Early‐life N‐arachidonoyl‐dopamine exposure increases antioxidant capacity of the brain tissues and reduces functional deficits after neonatal hypoxia in rats

Abstract

Perinatal hypoxia‐ischemia is one of the most common causes of perinatal brain injury and subsequent neurological disorders in children. The aim of this work was to evaluate the potential antioxidant and neuroprotective effects of N‐arachidonoyl‐dopamine (NADA) in the model of acute neonatal hypoxia (ANH) in rat pups. Male and female Wistar rats were exposed to a hypoxic condition (8% oxygen for 120 min) at postnatal day 2 (P2). Transcription factor HIF1‐α and glutathione peroxidases GPx2 and GPx4 gene expression was increased in rat brains in the hypoxic group compared to control 1.5 h but not 4 days after ANH. There were no post‐hypoxic changes in reduced (GSH) and oxidised (GSSG) glutathione levels in the brain of rat pups 1.5 h and 4 d after hypoxia. Hypoxic rats displayed retarded performance in the righting reflex and the negative geotaxis tests. ANH resulted in increased ambulation in Open field test and impaired retention in the Barnes maze task under stressful conditions as compared with the control group. Treatment with NADA significantly attenuated the delayed development of sensorimotor reflexes and stress‐evoked disruption of memory retention in hypoxic rats but had no effect on the hypoxia‐induced hyperactivity. In rats exposed to hypoxia, treatment with NADA decreased GPx2 gene expression and increased GSH/GSSG ratio in whole brains 1.5 h after ANH. These results suggest that the long‐lasting beneficial effects of NADA on hypoxia‐induced neurobehavioural deficits are mediated, at least in part, by its antioxidant properties.

Sulforaphane (SFA) protects neuronal cells from oxygen & glucose deprivation (OGD)

“…Astrocytes play a dominant role in the protection of neurons by increasing anti-oxidative enzymes through the Nrf2/ARE pathway which can neutralize ROS to prevent neuronal cell damage [25][26][27]. Neurons also use this same protective mechanism, though it is less efficient than in astrocytes, as neurons are inadequate up-regulators of anti-oxidants and have a low resting glutathione levels, which is central for redox homeostasis of the cell [2,21,25]. This paradigm is supported by our data which showed that the protective effect of SFA on OGD neurons ( Fig 5A), was not as effective compared to the protective effect of SFA on OGD astrocytes ( Fig 5B); the difference in cell death decrease from 0 μM to 2.5 μM was over 2 fold greater in astrocytes compared to neurons.…”

“…Excitotoxicty against oligodendrocytes works also by extracellular glutamate accumulation and results in an increase of ROSs causing oxidative stress. These processes are detrimental to the brain; by damaging oligodendrocytes they specifically reduce or attenuate the myelination process, thereby creating vulnerable neurons [2,7,9,30,31]. With all of these cellular constituents present in the co-culture, it is more likely to thrive compared to isolated neuron or astrocyte cultures; and their response to effects of SFA is more representative of what an in vivo response may look like.…”

“…Phase II anti-oxidant enzymes can directly remove ROSs and reduce oxidative stress [21]. An important anti-oxidant enzyme that is many times indirectly enhanced by SFA is GPX, a key component of the glutathione dependent anti-oxidant system, vitally important in maintaining endogenous redox homeostasis [2,31]. GPX is involved in the conversion of reduced glutathione (GSH) to oxidized glutathione (GSSG), by an oxidation process which also includes neutralizing ROSs [2,25].…”

“…Currently, hypothermia is the only rescue therapy accepted as a standard of care, and targets only 10-20% of newborn injuries at term. It therefore does not address the majority of perinatal brain injuries (PBIs) [1,2]. The extent of injury depends on the underlying cause and gestational age at the time of injury [3].…”

Beneficial effects of xenon inhalation on behavioral changes in a valproic acid-induced model of autism in rats

“…To assess locomotion and responsiveness of the animals to a novel environment, we tested rats on pnd 21 in open field apparatus as previously described [36].…”