Pomegranate (Punica granatum L.) flower improves learning and memory performances impaired by diabetes mellitus in rats.

Oxidative stress induced by diabetes mellitus leads to damages in the brain, as a consequence of which cognitive functions is impaired. Therefore, for the treatment of diabetes mellitus, in addition to antidiabetics, antioxidants are used to cope with oxidative stress. The antioxidant ability of pomegranate flowers (PGF) to cope with the oxidative stress was investigated. Rats were divided into five groups with 12 animals in each group as given below: control, diabetes (STZ), STZ + the PGF I (300 mg/kg/day), STZ + PGF II (400 mg/kg/day) and STZ + PGF III (500 mg/kg/day).The findings from Morris water maze and probe tests showed that the animals in STZ group had impairments in learning and memory performances compared to the control group. Supplementation of PGF led to improvements in learning and memory performances of diabetic rats.While lipid peroxidation (LPO) was increased (P<0.001), glutathione (GSH) content was decreased (P<0.001) in hippocampal tissue of STZ-induced diabetic rats when compared with control values. Supplementation of PGF restored the levels of LPO and GSH towards their control values. Daily PGF supplementation to diabetic rats reduced the increase in glial-fibrilar acidic protein (GFAP) contents induced by diabetes in the hippocampus, which was significant in STZ + PGF III in comparison to STZ group (p<0.05).In conclusion, these observations suggest that PGF supplementation decreases oxidative stress and ameliorates impairment in learning and memory performances in diabetic rats. Therefore, we suggest that PGF supplementation may be clinically useful in treating neuronal deficit in diabetic patients.

Effects of vitamin E against aluminum neurotoxicity in rats.

The present study examined the protective effects of vitamin E against aluminum-induced neurotoxicity in rats. Wistar rats were given daily aluminum via their drinking water containing 1600 mg/liter aluminum chloride for six weeks. Aluminum induced a significant increase in lipid peroxidation (LPO) in hippocampus and frontal cortex. Furthermore, aluminum caused marked elevation in the levels of the glial markers (glial fibrillary acidic protein (GFAP) and S100B) and proinflammatory cytokines (TNF-alpha and IL-1beta) in both brain areas. Vitamin E treatment reduced the contents of glial markers and cytokines and the levels of LPO. In conclusion, this study demonstrates that vitamin E ameliorates glial activation and reduces release of proinflammatory cytokines induced by aluminum.

Melatonin prevents oxidative stress and inhibits reactive gliosis induced by hyperhomocysteinemia in rats.

Homocysteine (Hcy), an independent risk factor for atherosclerosis, undergoes auto-oxidation and generates reactive oxygen species, which are thought to be main cause of Hcy neurotoxicity. However, the mechanisms leading to neurodegenerative disorders are poorly understood because studies that have investigated the potential neurotoxicity of hyperhomocysteinemia in vivo are scarce. The purpose of this study was to test whether daily administration of methionine, which induces hyperhomocysteinemia, causes glial hyperactivity, and also to investigate the protective effects of melatonin on the brain tissue against oxidative stress of Hcy in rats. There was a significant development of oxidative stress as indicated by an increase in malondialdehyde + 4-hydroxyalkenals in hippocampus and cortex of hyperhomocysteinemic rats, whereas significant reduction was found in the activity of glutathione peroxidase (GSH-Px). Co-treatment with melatonin inhibited the elevation of lipid peroxidation and significantly increased GSH-Px activity in the brain regions studied. Western blot analysis revealed an increase in glial fibrillary acidic protein (GFAP) contents both in hippocampus and frontal cortex (p < 0.001) of hyperhomocysteinemic rats compared to the controls. Administration of melatonin significantly decreased GFAP contents in hippocampus and cortex (p < 0.05). S100B contents increased only in frontal cortex in hyperhomocysteinemic rats compared to the control (p < 0.01) and was inhibited by melatonin treatment (p < 0.01). The present findings show that Hcy can sensitize glial cells, a mechanism which might contribute to the pathogenesis of neurodegenerative disorders, and further suggest that melatonin can be involved in protecting against the toxicity of Hcy by inhibiting free radical generation and stabilizing glial cell activity.

Melatonin inhibits neural apoptosis induced by homocysteine in hippocampus of rats via inhibition of cytochrome c translocation and caspase-3 activation and by regulating pro- and anti-apoptotic protein levels.

In the present study, we examined the molecular mechanism by which homocysteine causes neuronal cell apoptosis. We further investigated the mechanisms of melatonin's ability to reduce homocysteine-induced apoptosis. Consistent with its antioxidant properties, melatonin reduced homocysteine-induced lipid peroxidation and stimulated glutathione peroxidase enzyme activity in hippocampus of rats with hyperhomocysteinemia. Furthermore, melatonin treatment diminished cytochrome c release from mitochondria and reduced caspase 3 and caspase 9 activation induced by hyperhomocysteinemia. Chronic hyperhomocysteinemia also led to poly(ADP-ribose) polymerase cleavage and subsequently DNA fragmentation. Treatment with melatonin markedly inhibited poly(ADP-ribose) polymerase cleavage and reduced DNA damage. Hyperhomocysteinemia caused an elevation of pro-apoptotic Bax levels while reducing anti-apoptotic protein, Bcl-2, levels. Daily administration of melatonin up-regulated Bcl-2 and down-regulated Bax levels. We propose that, in addition to its antioxidant properties, melatonin has the ability to protect neuronal cells against apoptosis mediated homocysteine neurotoxicity by modulating apoptosis-regulatory proteins in the hippocampus of rats.

Neuroprotection by alpha-lipoic acid in streptozotocin-induced diabetes.

Glial cells provide structural and metabolic support for neurons, and these cells become reactive to any insult to the central nervous system. The streptozotocin (STZ) rat model was used to study glial reactivity and the prevention of gliosis by alpha-lipoic acid (alpha-LA) administration. The expression of glial fibrillary acidic protein (GFAP), S100B protein, and neuron specific enolase (NSE) was determined as well as lipid peroxidation (LPO) and glutathione (GSH) levels in some brain tissues. Western blot analyses showed GFAP, S100B, and NSE levels significantly increased under STZ-induced diabetes in brain, and LPO level increased as well. Administration of alpha-LA reduced the expression both of glial and neuronal markers. In addition, alpha-LA significantly prevented the increase in LPO levels found in diabetic rats. GSH levels were increased by the administration of alpha-LA. This study suggests that alpha-LA prevents neural injury by inhibiting oxidative stress and suppressing reactive gliosis.

Early changes in glial reactivity and lipid peroxidation in diabetic rat retina: effects of melatonin.

Diabetes mellitus, the most common serious metabolic disorder, is characterized by functional and structural changes in the peripheral and central nervous systems. Glial cells provide structural and metabolic support for retinal neurons. During diabetes, one of the early pathogenic events is retinal glial reactivity. We studied the effects of melatonin, which is known to reduce oxidation-based neurotoxicity, on glial reactivity and lipid peroxidation in the retina of diabetic rats. Diabetes was induced by a single injection of streptozotocin (STZ), and these diabetic rats were treated daily either with melatonin (10 mg/kg) or saline vehicle. After 6 weeks of diabetes, we determined the extents of lipid peroxidation and glial reactivity in retina. Lipid peroxidation, measured on the basis of malondialdehyde and 4-hydroxyalkenals concentrations, was increased in diabetic rats (p<0.01) and this increase was prevented by melatonin treatment (p<0.05). Furthermore, gial reactivity, determined immunohistochemically from the levels of glial fibrillary acid protein (GFAP), was also increased significantly (p<0.01). Melatonin administration partially prevented this increase in GFAP content (p<0.05). In conclusion, glial reactivity is an early pathogenic event in diabetic retina and both reactive gliosis and accumulation of malondialdehyde and 4-hydroxyalkenals are prevented by melatonin supplementation.

A novel role for melatonin: regulation of the expression of cell adhesion molecules in the rat hippocampus and cortex.

Neural cell adhesion molecules (NCAMs) are members of the immunoglobulin superfamily and are involved in synaptic rearrangements in the mature brain. There are three major NCAM forms: NCAM 180, NCAM 140 and NCAM 120. Several studies report that NCAMs play a central role in memory. In the present study we investigated the effects of melatonin on the expression of NCAMs in the hippocampus, cortex and cerebellum. The levels of NCAMs were determined by Western blotting. After administration of melatonin for 7 days, NCAM 180 expression increased both in the hippocampus and in the cortex as compared to controls. On the contrary, in rats exposed to the constant light for 7 days (which inhibits endogenous production of melatonin), NCAM 180 levels decreased in the hippocampus and became undetectable in cortex and cerebellum. NCAM 140 levels were also diminished in the hippocampus of constant light-exposed rats. There was no change in NCAM 120 expression in any brain regions. This is the first report indicating that melatonin has a modulatory effect on the expression of NCAM in brain areas concerned with cognitive function. Melatonin may be involved in structural remodeling of synaptic connections during memory and learning processes.

Effect of melatonin on oxidative status of rat brain, liver and kidney tissues under constant light exposure.

An enormous amount of data has been published in recent years demonstrating melatonin's defensive role against toxic free radicals. In the present study, we examined the role of melatonin as an antioxidant against the effect of continuous light exposure. Rats were divided into three groups. Control rats (group A) were kept under natural conditions whereas other group of rats (group B and C) were exposed to constant light for inhibition of melatonin secretion by the pineal gland. Group C rats also received melatonin via s.c. injection (1 mg x kg(- 1) body weight x day(- 1)). At the end of experiment, all animals were sacrificied by decapitation, serum and tissue samples were removed for determination of malondialdehyde (MDA), a product of lipid peroxidation, conjugated dienes levels and glutathione peroxidase (GSH-Px) activity levels. It was found that lipid peroxidation was increased in the rats which were exposed to constant light. Melatonin injection caused a decrease in lipid peroxidation, especially in the brain. In addition, melatonin application resulted in increased GSH-Px activity, which has an antioxidant effect. Thus, melatonin is not only a direct scavenger of toxic radicals, but also stimulates the antioxidative enzyme GSH-Px activity to detoxify hydroxyl radical produced by constant light exposure.

Effects of pinealectomy and exogenous melatonin on serum leptin levels in male rat.

The effects of pinealectomy and exogenous melatonin (N-acetyl-5-methoxytryptamine) on serum leptin levels were investigated in rats. Exogenous administration of melatonin to intact rats resulted in significant decreases in serum leptin levels (P < 0.05) compared to those of the intact control group. Serum leptin levels were significantly elevated in the pinealectomised rats in comparison to the sham-pinealectomised animals (P < 0.001) and were significantly suppressed by exogenous administration of melatonin compared to those of non-treated pinealectomised rats (P < 0.001). Hormone concentrations in the melatonin-treated pinealectomised group were found to be similar to those seen in the sham-pinealectomised group. These results suggest that pineal gland has an effect on leptin release.

Effects of pinealectomy on the circadian release pattern of leptin in male rat.

OBJECTIVES: Exogenous and endogenous melatonin decrease leptin release. It is not known whether melatonin also has an effect on circadian release pattern of leptin. So, this study was planned to investigate the possible changes in the circadian release of leptin following pinealectomy. METHODS: A group of rats were surgically pinealectomized while some others were exposed to sham operation. The animals were decapitated at 13.30 p.m. and 01.30 a.m. Serum leptin levels were measured by radioimmunoassay. RESULTS: Serum leptin levels at 13.30 p.m. were lower than the values at 01.30 a.m. in both pinealectomized (P<0.002) and sham rats P<0.001). Serum leptin levels measured at 13.30 p.m. and 01.30 a.m. were significantly elevated (P<0.05 and P<0.01, respectively) in the pinealectomized rats in comparison to sham animals. CONCLUSION: The circadian release of leptin does not seem to be regulated by melatonin release from the pineal gland whereas melatonin, physiologically released, may have a decreasing effect on leptin release.

Plasma beta-carotene concentrations in pregnancies, newborn infants and their mothers.

Concentrations of beta-carotene were determined in maternal and fetal blood. The samples were collected from 33 mothers, their 33 newborns and 50 pregnant and 29 non-pregnant women. Beta-carotene concentrations of the non-pregnant, pregnant, newborn infant and their mothers were 140.31, 171.54, 63.57 and 175.74 micrograms/dl, respectively. There was a significant correlation (P < 0.001) between beta-carotene values of the maternal plasma and cord plasma. Mean maternal plasma beta-carotene concentration was higher (P < 0.0005) than that of the cord. These results suggest that plasma transport capacity of beta-carotene was low from mother to their fetus.