiene propiedades neuroprotectoras (25) y a su vez altos niveles de nitratos están presentes en recién nacidos con asfixia, aunque estos niveles no son distintivos entre los grados de encefalopatía (8) . En nuestro estudio se obtuvieron valores menores, y no se encontró diferencias entre ambos grupos, lo que podría indicar que en forma similar al MDA podría estar relacionado a la frecuencia de contracciones, por lo que nuestras pacientes tendrían un nivel de estrés oxidativo aceptable.…”

First-in-Human Study of the Safety, Tolerability, Pharmacokinetics and - Preliminary Dynamics of Neuroprotectant 2-Iminobiotin in Healthy Subjects

“…2-IB exerts its neuroprotective effect by inhibition of neuronal and inducible isoform of NOS. It is intended to modulate the pathophysiological pathways triggered by oxygen shortage in the brain in the early phase after hypoxia-ischemia [ 13 , 14 ]. Based on in vitro cell culture data and an in vivo model in piglets, the neuroprotective 2-IB concentration in cerebrospinal fluid has been estimated to approximately 30 ng/mL [ 15 , 16 ].…”