M. Badruzzaman Khan

Resveratrol attenuates 6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinson's disease.

The present study was undertaken to investigate the neuroprotective effects of resveratrol (RES) on 6-hydroxydopamine (6-OHDA)-induced Parkinsons disease (PD) in rats. PD is an age-related neurodegenerative disorder in which the role of reactive oxygen species (ROS) is strongly implicated. RES, a polyphenolic antioxidant compound enriched in grapes, has been shown to have antioxidant and anti-inflammatory actions and thus was tested for its beneficial effects using 6-OHDA-induced PD rat model. Male Wistar rats were pretreated with RES (20mg/kg body weight i.p.) once daily for 15 days and subjected to unilateral intrastriatal injection of 6-OHDA (10 microg in 0.1% ascorbic acid in normal saline). Three weeks after 6-OHDA infusion, rats were tested for neurobehavioral activity and were killed after 4 weeks of 6-OHDA infusion for the estimation of lipid peroxidation, glutathione content, and activity of antioxidant enzymes (glutathione peroxidase [GPx], glutathione reductase [GR], catalase [CAT], and superoxide dismutase [SOD]. RES was found to be successful in upregulating the antioxidant status and lowering the dopamine loss. Conversely, the elevated level of thiobarbituric acid reactive substances (TBARS), protein carbonyl (PC), and activity of phospholipase A2 in 6-OHDA group was attenuated significantly in RES-pretreated group when compared with 6-OHDA-lesioned group. These results were supported by the immunohistochemical findings in the substantia nigra that has shown the protection of neurons by RES from deleterious effects of 6-OHDA. Thus, RES may be used to reduce the deterioration caused by free radicals thereby preventing subsequent behavioral, biochemical, and histopathological changes that occur during PD.

Amelioration of cognitive deficits and neurodegeneration by curcumin in rat model of sporadic dementia of Alzheimer's type (SDAT).

Recent evidence indicates that curcumin (CUR), the principal curcuminoid of turmeric, exhibits antioxidant potential and protects the brain against various oxidative stressors. The aim of the present study was to examine the modulating impacts of CUR against cognitive deficits and oxidative damage in intracerebroventricular-streptozotocin (ICV-STZ) infused rats. Rats were injected bilaterally with ICV-STZ (3 mg/kg), while sham rats received the same volume of vehicle and then supplemented with CUR (80 mg/kg) for three weeks. After two weeks of ICV-STZ infusion, rats were tested for cognitive performance using passive avoidance and water maze tasks and then sacrificed for biochemical and histopathological assays. ICV-STZ rats showed significant cognitive deficits, which were significantly improved by CUR supplementation. CUR supplementation significantly augmented increased 4-hydroxynonenal (4-HNE) and malonaldehyde (MDA), thiobarbituric reactive substances (TBARS), hydrogen peroxide (H2O2), protein carbonyl (PC) and oxidized glutathione (GSSG); decreased levels of reduced glutathione (GSH) and its dependent enzymes (Glutathione peroxidase [GPx] and glutathione reductase [GR]) in the hippocampus and cerebral cortex; and increased choline acetyltransferase (ChAT) activity in the hippocampus of ICV-STZ rats. The study suggests that CUR is effective in preventing cognitive deficits, and might be beneficial for the treatment of sporadic dementia of Alzheimers type (SDAT).

Selenium prevents cognitive decline and oxidative damage in rat model of streptozotocin-induced experimental dementia of Alzheimer's type

Selenium (Se), a nutritionally essential trace element with known antioxidant potential, protects the brain from oxidative damage in various models of neurodegeneration. Intracerebroventricular-streptozotocin (ICV-STZ) in rats causes impairment of brain glucose and energy metabolism along with oxidative damage and cholinergic dysfunction, and provides a relevant model for sporadic dementia of Alzheimers type (SDAT). The present study demonstrates the therapeutic efficacy of Se on cognitive deficits and oxidative damage in ICV-STZ in rats. Male Wistar rats were pre-treated with sodium selenite, a salt of Se (0.1 mg/kg; body weight) for 7 days and then were injected bilaterally with ICV-STZ (3 mg/kg), while sham rats received the same volume of vehicle. After two ICV-STZ infusions, rats were tested for memory deficits in passive avoidance and Morris water maze (MWM) tests and then were sacrificed for biochemical and histopathological assays. ICV-STZ-infused rats showed significant loss in learning and memory ability, which were significantly improved by Se supplementation. A significant increase in thio-barbituric acid reactive species (TBARS), protein carbonyl (PC) and a significant decrease in reduced glutathione (GSH), antioxidant enzymes (glutathione peroxidase [GPx] and glutathione reductase [GR]) and adenosine triphosphate (ATP) in the hippocampus and cerebral cortex and choline acetyltransferase (ChAT) in hippocampus were observed in ICV-STZ rats. Se supplementation significantly ameliorated all alterations induced by ICV-STZ in rats. Our study reveals that Se, as a powerful antioxidant, prevents cognitive deficits, oxidative damage and morphological changes in the ICV-STZ rats. Thus, it may have a therapeutic value for the treatment of SDAT.

Rutin protects the neural damage induced by transient focal ischemia in rats.

Free radical induced neural damage is implicated in cerebral ischemia-reperfusion (IR) injury and antioxidants are reported to have neuroprotective activity. The present study was designed to assess the neuroprotective role of rutin (Vitamin P), and mechanism of action. The middle cerebral artery (MCA) of an adult male Wistar rat was occluded for 2 h and reperfused for 22 h. The administration of rutin (25 mg/kg bwt., orally) once daily for 21 days before middle cerebral artery occlusion (MCAO) showed marked reduction in infarct size, reduced the neurological deficits in terms of behaviors, suppressed neuronal loss and diminished the p53 expression in MCAO rats. A significantly depleted activity of antioxidant enzymes, glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT) and superoxide dismutase (SOD) and content of glutathione (GSH) in MCAO group were protected significantly in MCAO group pretreated with rutin. Conversely, the elevated level of thiobarbituric acid reactive species (TBARS), H(2)O(2) and protein carbonyl (PC) in MCAO group was attenuated significantly in rutin-pretreated group when compared with MCAO group. These results indicate that rutin attenuates ischemic neural apoptosis by reducing the expression of p53, preventing morphological changes and increasing endogenous antioxidant enzymatic activities. Thus, rutin treatment may represent a novel approach in lowering the risk or improving the function of ischemia-reperfusion brain injury-related disorders.

Coenzyme Q10 modulates cognitive impairment against intracerebroventricular injection of streptozotocin in rats

Coenzyme Q10 (CoQ10), a peculiar lipophilic antioxidant, is an essential component of the mitochondrial electron-transport chain. It is involved in the manufacturing of adenosine triphosphate (ATP) and has been linked with improving cognitive functions. The present study shows the neuroprotective effect of CoQ10 on cognitive impairments and oxidative damage in hippocampus and cerebral cortex of intracerebroventricular-streptozotocin (ICV-STZ) infused rats. Male Wistar rats (1-year old) were infused bilaterally with an ICV injection of STZ (1.5 mg/kg b.wt., in normal saline), while sham group received vehicle only. After 24 h, the rats were supplemented with CoQ10 (10 mg/kg b.wt. i.p.) for 3 weeks. The learning and memory tests were monitored 2 weeks after the lesioning. STZ-infused rats showed the loss of cognitive performance in Morris water maze and passive avoidance tests. Three weeks after the lesioning, the rats were sacrificed for estimating the contents of thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), protein carbonyl (PC), ATP and the activities of glutathione peroxidase (GPx), glutathione reductase (GR), cholineacetyltransferase (ChAT) and acetylcholinesterase (AChE). Significant alteration in the markers of oxidative damage (TBARS, GSH, PC, GPx and GR) and a decline in the level of ATP were observed in the hippocampus and cerebral cortex of ICV-STZ rat. A significant decrease in ChAT activity and a concomitant increase in AChE activity were observed in the hippocampus. However, supplementation with CoQ10 in STZ-infused rats reversed all the parameters significantly. Thus, the study demonstrates that CoQ10 may have a therapeutic importance in the treatment of Alzheimers type dementia.

Ginkgo biloba affords dose‐dependent protection against 6‐hydroxydopamine‐induced parkinsonism in rats: neurobehavioural, neurochemical and immunohistochemical evidences

Ginkgo biloba extract (EGb), a potent antioxidant and monoamine oxidase B (MAO‐B) inhibitor, was evaluated for its anti‐parkinsonian effects in a 6‐hydroxydopamine (6‐OHDA) rat model of the disease. Rats were treated with 50, 100, and 150 mg/kg EGb for 3 weeks. On day 21, 2 µL 6‐OHDA (10 µg in 0.1% ascorbic acid saline) was injected into the right striatum, while the sham‐operated group received 2 µL of vehicle. Three weeks after 6‐OHDA injection, rats were tested for rotational behaviour, locomotor activity, and muscular coordination. After 6 weeks, they were killed to estimate the generation of thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) content, to measure activities of glutathione‐S‐transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD), and to quantify catecholamines, dopamine (DA) D2 receptor binding, and tyrosine hydroxylase‐immunoreactive (TH‐IR) fibre density. The increase in drug‐induced rotations and deficits in locomotor activity and muscular coordination due to 6‐OHDA injections were significantly and dose‐dependently restored by EGb. The lesion was followed by an increased generation of TBARS and significant depletion of GSH content in substantia nigra, which was gradually restored with EGb treatment. EGb also dose‐dependently restored the activities of glutathione‐dependent enzymes, catalase, and SOD in striatum, which had reduced significantly by lesioning. A significant decrease in the level of DA and its metabolites and an increase in the number of dopaminergic D2 receptors in striatum were observed after 6‐OHDA injection, both of which were significantly recovered following EGb treatment. Finally, all of these results were exhibited by an increase in the density of TH‐IR fibers in the ipsilateral substantia nigra of the lesioned group following treatment with EGb; the lesioning had induced almost a complete loss of TH‐IR fibers. Considering our behavioural studies, biochemical analysis, and immunohistochemical observation, we conclude that EGb can be used as a therapeutic approach to check the neuronal loss following parkinsonism.

Naringenin ameliorates Alzheimer’s disease (AD)-type neurodegeneration with cognitive impairment (AD-TNDCI) caused by the intracerebroventricular-streptozotocin in rat model

Oxidative stress is involved in Alzheimers disease (AD)-type neurodegeneration with cognitive impairment (AD-TNDCI) as well as age related cognitive deficit. The present study was designed to investigate the pre-treatment effects of naringenin (NAR), a polyphenolic compound on cognitive dysfunction, oxidative stress in the hippocampus, and hippocampal neuron injury in a rat model of AD-TNDCI. The rats were pre-treated with NAR at a selective dose (50mg/kg, orally) for 2 weeks followed by intracerebroventricular-streptozotocin (ICV-STZ) (3mg/kg; 5μl per site) injection bilaterally. Behavioral alterations were monitored after 2 weeks from the lesion using passive avoidance test and Morris water maze paradigm. Three weeks after the lesion, the rats were sacrificed for measuring non-enzymatic [4-hydroxynonenal (4-HNE), malonaldehyde (MDA), thiobarbituric reactive substances (TBARS), hydrogen peroxide (H(2)O(2)), protein carbonyl (PC), reduced glutathione (GSH)] content and enzymatic [glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) and Na(+)/K(+)-ATPase] activity in the hippocampus, and expression of choline acetyltransferase (ChAT) positive neuron, and histopathology of hippocampal neurons. The non-enzymatic level and enzymatic activity was significantly increased and decreased, respectively, with striking impairments in spatial learning and memory, loss of ChAT positive neuron and severe damage to hippocampal neurons in the rat induced by ICV-STZ. These abnormalities were significantly improved by NAR pre-treatment. The study suggests that NAR can protect against cognitive deficits, neuronal injury and oxidative stress induced by ICV-STZ, and may be used as a potential agent in treatment of neurodegenerative diseases such as AD-TNDCI.

Selenium plays a modulatory role against cerebral ischemia-induced neuronal damage in rat hippocampus

During cerebral ischemic cascade, a unifying factor which leads to mitochondrial dysfunctions is lack of oxygen followed by decrease in ATP production. The present study demonstrates the effect of selenium pretreatment (0.1 mg/kg as sodium selenite, i.p, 7 days) on cerebral ischemia-induced altered levels of mitochondrial ATP content, intracellular calcium (Ca(i)(2+)) in synaptosomes, expression of heat stress protein (Hsp70) and caspase-3 activity in hippocampus followed by neurobehavioral deficits and histopathological changes in Wistar rats. Cerebral ischemia was induced for 2 h followed by reperfusion for 22 h. It was observed that levels of (Ca(i)(2+)), Hsp70 and caspase-3 activity were significantly (p<0.01-0.001) higher with a marked decrease in ATP level in hippocampus of ischemic group as compared to sham values. Subsequently, a marked change was observed in neurobehavioral activities in ischemic animals as compared to control one. As a result of selenium pretreatment, a significant (p<0.05-0.001) trend of restoration was observed in the level of ATP, (Ca(i)(2+)), Hsp70, caspase-3 and behavioral outputs as compared to ischemic group. Histopathological analysis confirmed the protective effect of selenium against cerebral ischemia induced histological alterations as evidenced by lesser edema formation and separation of cells with minimal microglial cell infiltration in selenium pretreated group as compared to ischemic animals. The present study suggests that selenium may be able to salvage the ischemic penumbral zone neurons, thereby limiting ischemic cell death.

Attenuation by Nardostachys jatamansi of 6-hydroxydopamine-induced parkinsonism in rats: Behavioral, neurochemical, and immunohistochemical studies

Parkinsons disease (PD) is one of the commonest neurodegenerative diseases, and oxidative stress has been evidenced to play a vital role in its causation. In the present study, we evaluated whether ethanolic extract of Nardostachys jatamansi roots (ENj), an antioxidant and enhancer of biogenic amines, can slow the neuronal injury in a 6-OHDA-rat model of Parkinsons. Rats were treated with 200, 400, and 600 mg/kg body weight of ENj for 3 weeks. On day 21, 2 microl of 6-OHDA (12 microg in 0.01% in ascorbic acid-saline) was infused into the right striatum, while the sham-operated group received 2 microl of vehicle. Three weeks after the 6-OHDA injection, the rats were tested for neurobehavioural activity and were sacrificed after 6 weeks for the estimation of lipid peroxidation, reduced glutathione content, the activities of glutathione-S-transferase, glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase, quantification of catecholamines, dopaminergic D2 receptor binding and tyrosine hydroxylase expression. The increase in drug-induced rotations and deficits in locomotor activity and muscular coordination due to 6-OHDA injections were significantly and dose-dependently restored by ENj. Lesioning was followed by an increased lipid peroxidation and significant depletion of reduced glutathione content in the substantia nigra, which was prevented with ENj pretreatment. The activities of glutathione-dependent enzymes, catalase and superoxide dismutase in striatum, which were reduced significantly by lesioning, were dose-dependently restored by ENj. A significant decrease in the level of dopamine and its metabolites and an increase in the number of dopaminergic D2 receptors in striatum were observed after 6-OHDA injection, and both were significantly recovered following ENj treatment. All of these results were exhibited by an increased density of tyrosine hydroxylase immunoreactive (TH-IR) fibers in the ipsilateral striatum of the lesioned rats following treatment with ENj; 6-OHDA injection had induced almost a complete loss of TH-IR fibers. This study indicates that the extract of Jatamansi might be helpful in attenuating Parkinsonism.

Neuroprotective effects of curcumin on 6-hydroxydopamine-induced Parkinsonism in rats: Behavioral, neurochemical and immunohistochemical studies

Curcumin, the active principle of turmeric used in Indian curry is known for its antitumor, antioxidant, antiarthritic, anti-ischemic and anti-inflammatory properties and might inhibit the accumulation of destructive beta-amyloid in the brains of Alzheimers disease patients. A Parkinsonian model in rats was developed by giving 6-hydroxydopamine (10 μg/2 μl in 0.1% ascorbic acid-saline) in the right striatum. After 3 weeks of lesioning, the behavior activities (rotarod, narrow beam test, grip test and contra-lateral rotations) were increased in a lesioned group as compared to a sham group and these activities were protected significantly with the pretreatment of curcumin. A significant protection on lipid peroxidation, glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase, tyrosine hydroxylase and D(2) receptor binding was observed in the striatum of lesioned group animals pretreated with 80 mg/kg body weight of curcumin for 21 days as compared to lesion group animals. No significant alterations on behavior and biochemical parameters were observed in sham group animals and the animals of sham group pretreated with curcumin. This study indicates that curcumin, which is an important ingredient of diet in India and also used in various systems of indigenous medicine, is helpful in preventing Parkinsonism and has therapeutic potential in combating this devastating neurologic disorder.