Effects of normobaric oxygen and melatonin on reperfusion injury: role of cerebral microcirculation

Abstract

In order to protect the brain before an irreversible injury occurs, penumbral oxygenation is the primary goal of current acute ischemic stroke treatment. However, hyperoxia treatment remains controversial due to the risk of free radical generation and vasoconstriction. Melatonin is a highly potent free radical scavenger that protects against ischemic stroke. Considering its anti-oxidant activity, we hypothesized that melatonin may augment the survival-promoting action of normobaric oxygen (NBO) and prevent brain infarction. Herein, we exposed mice to 30 or 90 min of intraluminal middle cerebral artery occlusion (MCAo) and evaluated the effects of NBO (70% or 100% over 90 min), administered either alone or in combination with melatonin (4 mg/kg, i.p.), on disseminate neuronal injury, neurological deficits, infarct volume, blood-brain barrier (BBB) permeability, cerebral blood flow (CBF) and cell signaling. Both NBO and particularly melatonin alone reduced neuronal injury, neurological deficits, infarct volume and BBB permeability, and increased post-ischemic CBF, evaluated by laser speckle imaging (LSI). They also improved CBF significantly in the ischemic- core and penumbra, which was associated with reduced IgG extravasation, DNA fragmentation, infarct volume, brain swelling and neurological scores. Levels of phosphorylated Akt, anti-apoptotic Bcl-xL, pro-apoptotic Bax and endothelial nitric oxide synthase (NOS) were re-regulated after combined oxygen and melatonin delivery, whereas neuronal and inducible NOS, which were increased by oxygen treatment, were not influenced by melatonin. Our present data suggest that melatonin and NBO are promising approaches for the treatment of acute-ischemic stroke, which encourage proof-of-concept studies in human stroke patients.

Particular phosphorylation of PI3K/Akt on Thr308 via PDK-1 and PTEN mediates melatonin's neuroprotective activity after focal cerebral ischemia in mice

“…In a previous study, we demonstrated for the first time that melatonin activated Akt phosphorylation following FCI in mice [14], which was later shown in various tissues, including brain [4], [5], [15], seminiferous tubules [31] as well as in cancer cells [32]. Melatonin-induced apoptosis of cancer cells is intervened by Pi3K/Akt pathway [32].…”

“…It detoxifies oxygen-and nitrogen-based free radicals and oxidizing agents, including the highly toxic hydroxyl-and peroxynitrite radicals, initiating lipid peroxidation and neuronal injury [1], [2], [3]. It was previously revealed that melatonin reduced brain injury and DNA damage after ischemic stroke in rodents [4], [5]. So far, the neuroprotective effect of melatonin has been linked mainly to its direct free radical scavenging and indirect antioxidant activities [3].…”

Effects of Antenatal Melatonin Treatment on the Cerebral Vasculature in an Ovine Model of Fetal Growth Restriction

“…The growing fetal brain requires an adequate supply of oxygen and nutrients, delivered throughout the brain via the concurrent development of the vast neurovascular network structure. Microvascular damage is reportedly reduced by MLT in response to brain hypoperfusion and reperfusion injury [32] , suggesting that MLT might exert a neuroprotective effect by protecting the microvessels themselves. Indeed there is evidence that MLT acts directly on vasculature to mediate blood flow to various vascular beds including the brain, to stabilize blood brain barrier integrity [33] , prevent endothelial cell dysfunction [34] , decrease nitric oxide and VEGF production, and suppress ischemia-induced cerebral edema [35] .…”

Cocktail treatment, a promising strategy to treat acute cerebral ischemic stroke?

“…They reported that combined NBO and melatonin synergistically reduces neuronal injury after mild focal cerebral ischemia induced by 30-minute MCAO. Combination therapy of NBO and melatonin regulated levels of phosphorylated Akt, antiapoptotic Bcl-xL, pro-apoptotic Bax and endothelial NO synthase, as well as reduced neuronal injury, neurological deficits, infarct volume and BBB permeability which has been found by NBO and particularly melatonin treatment alone (Beker et al, 2015).…”