Prophylactic use of melatonin protects against focal cerebral ischemia in mice: role of endothelin converting enzyme‐1

Abstract

Melatonin has previously been shown to be neuroprotective in rodent models of ischemic stroke. Herein, we tested whether this antioxidant may also be suitable for prophylactic use against stroke. To clarify this issue, melatonin was administrated orally for 9 wk (4 mg/kg/day) in mice and its effects on subsequent injury development after 90 min of intraluminal middle cerebral artery (MCA) occlusion were tested. To evaluate its neuroprotective properties, the protective actions of prophylactic melatonin were compared with both acute melatonin (4 mg/kg, i.p.) administration and with a diluent (sham)-treated control condition. MCA occlusion resulted in reproducible ischemia, as revealed by laser Doppler flowmetry; this was followed by a rapid restoration of blood flow immediately after reperfusion onset. Laser Doppler flow values after reperfusion onset were moderately elevated by melatonin, both when the indole was given prophylactically and when acutely administrated after stroke. In control animals, reproducible brain infarcts were observed 24 hr after reperfusion onset. Treatment with melatonin significantly reduced the infarct size by approximately 30-35%, independent of whether the indole was given prophylactically before or acutely after ischemia. To test whether brain protection involved vascular mechanisms, as suggested earlier, the effects of melatonin on endothelin converting enzyme-1 (ECE-1) levels were studied using Western blots. Interestingly, delivery of melatonin was accompanied by a marked inhibition of ECE-1 levels, which was similarly seen after both acute and chronic melatonin treatment. Our data suggest that melatonin, given at pharmacological doses, may be suitable as a prophylaxis against stroke. Tissue protection may involve an inhibition of ECE-1, which improves vasodilation, after ischemia.

Melatonin Regulates Nitric Oxide Synthase Expression in Ischemic Brain Injury

“…Our previous study as well as the work of others have shown that melatonin decreases infarct size and apoptotic cell death from MCAO-induced damage [9,11,16]. This study confirmed the neuroprotective effect of melatonin in ischemic brain injury using TTC staining.…”

“…Melatonin provides a significant microvascular protection through the activation of eNOS [23]. Moreover, melatonin-induced protection involves vascular mechanism through the vasodilatation after cerebral ischemia [9]. Melatonin represses up-regulation of iNOS and nNOS, and the down-regulation of eNOS in MCAOinduced brain injury.…”

Effect of melatonin on the thymus, adrenal glands, and spleen in rats during acute stress

“…Experiments on rats with middle cerebral artery occlusion showed that melatonin improves blood circulation due to inhibition of endothelin-1-converting enzyme and suppression of endothelin formation (one of the most potent vasoconstrictors) [8]. Moreover, melatonin consumption with drinking water led to hypertrophy of arteriolar walls, increased vascular distensibility, and decreased the lower limit of blood flow self-regulation in rats [7].…”

Melatonin in aging women

“…Melatonin and cancer: Melatonin has been shown to have significant antineoplastic properties 35 , both at initiation and during cancer cell growth 36 . Its proposed mechanisms of action include the reduction of severe DNA damage, inhibition of the expression of growth-and differentiation-related genes, reduction of oxygen-and nitrogen-based reactants, and reduction of the growth of cancer cells through the inhibition of mitogenic signals such as Endothelin-1and telomerase activity[37][38][39][40][41] .…”