Melatonin reduces cerebral edema formation caused by transient forebrain ischemia in rats
AJINOMOTO CO., INC., Edo, Tokyo, Japan Life Sciences
(Impact Factor: 2.7).
12/2002; 72(4-5):583-90. DOI: 10.1016/S0024-3205(02)02256-7
Reduction of cerebral edema, an early symptom of ischemia, is one of the most important remedies for reducing subsequent chronic neural damage in stroke. Melatonin, a metabolite of tryptophan released from the pineal gland, has been found to be effective against neurotoxicity in vitro. The present study was aimed to demonstrate the effectiveness of melatonin in vivo in reducing ischemia-induced edema using magnetic resonance imaging (MRI). Rats were subjected to middle cerebral artery (MCA) occlusion/reperfusion surgery. Melatonin was administered twice (6.0 mg/kg, p.o.): just prior to 1 h MCA occlusion and 1 day after the surgery. T2-weighted multislice spin-echo images were acquired 1 day after the surgery. Increases in T2-weighted signals in ischemic sites of the brain were clearly observed after MCA occlusion. The signal increase was found mainly in the striatum and in the cerebral cortex in saline-treated control rats. In the melatonin-treated group, the total volume of cerebral edema was reduced by 45.3% compared to control group (P < 0.01). The protective effect of melatonin against cerebral edema was more clearly observed in the cerebral cortex (reduced by 56.1%, P < 0.01), while the reduction of edema volume in the striatum was weak (reduced by 23.0%). The present MRI study clearly demonstrated that melatonin is effective in reducing edema formation in ischemic animals in vivo, especially in the cerebral cortex. Melatonin may be highly useful in preventing cortical dysfunctions such as motor, sensory, memory, and psychological impairments.
Available from: Pallab Bhattacharya
- "Our main objective was to characterize the effects of melatonin post-treatment to ischemia in inhibiting formation of AQP4 mediated brain edema. Although, melatonin has previously been reported to attenuate brain edema following cerebral ischemia in association with the downregulation of vascular endothelial growth factor (VEGF) and astrocytic aquaporin-4 (AQP4) protein expressions (Gorgulu et al., 2001b; Kaur et al., 2006; Kondoh et al., 2002; Torii et al., 2004; Badaut et al., 2003; Yatsushige et al., 2007) however Torii et al. (2004) and Kondoh et al. (2002) also found that melatonin treatment before and after MCA occlusion (MCAO) resulted in reductions in cerebral edema that were greatest in areas of increased astrocyte density. These studies strongly suggest a role for melatonin in the reduction of cerebral edema following ischemic insults, and imply that it may act through the modulation of VEGF and astrocyte AQP4 expression. "
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Aquaporin-4(AQP4) expression in brain with relation to edema formation following focal cerebral ischemia was investigated. Studies have shown that brain edema is one of the significant factors in worsening stroke outcomes. While many mechanisms may aggravate brain injury, one such potential system may involve AQP4 up regulation in stroke patients that could result in increased edema formation. Post administration of melatonin following ischemic stroke reduces AQP4 mediated brain edema and confer neuroprotection.
Materials and Methods
An in-silico approach was undertaken to confirm effective melatonin-AQP4 binding. Rats were treated with 5mg/kg, i.p. melatonin OR placebo at 30 min prior, 60 min post and 120 min post 60 minutes of MCAO followed by 24 hour reperfusion. Rats were evaluated for battery of neurological and motor function tests just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, biochemical analysis, apoptosis study and western blot experiments.
Melatonin at sixty minutes post ischemia rendered neuroprotection as evident by reduction in cerebral infarct volume, improvement in motor and neurological deficit and reduction in brain edema. Furthermore, ischemia induced surge in levels of nitrite and MDA were also found to be significantly reduced in ischemic brain regions in treated animals. Melatonin potentiated intrinsic antioxidant status, inhibited acid mediated rise in intracellular calcium levels, decreased apoptotic cell death and also markedly inhibited protein kinase C influenced AQP4 expression in the cerebral cortex and dorsal striatum.
Melatonin confer neuroprotection by Protein Kinase C mediated AQP4 inhibition in ischemic stroke.
Available from: Takashi Kondoh
- "After overnight fasting, rats were subjected to 1 h of middle cerebral artery (MCA) occlusion (MCAO) followed by reperfusion, a model of focal ischemia resembling that of human stroke (Belayev et al. 1996). The ischemic surgery (intraluminal occlusion technique) was as reported earlier (Kondoh et al., 2002; Torii et al., 2004). Briefly, rats were anesthetized with 1.5% halothane in a mixture of 30%O 2 /70%N 2 O gas and maintained the rectal temperature at 37°C by a heating pad. "
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ABSTRACT: Intravenous administration of arginine was shown to be protective against cerebral ischemic insults via nitric oxide production and possibly via additional mechanisms. The present study aimed at evaluating the neuroprotective effects of oral administration of lysine (a basic amino acid), arginine, and their combination on ischemic insults (cerebral edema and infarction) and hemispheric brain swelling induced by transient middle cerebral artery occlusion/reperfusion in rats. Magnetic resonance imaging and 2,3,5-triphenyltetrazolium chloride staining were performed 2 days after ischemia induction. In control animals, the major edematous areas were observed in the cerebral cortex and striatum. The volumes associated with cortical edema were significantly reduced by lysine (2.0 g/kg), arginine (0.6 g/kg), or their combined administration (0.6 g/kg each). Protective effects of these amino acids on infarction were comparable to the inhibitory effects on edema formation. Interestingly, these amino acids, even at low dose (0.6 g/kg), were effective to reduce hemispheric brain swelling. Additionally, the effects of in vivo microiontophoretic (juxtaneuronal) applications of these amino acids on glutamate-evoked neuronal activity in the ventromedial hypothalamus were investigated in awake rats. Glutamate-induced neuronal activity was robustly inhibited by microiontophoretic applications of lysine or arginine onto neuronal membranes. Taken together, our results demonstrate the neuroprotective effects of oral ingestion of lysine and arginine against ischemic insults (cerebral edema and infarction), especially in the cerebral cortex, and suggest that suppression of glutamate-induced neuronal activity might be the primary mechanism associated with these neuroprotective effects.
Available from: Suleyman Kaplan
- "It is shown to play an important role as a neuroprotective agent against a wide variety of processes that damage tissues by free radicals [9,10,12-15,39,40]. At present, it is accepted that the antioxidative enzymes such as superoxide dismutase, glutathione peroxidase and glutathione reductase are also stimulated by melatonin [5,10,12-14,40]. Recently, Andrabi et al.  suggested that melatonin has also an anti-apoptotic effect, by inhibition of the mitochondrial permeability. "
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ABSTRACT: Although the injury to the peripheral nervous system is a common clinical problem, understanding of the role of melatonin in nerve degeneration and regeneration is incomplete.
The current study investigated the effects of neonatal pinealectomy on the sciatic nerve microarchitecture in the chicken. The chickens were divided into two equal groups: unpinealectomized controls and pinealectomized chickens. At the end of the study, biochemical examination of 10 sciatic nerve samples from both groups was performed and a quantitative stereological evaluation of 10 animals in each group was performed. The results were compared using Mann-Whitney test.
In this study, the results of axon number and thickness of the myelin sheath of a nerve fiber in newly hatched pinealectomy group were higher than those in control group. Similarly, surgical pinealectomy group had significantly larger axonal cross-sectional area than the control group (p < 0.05). In addition, the average hydroxyproline content of the nerve tissue in neonatal pinealectomy group was higher than those found in control group. Our results suggest that melatonin may play a role on the morphologic features of the peripheral nerve tissue and that melatonin deficiency might be a pathophysiological mechanism in some degenerative diseases of peripheral nerves. The changes demonstrated by quantitative morphometric methods and biochemical analysis has been interpreted as a reflection of the effects of melatonin upon nerve tissue.
In the light of these results from present animal study, changes in sciatic nerve morphometry may be indicative of neuroprotective feature of melatonin, but this suggestion need to be validated in the human setting.
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