盐酸美金刚对血管性痴呆大鼠疗效观察

目的 观察盐酸美金刚对血管性痴呆大鼠的疗效及作用机制.方法 80只健康Wistar大鼠(月龄12～14个月),体质量300～400 g,随机分为对照组、模型组、美金刚对照组及美金刚治疗组,每组20只.采用持久双侧颈总动脉结扎术造成血管性痴呆大鼠模型,美金刚对照组及美金刚治疗组于术后8周开始以美金刚(5 mg·kg-1)每天灌胃,对照组和模型组以同等量的0.5 g/L羧甲基纤维素钠灌胃,连续4周.采用Morris水迷宫衡量大鼠学习记忆水平;测定大鼠脑皮层、海马组织乙酰胆碱酯酶(AChE)、胆碱乙酰转移酶(ChAT)、丙二醛(MDA)、谷胱甘肽(GSH)活性的变化.结果 术后12周,与对照组相比,模型组大鼠的学习记忆能力明显下降(P<0.05);脑皮层、海马组织内AChE活性明显升高(P<0.05),ChAT活性明显降低(P<0.05),MDA活性明显升高(P<0.05),GSH活性明显降低(P<0.05);与模型组相比,美金刚治疗组大鼠的学习记忆能力明显提高(P<0.05);脑皮层、海马组织内AChE活性及ChAT活性差异无统计学意义(P>0.05)、MDA活性明显降低(P<0.05)、GSH活性明显升高(P<0.05).结论 盐酸美金刚对血管性痴呆大鼠的学习记忆能力有明显提高,作用机制是通过调节脑组织内MDA及GSH的活性来实现的,该实验研究为临床上血管性痴呆的治疗提供实验基础及理论依据.     

Risperidone reverses phencyclidine induced decrease in glutathione levels and alterations of antioxidant defense in rat brain

Perinatal phencyclidine (PCP) administration to rats represents one of the actual animal models of schizophrenia. Numerous data suggest redox dysregulation in this disease. We have previously demonstrated decreased content of the reduced glutathione (GSH) and complex disbalance of antioxidant enzymes in the brain of rats perinatally treated with PCP. The aim of this study was to elucidate whether chronic risperidone treatment can reverse these changes. The Wistar rats were perinatally treated with either PCP (10mg/kg; PCP, two groups) or saline (0.9% NaCl, two groups). At postnatal day (PN) 35, two groups of rats one NaCl and one PCP have started to receive risperidone in drinking water for nine weeks (NaCl-RSP and PCP-RSP groups). Animals were sacrificed on PN100 and the levels of GSH, the activities of γ-glutamate cysteine ligase (GCL), glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase (SOD), as well as, the concentration of lipid peroxides were determined in the different brain structures. Risperidone restored decreased GSH levels, as well as decreased γ-GCL activity in cortex and hippocampus of animals perinatally treated with PCP. Alterations in GPx and GR activities caused by perinatal PCP treatment were also reversed by risperidone in most investigated brain structures. Furthermore, chronic risperidone treatment caused the decrease in SOD activity both in control and in PCP perinatally treated groups. Increased levels of lipid peroxides noticed in hippocampus and thalamus were reversed after chronic risperidone treatment. The results of the present study demonstrate that risperidone treatment restores GSH levels and to great measure reverses antioxidant defense alterations in the brain of perinatally PCP treated rats. Further studies are necessary in order to clarify the significance of risperidone influence on oxidative stress parameters in schizophrenia.     

The Combined Effect of Sleep Deprivation and Western Diet on Spatial Learning and Memory: Role of BDNF and Oxidative Stress

Either sleep deprivation or Western diet can impair learning and memory via induction of oxidative stress, which results in neuronal damage and interference with the neurotransmission. In this study, we examined the combined effect of sleep deprivation and Western diet on hippocampus-dependent spatial learning and memory. In addition, possible molecular targets for sleep deprivation and Western diet-induced cognitive impairments were investigated. Sleep deprivation was induced in rats using the modified multiple platform model simultaneous with the administration of Western diet for 6 weeks. Thereafter, spatial learning and memory were tested using radial arm water maze. At the molecular level, BDNF protein and antioxidant markers including superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG, and thiobarbituric acid reactive substances (TBARS) were assessed. The results of this study revealed that sleep deprivation, Western diet, or a combination of both impair short- and long-term memory (P?<?0.05). The magnitude of the impairment induced by the combined treatment at the 24-h long-term memory was higher than that caused by each factor alone (P?<?0.05). In addition, the combined treatment reduced the levels of hippocampal BDNF, a reduction that was not detected with each factor alone. Moreover, the combined treatment reduced the hippocampal activities of SOD, catalase, GPx, ratio of GSH/GSSG, and elevated TBARS level (P?<?0.05). In conclusion, the combination of sleep deprivation and Western diet decreases BDNF levels and increases oxidative stress in the hippocampus, thus inducing memory impairment that is greater than the impairment produced by each factor alone.     

Antioxidant intervention attenuates oxidative stress in children and teenagers with Down syndrome

We previously demonstrated that systemic oxidative stress is present in Down syndrome (DS) patients. In the present study we investigated the antioxidant status in the peripheral blood of DS children and teenagers comparing such status before and after an antioxidant supplementation. Oxidative stress biomarkers were evaluated in the blood of DS patients (n = 21) before and after a daily antioxidant intervention (vitamin E 400 mg, C 500 mg) during 6 months. Healthy children (n = 18) without DS were recruited as control group. The activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), gamma-glutamyltransferase (GGT), glucose-6-phosphate dehydrogenase (G6PD) and myeloperoxidase (MPO), as well as the contents of reduced glutathione (GSH), uric acid, vitamin E, thiobarbituric acid reactive substances (TBARS), and protein carbonyls (PC) were measured. Before the antioxidant therapy, DS patients presented decreased GST activity and GSH depletion; elevated SOD, CAT, GR, GGT and MPO activities; increased uric acid levels; while GPx and G6PD activities as well as vitamin E and TBARS levels were unaltered. After the antioxidant supplementation, SOD, CAT, GPx, GR, GGT and MPO activities were downregulated, while TBARS contents were strongly decreased in DS. Also, the antioxidant therapy did not change G6PD and GST activities as well as uric acid and PC levels, while it significantly increased GSH and vitamin E levels in DS patients. Our results clearly demonstrate that the antioxidant intervention with vitamins E and C attenuated the systemic oxidative damage present in DS patients.     

Pro-oxidant status based alterations in cerebellar antioxidant response to aluminum insult

Cerebellum is unique in restraining amyloid-induced neurodegenerative changes. Amyloidosis and oxidant imbalance is common in aluminum exposure. Interestingly, aluminum itself does not pose any redox activity still it is associated with oxidant imbalance, and, it can aggravate the situation of already existing oxidant threat. Male rats were exposed to aluminum for 4 weeks along with exposure to 4 different doses of ethanol. After the treatment period, cerebellar level of protein, reduced glutathione (GSH), lipid perioxidation (TBARS) were measured. Activities of catalase, superoxide dismutase (SOD), glutathione reductase (GR) and glutathione perioxidase (GPx) were also estimated from the homogenized cerebellar tissue. In the present regimen of aluminum exposure, the cerebellum has shown significant reduction only in GPx activity. However, when aluminum was coexposed with ethanol, it contributed significantly to increase the cerebellar oxidant imbalance by (a) compromising the GSH restoration system, (b) reducing enzymatic peroxide scavenging system of cerebellum, (c) restricting the capability to cope with oxidative stress, as well as (d) downgrading the resistance to oxidative damage in response to chemical stress. Present study demonstrates that coexposure of aluminum with pro-oxidant favored development of aluminum-induced oxidative stress in cerebellum. These observations enlighten the role of pro-oxidants in the process of oxidative degeneration of cerebellum. With further studies, the present observation can be useful to understand the mechanism of neurodegenerative disorders and ways to ameliorate them.     

Oxidative stress status and RNA expression in hippocampus of an animal model of Alzheimer's disease after chronic exposure to aluminum

It is well established that aluminum (Al) is a neurotoxic agent that induces the production of free radicals in brain. Accumulation of free radicals may cause degenerative events of aging such as Alzheimer's disease. On the other hand, melatonin (Mel) is a known antioxidant, which can directly act as free radical scavenger, or indirectly by inducing the expression of some genes linked to the antioxidant defense. In this study, AβPP female transgenic (Tg2576) (Tg) and wild‐type mice (5 months of age) were fed with Al lactate supplemented in the diet (1 mg Al/g diet). Simultaneously, animals received oral Mel (10 mg/kg) dissolved in tap water until the end of the study at 11 months of age. Four treatment groups were included for both Tg and wild‐type mice: control, Al only, Mel only, and Al+Mel. At the end of the period of treatment, hippocampus was removed and processed to examine the following oxidative stress markers: reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), and thiobarbituric acid reactive substances (TBARS). Moreover, the gene expression of Cu‐ZnSOD, GR, and CAT was evaluated by real‐time RT‐PCR. Aluminum concentration in hippocampus was also determined. The biochemical changes observed in this tissue suggest that Al acts as a pro‐oxidant agent. Melatonin exerts an antioxidant action by increasing the mRNA levels of the antioxidant enzymes SOD, CAT, and GR evaluated in presence of Al and Mel, with independence of the animal model. © 2009 Wiley‐Liss, Inc.     

The neuroprotective effect of vitamin E on chronic sleep deprivation-induced memory impairment: the role of oxidative stress

Sleep deprivation induces oxidative stress and impairs learning and memory processes. Vitamin E, on the other hand, is a strong antioxidant that has neuroprotective effect on the brain. In this study, we examined the potential protective effect of chronic administration of vitamin E on chronic sleep deprivation-induced cognitive impairment. In addition, possible molecular targets for vitamin E effects on chronic sleep deprivation-induced cognitive impairment were determined. Sleep deprivation was induced in rats using modified multiple platform model. Vitamin E (100 mg/kg) was administered to animals by oral gavage. Behavioral study was conducted to test the spatial learning and memory using the radial arm water maze (RAWM). In addition, the hippocampus was dissected out and antioxidant markers including glutathione (GSH), oxidized glutathione (GSSG) and GSH/GSSG, glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD) were assessed. The results of this project revealed that chronic sleep deprivation impaired both (short- and long-term) memories (P < 0.05), while vitamin E treatment prevented such effect. Additionally, vitamin E normalized chronic sleep deprivation-induced reduction in the hippocampus GSH/GSSG ratio, and activity of catalase, SOD, and GPx. In conclusion, sleep deprivation induces memory impairment, and treatment with vitamin E prevented this impairment probably through its antioxidant action in the hippocampus.     

Evaluation of the effect of pentoxifylline on sleep‐deprivation induced memory impairment

In this study, we examined the ability of Pentoxifylline (PTX) to prevent sleep deprivation induced memory impairment probably through decreasing oxidative stress. Sleep deprivation was chronically induced 8 h/day for 6 weeks in rats using modified multiple platform model. Concurrently, PTX (100 mg/kg) was administered to animals on daily basis. After 6 weeks of treatment, behavioral studies were conducted to test the spatial learning and memory using the Radial Arm Water Maze. Additionally, the hippocampus was dissected; and levels/activities of antioxidant defense biomarkers glutathione reduced (GSH), glutathione oxidized (GSSG), GSH/GSSG ratio, glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD), were assessed. The results show that chronic sleep deprivation impaired short‐ and long‐term memories, which was prevented by chronic treatment with PTX. Additionally, PTX normalized sleep deprivation‐induced reduction in the hippocampus GSH/GSSG ratio (P < 0.05), and activities of GPx, catalase, and SOD (P < 0.05). In conclusion, chronic sleep deprivation induces memory impairment, and treatment with PTX prevented this impairment probably through normalizing antioxidant mechanisms in the hippocampus. © 2013 Wiley Periodicals, Inc.     

Neuroprotective effects of edaravone on cognitive deficit,oxidative stress and tau hyperphosphorylation induced by intracerebroventricular streptozotocin in rats

Oxidative stress is implicated as an important factor in the development of Alzheimer's disease (AD). In the present study, we have investigated the effects of edaravone (9 mg/kg, 3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, in a streptozotocin (STZ-3 mg/kg) induced rat model of sporadic AD (sAD). Treatment with edaravone significantly improved STZ-induced cognitive damage as evaluated in Morris water maze and step-down tests and markedly restored changes in malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE) adducts, hydroxyl radical (OH), hydrogen peroxide (H₂O₂), total superoxide dismutase (T-SOD), reduced glutathione (GSH), glutathione peroxidase (GPx) and protein carbonyl (PC) levels. In addition, histomorphological observations confirmed the protective effect of edaravone on neuronal degeneration. Moreover, hyperphosphorylation of tau resulting from intracerebroventricular streptozotocin (ICV-STZ) injection was decreased by the administration of edaravone. These results provide experimental evidence demonstrating preventive effects of edaravone on cognitive dysfunction, oxidative stress and hyperphosphorylation of tau in ICV-STZ rats. Since edaravone has been used for treatment of patients with stroke, it represents a safe and established therapeutic intervention that has the potential for a novel application in the treatment of age-related neurodegenerative disorders associated with cognitive decline, such as AD.     

The neurobiological effects of colchicine: modulation by nerve growth factor.

To study the effects of exogenously applied nerve growth factor (NGF) on colchicine-induced neurodegeneration in the dentate gyrus of the rat hippocampal formation, colchicine (COLCH) or artificial cerebrospinal fluid (ACSF) was infused into the dorsal hippocampus (HPC) followed by unilateral infusion of either purified beta-NGF (in ACSF) or cytochrome C. One week later, animals were tested in activity chambers when NGF treatment was found to reduce the COLCH-induced hyperactivity. Animals were sacrificed 3 or 12 weeks postlesion for neurochemical or morphological analysis. Carbachol-stimulated phosphatidyl inositol (PI) turnover performed in hippocampal slices was not affected by any treatment at 3 weeks. However, 12 weeks after the lesion, CARB stimulation of PI hydrolysis was increased in the COLCH/ACSF group. NGF treatment significantly reduced the hyperstimulation in COLCH-treated rats. Morphological analysis showed that COLCH treatment increased AChE staining in the hippocampus, whereas NGF treatment had no effect on AChE staining. There was no difference in the number of septal ChAT immunoreactive cell bodies of controls or colchicine-treated rats at either time point examined. However, NGF treatment resulted in a significant increase in the number of ChAT immunoreactive cell bodies 3 weeks postlesion. Results from this study indicate that NGF can modify colchicine-induced compensatory changes in hippocampal signal transduction and has transitory influences on cholinergic cells in the medial septum.     

Persistence of the benefit of an antioxidant therapy in children and teenagers with Down syndrome

This study examined the effect of an antioxidant intervention in biomarkers of inflammation and oxidative stress (OS) in the blood of Down syndrome (DS) children and teenagers during four different stages. A control group was composed by healthy children (n = 18), assessed once, and a Down group composed by DS patients (n = 21) assessed at the basal period (t₀), as well as after 6 months of antioxidant supplementation (t₁), after 12 months (after interruption of the antioxidant intervention for 6 months) (t₂), and again after further 6 months of antioxidant supplementation (t₃). Biomarkers of inflammation (myeloperoxidase activity – MPO and levels of IL-1β and TNF-α) and OS (thiobarbituric acid reactive substances – TBARS, protein carbonyls – PC), reduced glutathione (GSH), uric acid (UA) and vitamin E levels, as well as antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) and gamma-glutamyltransferase (GGT) activities, were measured after each period. After the antioxidant supplementation, the activities of SOD, CAT, GPx, GR, GGT and MPO were downregulated, while TBARS contents were strongly decreased, the contents of GSH and vitamin E were significantly increased, and no changes in G6PD and GST activity as well as in UA and PC levels were detected. After the interruption of the antioxidant therapy for 6 months, DS patients showed elevated GPx and GGT activities and also elevated UA and TBARS levels. No changes in SOD, CAT, GR, GST, G6PD and MPO activities as well as in GSH, vitamin E, PC, TNF-α and IL-1β levels were detected. The results showed that the antioxidant intervention persistently attenuated the systemic oxidative damage in DS patients even after a relatively long period of cessation of the antioxidant intervention.     

Folic acid administration prevents ouabain‐induced hyperlocomotion and alterations in oxidative stress markers in the rat brain

Brocardo PS, Budni J, Pavesi E, Franco JL, Uliano‐Silva M, Trevisan R, Terenzi MG, Dafre AL, Rodrigues ALS. Folic acid administration prevents ouabain‐induced hyperlocomotion and alterations in oxidative stress markers in the rat brain.
Bipolar Disord 2010: 12: 414–424. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objective: Bipolar disorder (BD) is a chronic, prevalent, and highly debilitating psychiatric illness. Folic acid has been shown to have antidepressant‐like effects in preclinical and clinical studies and has also been suggested to play a role in BD. The present work investigates the therapeutic value of folic acid supplementation in a preclinical animal model of mania induced by ouabain. Methods: Male Wistar rats were treated twice daily for seven days with folic acid (10, 50, and 100 mg/kg, p.o.) or the mood stabilizer lithium chloride (LiCl) (45 mg/kg, p.o.). One day after the last dose was given, the animals received an i.c.v. injection of ouabain (10 μM), a Na⁺,K⁺‐ATPase‐inhibiting compound. Locomotor activity was assessed in the open‐field test. Thiobarbituric acid‐reactive substance (TBARS) levels, glutathione peroxidase (GPx), and glutathione reductase (GR) activities were measured in the cerebral cortex and hippocampus. Results: Ouabain (10 μM, i.c.v.) significantly increased motor activity in the open‐field test, and seven days of pretreatment with folic acid (50 mg/kg, p.o.) or LiCl (45 mg/kg, p.o.) completely prevented this effect. Ouabain treatment elicited lipid peroxidation (increased TBARS levels) and reduced GPx activity in the hippocampus. GR activity was decreased in the cerebral cortex and hippocampus. These effects were prevented by pretreatment with folic acid and LiCl. Conclusions: Our results show that folic acid, similarly to LiCl, produces a clear antimanic action and prevents the neurochemical alterations indicative of oxidative stress in an animal model of mania.     

Changes in oxidative stress markers in patients with schizophrenia: The effect of antipsychotic drugs

The aim of this study was to investigate the serum levels or activities of oxidative stress markers in patients with schizophrenia in acute phase and evaluate the changes in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH) and thiobarbituric acid-reactive substances (TBARS) after treatment. We consecutively enrolled 41 patients with schizophrenia in acute phase, and 27 patients were followed up with a 4-week antipsychotic treatment. Serum oxidative stress markers were measured with assay kits. We found that Positive and Negative Syndrome Scale (PANSS) total scores were significantly negatively correlated with serum GPx activity and GSH levels and positively correlated with serum SOD activity in patients with schizophrenia in acute phase. In addition, serum GPx activity had a positive correlation with GSH levels and negative correlation with SOD activity. We also found that serum SOD activity was significantly negatively correlated with TBARS levels in patients in acute phase. Furthermore, we found significantly increased changes only in GPx activity in female patients receiving the 4-week treatment (P=0.006). In conclusion, our results suggest that SOD, GPX and GSH might be indicators of schizophrenia severity in acute phase. Furthermore, antipsychotic drugs might affect serum GPx activity in female patients receiving the 4-week treatment.     

Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer's disease

Oxidative stress has been associated with normal aging and Alzheimer's disease (AD). However, little is known about oxidative stress in mild cognitive impairment (MCI) patients who present a high risk for developing AD. The aim of this study was to investigate plasma production of the lipid peroxidation marker, malonaldehyde (MDA) and to determine, in erythrocytes, the enzymatic antioxidant activity of catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST) in 33 individuals with MCI, 29 with mild probable AD and 26 healthy aged subjects. GR/GPx activity ratio was calculated to better assess antioxidant defenses. The relationship between oxidative stress and cognitive performance was also evaluated by the Mini Mental State Examination (MMSE). AD patients showed higher MDA levels than both MCI and healthy elderly subjects. MCI subjects also exhibited higher MDA levels compared to controls. Catalase and GPx activity were similar in MCI and healthy individuals but higher in AD. GR activity was lower in MCI and AD patients than in healthy aged subjects. Additionally, GR/GPx ratio was higher in healthy aged subjects, intermediate in MCI and lower in AD patients. No differences in GST activity were detected among the groups. MMSE was negatively associated with MDA levels (r = -0.31, p = 0.028) and positively correlated with GR/GPx ratio in AD patients (r = 0.68, p < 0.001). MDA levels were also negatively correlated to GR/GPx ratio (r = -0.31, p = 0.029) in the AD group. These results suggest that high lipid peroxidation and decreased antioxidant defenses may be present early in cognitive disorders.     

Naringenin neutralises oxidative stress and nerve growth factor discrepancy in experimental diabetic neuropathy

Abstract

Objectives:

Present study aims to investigate the ameliorative effects of naringenin (NG) on experimentally induced diabetic neuropathy (DN) in rats.

Methods:

Diabetes was induced by single intraperitoneal injection of streptozotocin (STZ, 60?mg/kg). Naringenin (25 and 50?mg/kg/day) treatment was started 2?weeks after the diabetes induction and continued for five consecutive weeks. Pain threshold behaviour tests were performed at the end of the treatment. Serum levels of glucose, insulin and pro-inflammatory cytokines were assessed. In sciatic tissues, markers oxidative stress, cytokines and neurotrophic factors were measured.

Results:

NG treatments showed significant decrease in paw-withdrawal (P?<?0.01) and tail-flick latency (P?<?0.01). The drug attenuated the diabetic-induced changes in serum glucose, insulin and pro-inflammatory cytokines including tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6). In sciatic nerve, the diabetic-induced alterations in interleukins and oxidative stress biomarkers were significantly attenuated by NG. Decreased sciatic expressions of insulin growth factor (IGF) and nerve growth factor (NGF) in diabetic rats were also ameliorated by NG. Diabetes-induced dysregulated levels of nitric oxide (NO), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were ameliorated by NG. Histological analysis showed that NG corrected the altered sciatic changes in diabetic animals.

Discussion:

We suggest that neuro-protective effect of NG molecules in sciatic nerve of diabetic rats, through its anti-diabetic as well as antioxidant and anti-inflammatory properties.     

Intranasal Insulin Ameliorates Cerebral Hypometabolism,Neuronal Loss,and Astrogliosis in Streptozotocin-Induced Alzheimer’s Rat Model

Intracerebroventricular injection of streptozotocin (ICV-STZ) in rodents leads to cognitive impairments and several pathological changes like Alzheimer’s disease (AD). However, there is hardly any research about the effect of ICV-STZ on regional cerebral glucose metabolism in rodents. Previous studies have demonstrated that intranasal insulin improves cognition in AD patients. However, the underlying mechanism remains elusive. Here, we treated the ICV-STZ rats with daily intranasal delivery of insulin (2 U/day) for 6 consecutive weeks, then monitored ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) uptake using a high-resolution small-animal positron emission tomography (microPET) and studied the expression of neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) using immunohistochemical staining. We observed that ¹⁸F-FDG uptake decreased significantly at the prefrontal cortex, cingulate cortex, striatum, hippocampus, and entorhinal cortex in ICV-STZ rats as compared with the control rats. Intranasal insulin restores the cerebral glucose metabolism in prefrontal and cingulate cortex and attenuates astroglia activation and neuronal loss in the hippocampus of ICV-STZ rats. These findings provide the mechanistic basis for treating AD patients with intranasal insulin.     

Protective Efficacy of Coenzyme Q10 Against DDVP-Induced Cognitive Impairments and Neurodegeneration in Rats

The present study was carried out to elucidate the effects of coenzyme Q(10) (CoQ(10)) against cognitive impairments induced by dichlorvos (DDVP). We have previously shown organophosphate, DDVP-induced impairments in neurobehavioral indices viz. rota rod, passive avoidance, and water maze tests. In addition to this, we have also reported that chronic DDVP exposure leads to decreased mitochondrial electron transfer activities of cytochrome oxidase along with altered mitochondrial complexes I-III activity. Administration of CoQ(10) (4.5 mg/kg, i.p. for 12 weeks prior to DDVP administration daily) to DDVP-treated rats improved cognitive performance in passive avoidance task and Morris water maze test. Furthermore, CoQ(10) treatment also reduced oxidative stress (as evident by reduced malondialdehyde, decreased ROS and increased Mn-SOD activity) in DDVP-treated rats' hippocampus region, along with enhanced activity of complexes I-III and complex IV. Electron microscope studies of rat hippocampus mitochondria revealed that CoQ(10) administration leads to near normal physiology of mitochondria with well-defined cristae compared with DDVP-treated animals where enlarged mitochondria with distorted cristae are observed. CoQ(10) administration also attenuated neuronal damage in hippocampus as evident from histopathological studies. These results demonstrate the beneficial effects of CoQ(10) against organophosphate-induced cognitive impairments and hippocampal neuronal degeneration.     

Changes in endogenous antioxidant enzymes during cerebral ischemia and reperfusion

OBJECTIVE: The purpose of this study was to investigate the role of catalase (Cat), glutathione S transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx) in cerebral ischemia induced by occluding the carotid arteries of male Wistar rats. METHODS: The activities of the antioxidant enzymes Cat, GR, GPx and GST were measured in the cerebral cortex, cerebellum and hippocampus regions after varying periods of ischemia and reperfusion. RESULTS: In all ischemia/reperfusion groups (0, 1 and 24 hours of reperfusion), the enzyme activities were found to be altered when compared to the sham-operated controls. The alterations were significant (p< or =0.05) in all reperfusion groups, particularly after 1 hour of reperfusion in all brain regions; however, maximum alterations were detected in the more vulnerable hippocampus. DISCUSSION: Our findings indicate that the endogenous antioxidant enzymes are activated as soon as 1 hour after ischemia. In spite of significant up-regulation of these enzymes, a large number of neurons in selectively vulnerable regions of hippocampus undergo neurodegeneration. These biochemical changes suggest that vulnerability to oxidative stress in brain is region-specific. However, these changes which are adaptive or compromise the capacity of the brain to deal with the oxidative stress that could lead to neurodegeneration remains to be understood.     

The neurotrophic effects of ebiratide,an analog of ACTH4–9, on cultured septal cells and aged rats

Summary The neurotrophic effects of ebiratide, an ACTH_4–9 analog, have been examined using both fetal rat septal cultures and aged rats. The 5-day treatment with ebiratide (10–100 pmol/ml) partially prevented neuronal degeneration that occurred in the cultures in which cells were sparsely plated. Ebiratide (10 pmol/ ml) increased choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities up to 1.5 and 1.2 times the respective control values in the sub-confluent cultures. AChE cytochemistry of the cultures has shown that ebiratide increased the stained area per cell. Ebiratide subcutaneously administered by constant infusion (10 nmol/body/hr) for 4 weeks elevated ChAT activities in the septum (35% over control), neocortex (79%) and hippocampus (89%) of aged rats. Thus, the present study indicates that ebiratide shares neurotrophic properties which may prove beneficial in the therapy for CNS degenerative disorders, especially Alzheimer's disease.     

Brain antioxidant markers, cognitive performance and acetylcholinesterase activity of rat: Efficiency of Sonchus asper

ABSTRACT: BACKGROUND: Sonchus asper (SA) is traditionally used as a folk medicine to treat mental disorders in Pakistan. The aim of this study was to investigate the effect of polyphenolic rich methanolic fraction of SA on cognitive performance, brain antioxidant activities and acetylcholinesterase activity in male rats. METHODS: 30 male Sprague-Dawley rats were equally divided into three groups in this study. Animals of group I (control) received saline (vehicle), group II received SA (50 mg/kg) body weight (b.w.), and group III treated with SA (100 mg/kg b.w.,) orally in dimethyl sulphoxide (DMSO) for 7 days. The effect of SA was checked on rat cognitive performance, brain antioxidatant and acetylcholinesterase activities. Evaluation of learning and memory was assessed by a step-through a passive avoidance test on day 6 after two habituation trials and an initial acquisition trial on day 5. Antioxidant potential was determined by measuring activities of superoxide dismutase (SOD), catalase (CAT), contents of thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) in whole-brain homogenates. Acetylcholinesterase (AChE) activity was determined by the colorimetric method. RESULTS: Results showed that 100 mg/kg b.w., SA treated rats exhibited a significant improvement in learning and memory (step-through latency time). SA administration reduced lipid peroxidation products and elevated glutathione levels in the SA100-treated group. Furthermore, salt and detergent soluble AChE activity was significantly decreased in both SA-treated groups. Short-term orally supplementation of SA showed significant cognitive enhancement as well as elevated brain antioxidant enzymes and inhibited AChE activity. CONCLUSION: These findings stress the critical impact of Sonchus asper bioactive components on brain function. KEYWORDS: Sonchus asper, Cognitive performance, Acetylcholinesterase activity, Antioxidant enzymes.