Mohd. Moshahid 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.

Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type

The objective of the present study was to assess the neuroprotective role of rutin (vitamin P) and delineate the mechanism of action. Recent evidence indicates that rutin exhibits antioxidant potential and protects the brain against various oxidative stressors. More precisely, the aim of the present study was to examine the modulating impacts of rutin against cognitive deficits and oxidative damage in intracerebroventricular-streptozotocin (ICV-STZ)-infused rats. Rats were injected bilaterally with ICV-STZ (3 mg/kg), whereas sham rats received the same volume of vehicle. After 2 weeks of streptozotocin (STZ) infusion, rats were tested for cognitive performance using Morris water maze tasks and thereafter euthanized for further biochemical, histopathological, and immunohistochemical studies. Rutin pretreatment (25 mg/kg, orally, once daily for 3 weeks) significantly attenuated thiobarbituric acid reactive substances (TBARS), activity of poly ADP-ribosyl polymerase, and nitrite level and decreased level of reduced glutathione (GSH) and activities of its dependent enzymes (glutathione peroxidase [GPx] and glutathione reductase [GR]) and catalase in the hippocampus of ICV-STZ rats. ICV-STZ rats showed significant cognitive deficits, which was improved significantly by rutin supplementation. The results indicate that rutin attenuates STZ-induced inflammation by reducing the expression of cyclooxygenase-2 (COX-2), glial fibrillary acidic protein (GFAP), interleukin-8 (IL-8), inducible nitric oxide synthase (iNOS), nuclear factor-kB, and preventing the morphological changes in hippocampus. The study thereby suggests the effectiveness of rutin in preventing cognitive deficits and might be beneficial for the treatment of sporadic dementia of Alzheimer type (SDAT).

Hesperidin ameliorates functional and histological outcome and reduces neuroinflammation in experimental stroke.

Incidence of stroke is considered to be a major cause of death throughout the world. The middle cerebral artery occlusion (MCAO) for 2h followed by 22h of reperfusion model was used in male Wistar rats to study the protection of stroke by hesperidin. Hesperidin administration (50mg/kg b.wt.) once daily for 15days has improved the infarct size, reduced the neurological deficits in terms of behaviors, and protected the elevated level of thiobarbituric acid reactive species (TBARS). 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 hesperidin. Moreover, inflammatory mediators like TNF-α, IL-1β levels, expression of iNOS and glial fibrillary acidic protein (GFAP) were significantly attenuated in H+MCAO group as compared to MCAO group. In conclusion, prophylactic treatment with hesperidin ameliorated the functional and histological outcomes with elevated endogenous antioxidants status as well as reduced induction of proinflammatory cytokines in MCA occluded rat. We theorized that hesperidin is among the pharmacological agents that reduce free radicals and its associated inflammation and have been found to limit the extent of brain damage following stroke.

S-allyl cysteine attenuates oxidative stress associated cognitive impairment and neurodegeneration in mouse model of streptozotocin-induced experimental dementia of Alzheimer's type

S-allyl cysteine (SAC), a sulfur containing amino acid derived from garlic, has been reported to have antioxidant, anti-cancer, antihepatotoxic and neurotrophic activity. This study was designed to examine the pre-treatment effects of SAC on cognitive deficits and oxidative damage in the hippocampus of intracerebroventricular streptozotocin (ICV-STZ)-infused mice. Mice pre-treated with SAC (30mg/kg) and vehicle (intraperitoneal; once daily for 15days) were bilaterally injected with ICV-STZ (2.57mg/kg body weight), whereas sham rats received the same volume of vehicle. The pre-treatment of this drug to Swiss albino mice has prevented the cognitive and neurobehavioral impairments. An increased latency and path length were observed in lesion, i.e. streptozotocin (STZ) group as compared to sham group and these were protected significantly in STZ group pre-treated with SAC. Levels of reduced glutathione (GSH) and its dependent enzymes (Glutathione peroxidase [GPx] and glutathione reductase [GR]) were decreased in STZ group as compared to sham group and pre-treatment of STZ group with SAC has protected their activities significantly. Conversely, the elevated level of thiobarbituric acid reactive substances (TBARS) in STZ group was attenuated significantly in SAC pre-treated group when compared with STZ lesioned group. Apoptotic parameters like DNA fragmentation, expression of Bcl2 and p53 were protected by the pre-treatment of SAC against STZ induced cognitive impairment. This study concludes that intervention of SAC could prevent free radicals associated deterioration of cognitive functions and neurobehavioral activities.

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.

S-allyl cysteine mitigates oxidative damage and improves neurologic deficit in a rat model of focal cerebral ischemia

Oxidative stress and inflammatory damage play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. The present study examined the hypothesis that S-allyl cysteine (SAC), organosulfur compounds found in garlic extract, would reduce oxidative stress-associated brain injury after middle cerebral artery occlusion (MCAO). To test this hypothesis, male Wistar rats were subjected to MCAO for 2 hours and 22-hour reperfusion. S-allyl cysteine was administered (100 mg/kg, b.wt.) intraperitoneally 30 minutes before the onset of ischemia and after the ischemia at the interval of 0, 6, and 12 hours. After 24 hours of reperfusion, rats were tested for neurobehavioral activities and were killed for the infarct volume, estimation of lipid peroxidation, glutathione content, and activity of antioxidant enzymes (glutathione peroxidase, glutathione reductase, catalase, and superoxide dismutase). S-allyl cysteine treatment significantly reduced ischemic lesion volume, improved neurologic deficits, combated oxidative loads, and suppressed neuronal loss. Behavioral and biochemical alterations observed after MCAO were further associated with an increase in glial fibrillary acidic protein and inducible nitric oxide expression and were markedly inhibited by the treatment with SAC. The results suggest that SAC exhibits exuberant neuroprotective potential in rat ischemia/reperfusion model. Thus, this finding of SAC-induced adaptation to ischemic stress and inflammation could suggest a novel avenue for clinical intervention during ischemia and reperfusion.

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.