Uncaria rhynchophylla ameliorates cognitive deficits induced by D-galactose in mice

The stem with hooks of Uncaria rhynchophylla is a component herb of many traditional formulae for the treatment of neurodegenerative diseases. However, scientific evidence of the efficacy of Uncaria rhynchophylla in the treatment of Alzheimer's disease (AD) in animal models is lacking. Thus, in the present study, we investigated whether the 70?% aqueous ethanol extract of Uncaria rhynchophylla (EUR) could protect against D-galactose (D-gal)-induced cognitive deficits in mice. Mice were given a subcutaneous injection of D-gal (50?mg/kg) and orally administered EUR (100, 200, or 400?mg/kg) daily for 8 weeks. The effect of EUR on D-gal-induced cognitive deficits was evaluated by measuring behavioral and neurochemical parameters of AD and the antioxidant status of brain tissue. The results showed that EUR (200 or 400?mg/kg) significantly increased exploratory behavior (assessed by an open-field test) and improved spatial learning and memory function (assessed by the Morris water maze test) in D-gal-treated mice. In addition, EUR (200 or 400?mg/kg) significantly increased the levels of acetylcholine and glutathione and decreased the activity of acetylcholinesterase and the level of malondialdehyde in the brains of D-gal-treated mice. These results indicate that EUR ameliorates cognitive deficits induced by D-gal in mice, and that this action may be mediated, at least in part, by the inhibition of acetylcholinesterase activity and the enhancement of the antioxidant status of brain tissue.     

Diphenyl diselenide protects against metabolic disorders induced by acephate acute exposure in rats

The present study investigated the effect of diphenyl diselenide [(PhSe)₂] on metabolic disorders induced by acephate acute exposure in rats. We also investigated a possible mechanism of action of (PhSe)₂ against hyperglycemia induced by acephate. (PhSe)₂ was administered to rats at a dose of 10 or 30 mg/kg by oral gavage (p.o.) 1 hour prior to acephate administration (140 mg/kg; p.o.). Glucose and corticosterone levels as well as the lipid status were determined in plasma of rats. Cardiovascular risk factors and the atherogenic index were calculated. Glycogen levels as well as tyrosine aminotransferase (TAT) and glucose‐6‐phosphatase (G6Pase) activities were determined in livers of rats. Cerebral acetylcholinesterase (AChE) activity was assayed. Acephate induced an increase in glucose and corticosterone levels as well as in TAT and G6Pase activities. AChE activity was inhibited by acephate. Triglyceride (TG) levels and the cardiovascular risk factor TG/high‐density lipoprotein‐cholesterol (HDL) were increased by acephate. (PhSe)₂ was effective against the metabolic disorders induced by acephate acute exposure in rats. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 665–671, 2014.     

Diphenyl diselenide decreases the prevalence of vacuous chewing movements induced by fluphenazine in rats

Rationale Chronic treatment with neuroleptics causes, as a side effect, tardive dyskinesia in humans; however, the mechanisms involved in its pathophysiology remain unclear. Objectives The purpose of this study was to examine the effects of diphenyl diselenide, an organoselenium compound with antioxidant properties, in an animal model of vacuous chewing movements (VCMs) induced by long-term treatment with fluphenazine. Results Adult male rats were treated during 24 weeks with fluphenazine (25 mg/kg, intramuscularly [i.m.], once every 21 days) and diphenyl diselenide (1 mg/kg, subcutaneously, three times a week). VCMs and body weight gain were quantified every 3 weeks. The fluphenazine treatment produced VCMs in the majority of the treated rats (87% after 24 weeks). Concomitant treatment with diphenyl diselenide decreased the prevalence of VCMs to 50%. Additionally, we separated the rats that developed or did not develop VCMs. We did not find any statistical differences among the groups when oxidative stress parameters were evaluated. Chronic fluphenazine treatment significantly decreased [³H]-dopamine uptake. Concomitant treatment with diphenyl diselenide was not able to prevent this decrease in those rats that developed VCMs. Conclusions Our data suggest that the reduction in dopamine transport can be a possible mechanism related to the maintenance of VCMs in rats. Moreover, diphenyl diselenide seems to be a promising pharmacological agent in the reduction in the prevalence of VCMs in rats.     

Diphenyl diselenide protects against glycerol‐induced renal damage in rats

In this study we evaluated the effect of diphenyl diselenide (PhSe)₂ on glycerol‐induced acute renal failure in rats. Rats were pre‐treated by gavage every day with (PhSe)₂ (7.14 mg kg^?1) for 7 days. On the eighth day, rats received an intramuscular injection of glycerol (8 mL kg^?1). Twenty‐four hours afterwards, rats were euthanized and the levels of urea and creatinine were measured in plasma. Catalase (CAT), glutathione peroxidase (GPx), glutathione S‐transferase (GST), δ‐aminolevulinate dehydratase (δ‐ALA‐D) and Na⁺, K⁺‐ATPase activities and ascorbic acid levels were evaluated in renal homogenates. Histopathological evaluations were also performed. The results demonstrated that (PhSe)₂ was able to protect against the increase in urea and creatinine levels and histological alterations in kidney induced by glycerol. (PhSe)₂ protected against the inhibition in δ‐ALA‐D, CAT and GPx activities and the reduction in ascorbic acid levels induced by glycerol in kidneys of rats. In conclusion, the present results indicate that (PhSe)₂ was effective in protecting against acute renal failure induced by glycerol. Copyright © 2009 John Wiley & Sons, Ltd.     

Diphenyl diselenide potentiates nephrotoxicity induced by mercuric chloride in mice

Following our long‐standing interest in the mechanisms involved in selenium toxicity, the aim of this work was to extend our previous studies to gain a better understanding of mercuric chloride (HgCl₂) + diphenyl diselenide (PhSe)₂ toxicity. Mice received one daily dose of HgCl₂ (4.6 mg kg^?1, subcutaneously) for three consecutive days. Thirty minutes after the last injection of HgCl₂, mice received a single dose of (PhSe)₂ (31.2 mg kg^?1, subcutaneously). Five hours after (PhSe)₂ administration, mice were euthanized and δ‐aminolevulinate dehydratase, catalase (CAT), glutathione S‐transferase (GST) and Na⁺, K⁺‐ATPase activities as well as thiobarbituric acid‐reactive substances (TBARS), ascorbic acid and mercury levels were determined in kidney and liver. Parameters in plasma (urea, creatinine, protein and erythropoietin), whole blood (hematocrit and hemoglobin) and urine (protein) were also investigated. HgCl₂ + (PhSe)₂ exposure caused a decrease in renal GST and Na⁺, K⁺‐ATPase activities and an increase in renal ascorbic acid and TBARS concentrations when compared with the HgCl₂ group. (PhSe)₂ potentiated the increase in plasma urea caused by HgCl₂. HgCl₂ + (PhSe)₂ exposure caused a reduction in plasma protein levels and an increase in hemoglobin and hematocrit contents when compared with the HgCl₂ group. There was a significant reduction in hepatic CAT activity and an increase in TBARS levels in mice exposed to HgCl₂ + (PhSe)₂ when compared with the HgCl₂ group. The results demonstrated that (PhSe)₂ did not modify mercury levels in mice. In conclusion, (PhSe)₂ potentiated damage caused by HgCl₂ affecting mainly the renal tissue. Copyright © 2011 John Wiley & Sons, Ltd.     

Antioxidant treatment ameliorates prefrontal hypomyelination and cognitive deficits in a rat model of schizophrenia

Cognitive dysfunction in schizophrenia (SZ) is thought to arise from neurodevelopmental abnormalities that include interneuron hypomyelination in the prefrontal cortex (PFC). Here we report that RNA-sequencing of the medial (m)PFC of the APO-SUS rat model with SZ-relevant cognitive inflexibility revealed antioxidant metabolism as the most-enriched differentially expressed pathway. Antioxidant-related gene expression was altered throughout postnatal development and preceded hypomyelination. Furthermore, reduced glutathione levels and increased mitochondria numbers were observed in the mPFC. Strikingly, chronic treatment with the glutathione precursor N-acetylcysteine (NAC) from postnatal days 5–90 restored not only antioxidant-related mRNA expression and mitochondria numbers, but also myelin-related mRNA expression and mPFC-dependent cognitive dysfunction, while blood glutathione levels remained unaffected. The promyelinating effect of NAC was at least partly due to a positive effect on oligodendrocyte lineage progression. Together, our findings highlight that oxidative stress may contribute to cognitive symptoms in the APO-SUS rat model of SZ and encourage antioxidant therapy in early phases of SZ.Subject terms: Neuroscience, Schizophrenia     

Baicalein improves cognitive deficits induced by chronic cerebral hypoperfusion in rats

The aim of this study is to investigate the effects of baicalein on cognitive impairment and neuronal degeneration in a rat model of chronic cerebral hypoperfusion induced by permanent occlusion of bilateral common carotid arteries (2VO). It was found that baicalein (2 or 4 mg/kg/day, i.p.) significantly improved 2VO-induced cognitive deficits and neuropathological changes. Biochemical and histological examinations revealed that baicalein reduced the increased activities of superoxide dismutase (SOD) and malondialdehyde (MDA), and attenuated the decreased activities of glutathione peroxidase (GPx) and catalase in 2VO rats. The results of the present observation suggest that baicalein has therapeutic potential for the treatment of vascular dementia, which is most likely related, at least in part, to its antioxidant action.     

Environmental enrichment ameliorates phencyclidine-induced cognitive deficits

Recent work has suggested that environmental enrichment during development can enhance aspects of learning and memory, however its effects on executive function and cognitive flexibility have not been well studied. The goal of this research was to evaluate whether environmental enrichment (EE) that included wheel running would improve cognitive performance in young male Long Evans rats that received subchronic administration of either phencyclidine (PCP) or saline. We used a sensitive extradimensional/intradimensional (ED/ID) test of cognitive flexibility similar to that used in humans and nonhuman primates for assessing executive function. PCP-treated rats demonstrated a selective impairment on ED shift (EDS) performance without significant impairment on other discrimination problems when compared to saline treated control animals. A separate group of animals that received PCP + EE demonstrated significantly improved performance on EDS and reversal learning problems, whereas the saline + EE group demonstrated a non-selective improvement in overall performance when compared to non-enriched saline controls. The saline + EE group demonstrated greater activity levels as measured by wheel running when compared to the PCP + EE group, but no significant associations were found between wheel running and cognitive performance. Together, these data suggest that EE that features wheel running may have promoted a general cognitive enhancement while also selectively acting upon neurobiological mechanisms that subserve executive function and cognitive flexibility in impaired animals. Development of novel treatment methodologies that target mechanisms underlying the ameliorative effects of EE in this model of cognitive impairment may be a useful tool in the development of new therapeutic strategies for disorders that feature cognitive dysfunction as a key symptom.     

Diphenyl diselenide prevents oxidative damage induced by cigarette smoke exposure in lung of rat pups

The effect of cigarette smoke exposure on lungs of rat pups was evaluated. Animals were exposed to passive cigarette smoke during 3 weeks and a number of toxicological parameters in lung of pups were examined, such as lipid peroxidation, δ-aminolevulic acid dehydratase (δ-ALA-D) activity, components of the enzymatic antioxidant defenses (superoxide dismutase (SOD) and catalase activities) and non-enzymatic antioxidant defenses (Vitamin C and non-protein thiol (NPSH) levels). Furthermore, a possible protective effect of diphenyl diselenide, (PhSe)₂, was studied. The results demonstrated an increase in lipid peroxidation, an inhibition of δ-ALA-D activity, a reduction of Vitamin C and NPSH levels induced by cigarette smoke exposure, indicating damage in lungs of rat pups. Oral administration of (PhSe)₂ (0.5 mg/kg) restored TBARS levels, non-enzymatic antioxidant defenses and activity of δ-ALA-D. These results indicated that exposure to cigarette smoke enhanced oxidative stress, thereby disturbing the tissue defense system. (PhSe)₂ protected against oxidative damage induced by cigarette smoke exposure in lung of rat pups.     

Diphenyl diselenide reverses gastric lesions in rats: Involvement of oxidative stress

The aim of the present study was to evaluate if diphenyl diselenide administered by oral route was effective in restoring gastric lesions induced by ethanol. The possible involvement of oxidative stress in diphenyl diselenide antiulcer effect was also evaluated. Different doses of diphenyl diselenide (dissolved in soya bean oil, 1 mL/kg) were administered orally 1 h before (pre-treatment study) or 1 h after ethanol (70%, v/v, 2 mL/kg, post-treatment study). Ulcer lesions were quantified 1 h after ethanol administration (pre-treatment protocol) or 1 h after diphenyl diselenide study (post-treatment protocol). Diphenyl diselenide (0.1–10 mg/kg or 0.32–32 μmol/kg), when administered previously or posteriorly prevented and reversed respectively, the development of gastric lesions induced by ethanol in rats. A number of markers of oxidative stress were examined in rat stomach including thiobarbituric acid reactive species (TBARS), catalase (CAT), superoxide dismutase (SOD), non-protein thiol groups (NPSH) and ascorbic acid. In addition to attenuating the gastric lesions, low doses of diphenyl diselenide prevented (pre-treatment) or reversed (post-treatment) the ethanol-induced changes in TBARS, SOD activity and ascorbic acid content. In conclusion, the present data reveal that diphenyl diselenide, administered by oral route, possesses an antiulcer effect by modulating antioxidant mechanisms.     

Rosiglitazone attenuates the cognitive deficits induced by high fat diet feeding in rats

The present study was designed to test the hypothesis that insulin resistance plays a role in high fat diet feeding induced cognitive deficits. Rats consuming the high fat diet exhibited characteristic features of insulin resistance viz. mild hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and hyperinsulinemia. Further, these rats showed a severe deficit in learning and memory. In contrast, rosiglitazone at the dose of 5 mg/kg, p.o. for 7 days prior to biochemical and behavioral testing significantly lowered the plasma glucose, triglycerides, cholesterol, and insulin levels. These animals also performed better on Morris water maze task, suggesting improved spatial memory. Our data demonstrate that the insulin sensitizers can overcome the cognitive deficits arising from high fat diet feeding, which may be in part mediated through the development of peripheral insulin resistance.     

Diphenyl diselenide changes behavior in female pups

Diphenyl diselenide, (PhSe)(2), is an organoselenium compound that affects a number of neuronal processes. The effect of maternal subcutaneous (s.c.) injection of 25 mg/kg (PhSe)(2) once daily during early postnatal development (from PND 1 to 21) was evaluated in offspring of Wistar rats. The physical and neural reflexes were recorded at pre-weaning period. The behavioral changes in the elevated plus-maze (EPM), open-field and rotarod tasks were performed in 28-day-old pups. Selenium brain status was significantly increased ( approximately 41%) in rat pups. Statistically significant decreases in body weight were observed during lactation period in male and female pups exposed to 25 mg/kg (PhSe)(2). There were no dose-related changes on landmarks indicative of physical and reflexologic parameters of development in rats. (PhSe)(2) induced a disinhibitory effect in EPM behavior according to gender. Specifically, exposure to (PhSe)(2) increased entries and duration in the open arms of the EPM in females but not in males. Locomotor activity and rearing increased by (PhSe)(2) exposure in both male and female offspring in the open field. Both groups were similar in response to motor coordination in the rotarod. We concluded that maternal (PhSe)(2) exposure during lactation increased selenium levels in the pup brain and caused changes on developmental and behavioral parameters of Wistar rat offspring.     

Chrysin improves cognitive deficits and brain damage induced by chronic cerebral hypoperfusion in rats

Chronic cerebral hypoperfusion, induced by permanent occlusion of bilateral common carotid arteries (2VO), is related to neurological disorders and contributes to cognitive decline. Chrysin (5,7-dihydroxyflavone) is an important member of the flavonoid family. The aim of this study is to investigate the effects of chrysin on cognitive deficits and brain damage in this rat 2VO model. At 52days after ligation, the escape latency in Morris water maze was significantly increased in rats subjected to 2VO, the neuronal damage was also increased accompanied by a large proliferation in glial fibrillary acidic protein (GFAP) immunoreactivity with marked white matter lesions, and neuronal cell apoptosis, all of which were significantly alleviated by long treatment of chrysin (30mg/kg). Biochemical examinations revealed that chrysin decreased lipid peroxide, reduced the increased activities of superoxide dismutase, and attenuated the decreased activities of glutathione peroxidase in 2VO rats. The results suggest that chrysin may have therapeutic potential for the treatment of neurodegeneration and dementia caused by decreased cerebral blood flow, which is most likely related, at least in part, to its anti-inflammatory and antioxidant properties.     

Microglial inhibitory effect of ginseng ameliorates cognitive deficits and neuroinflammation following traumatic head injury in rats

Traumatic brain injury produces several neuropathological alterations, some of them are analogous to patients suffering from memory disorders. Role of neuroinflammation and oxidative stress has been suggested in the pathophysiology of brain injury-induced cognitive dysfunction. Therefore, the present study was designed to explore the possible role of ginseng and its interaction with minocycline (microglial inhibitor) against experimental brain trauma-induced behavioral, biochemical and molecular alterations. Wistar rats were exposed to brain traumatic injury using weight-drop method. Following injury and a post-injury rehabilitation period of 2 weeks, animals were administered vehicle/drugs for another 2 weeks. Brain injury caused significant memory impairment in Morris water maze task as evident from increase in escape latency and total distance travelled to reach the hidden platform. This was followed by a significant decrease in time spent in target quadrant and frequency of appearance in target quadrant. Further, there was a significant increase in oxidative stress markers, neuroinflammation (TNF-α and IL-6) and acetylcholinesterase levels in both cortex and hippocampal regions of traumatized rat brain. Ginseng (100 and 200 mg/kg) and minocycline (50 mg/kg) treatment for 2 weeks significantly attenuated all these behavioral, biochemical and molecular alterations. Further, combination of sub-effective doses of ginseng (50 and 100 mg/kg) and minocycline (25 mg/kg) potentiated their protective effects which was significant as compared to their effects alone. The results of the present study suggest that the therapeutic effects of ginseng might involve inhibition of microglial pathway against head trauma-induced cognitive impairment and neuroinflammation in rats.     

Cognitive deficits induced by melamine in rats

Many studies reported that infants and animals were affected by food containing melamine, and the renal pathology was the main manifestation in intoxicated case. Our previous studies showed that melamine could impair hippocampal function and inhibited differentiated PC12 cell proliferation in vitro. The present study aimed to examine the effect on hippocampus and the possible mechanism induced by melamine in vivo. To address the hypothesis that melamine would impair the hippocampal function in vivo and then induce cognitive deficits, male Wistar rats were used to establish an animal model and melamine administered at a dose of 300 mg kg/day for 4 weeks. Morris water maze (MWM) test was employed to evaluate the learning and memory. The long term potentiation (LTP) from Schaffer collaterals to CA1 region in the hippocampus was recorded. The result of MWM test showed that there were significant deficits of learning and memory induced by melamine. LTP test presented that field excitatory postsynaptic potentials (fEPSPs) slopes were significantly lower in melamine group compared to that in control group. In conclusion, melamine had a toxic influence on hippocampus, which induced the learning and memory deficits. It suggested that the potential mechanism was associated with impairments of synaptic plasticity.     

Persisting cognitive deficits induced by low-dose, subchronic treatment with MK-801 in adolescent rats

Cognitive impairments have been proposed as a core feature of schizophrenia. Studies have shown that chronic or subchronic treatment with N-methyl-d-aspartate (NMDA) antagonists could induce cognitive deficits that resemble the symptoms of schizophrenia, yet few studies have investigated the effects of repeated NMDA blockade during adolescence on cognition. In the current study, adolescent, male rats were treated with an intraperitoneal injection of MK-801 (0.05, 0.1, and 0.2mg/kg) once daily for 14days. They were then tested 24h and 14days after drug cessation, respectively, in a series of behavioural tasks, including the object recognition task, the object-in-context recognition task and the working memory task of the Morris water maze (MWM). Results showed that object-in-context recognition and spatial working memory in the MWM were significantly impaired by repeated MK-801 treatment when animals were tested 24h after drug cessation, but object recognition was left intact. In particular, such deficits were observed 14days after drug cessation in the 0.2mg/kg group. The cognition-impairing effect of MK-801 could not be attributed to malnutrition or alterations in motor functions. Taken together, this study may provide support for establishing an animal model of cognitive deficits of schizophrenia based on low-dose, repeated treatment of MK-801 during adolescence.     

Quetiapine ameliorates stress-induced cognitive inflexibility in rats

The antidepressant action of quetiapine has been demonstrated in clinical and preclinical studies. Nevertheless, little is known about its effectiveness in the treatment of frontal-like cognitive disturbances that may be associated with stress-related disorder. Therefore, the aim of the present study was to investigate whether quetiapine would prevent and/or reverse stress-induced cognitive impairments in a rat model of prefrontal cortex (PFC)-dependent attentional set-shifting task (ASST). Because quetiapine augmentation to selective serotonin reuptake inhibitors (SSRIs) has recently been proven to be beneficial in neuropsychiatric disorders, a separate experiment was designed to assess the impact of combined administration of inactive doses of quetiapine and escitalopram on ASST performance in rats. According to our previous studies, 1?h daily exposure to restraint stress for 7 days significantly and specifically impaired extra-dimensional (ED) set-shifting ability of rats. Quetiapine (2.5?mg/kg, PO) given to rats prior to the restraint sessions completely prevented this stress-induced cognitive inflexibility. Similar effect was demonstrated after pretreatment with the α1-adrenoceptor antagonist, prazosin (1?mg/kg, IP). Moreover, acute administration of quetiapine before the test reversed set-shifting deficits in stressed rats (0.63, 1.25 and 2.5?mg/kg, PO) and improved ED performance of cognitively unimpaired control animals (1.25 and 2.5?mg/kg, PO). Finally, the combined administration of inactive doses of quetiapine (0.63 and 0.3?mg/kg in control and stressed rats, respectively) and escitalopram (0.3?mg/kg, IP) facilitated set-shifting performance in either control or stressed rats. In conclusion, quetiapine administration either prevented or reversed stress-induced cognitive inflexibility in rats. In addition to promoting of set-shifting by itself, quetiapine also enhanced the procognitive efficacy of escitalopram. The potential contribution of the antagonism at α1-adrenoceptors to the mechanisms underlying the protective action of quetiapine requires further evaluation. These findings may have therapeutic implications for the treatment of frontal-like disturbances, particularly cognitive inflexibility, in stress-related psychiatric disorders. This article is part of a Special Issue entitled 'Cognitive Enhancers'.     

Thunbergia laurifolia extract ameliorates cognitive and emotional deficits in olfactorectomized mice

Abstract

Context: Thunbergia laurifolia Lindl. (Acanthaceae) is a Thai medicinal plant used for the detoxification of poison which is likely to be beneficial for the treatment of cognitive deficits including Alzheimer's disease.

Objective: To elucidate the effects of Thunbergia laurifolia leaf extract (TLL) on cognitive dysfunction and depression-like behavior in olfactory bulbectomized mice (OBX).

Materials and methods: OBX mice were treated daily with TLL at the dose of 250 and 500?mg/kg, tacrine, and imipramine, on the day after 10?d of OBX operation. The effects of TLL on cognitive and depression-like behavior of the animals were analyzed. After completing behavioral experiments, the expression levels of cholinergic marker genes encoding ChAT and muscarinic M₁ receptor were quantitatively analyzed.

Results: TLL and tacrine reduced OBX-induced cognitive deficits in the object recognition test (ORT) with the time spent for the novel object two times longer than that of the familiar object. Moreover, TLL at the dose of 500?mg/kg and imipramine ameliorated depression-like behavior in the tail suspension test (TST) by reducing the duration of immobility from 25.18% to 3.16% and from 25.18% to 6.48%, respectively. TLL at the dose of 250 and 500?mg/kg reversed the OBX-induced down-regulation of ChAT mRNA expression in the hippocampus from 0.12 to 0.17 and 0.24, respectively, while the down-regulation of mRNA expression of muscarinic M₁ receptor was also reversed by TLL from 0.23 to 0.38 and 0.48, respectively.

Conclusions: TLL ameliorates non-spatial short-term memory deficits in OBX mice, and has the potential to exhibit an antidepressant-like action.     

Postischemic administration of Z-Ligustilide ameliorates cognitive dysfunction and brain damage induced by permanent forebrain ischemia in rats

Previous studies have demonstrated that Z-Ligustilide (LIG), a characterized phthalide constituent present in numerous medical Umbelliferae plants, has significant neuroprotective effects in transient forebrain ischemia and permanent cerebral focal ischemia. The present study further investigated the effect of LIG on chronic cerebral hypoperfusion. Male Wistar rats were subjected to permanent ligation of both common carotid arteries (2VO). On Days 8-12 postsurgery, rat cognition was assessed in the Morris water maze. Rats with significantly impaired acquisition of spatial information were randomly allocated to three groups and orally administered LIG (10 or 40 mg/kg/day) or volume-matched vehicle on Days 13-40 post-2VO surgery. The sham-operated group served as controls. After long-term treatment with LIG, the impaired animals' behavioral, biochemical, and histopathological features were examined. Compared to the sham-operated group, significant cognitive impairment was observed in the vehicle-treated group 40 days after 2VO. Shortened mean escape latency was detected in the Morris water maze in rats treated with LIG (p<0.01 vs. vehicle-treated group) during the same trial days. Chronic 2VO-induced pathological changes included neuronal loss and an increase of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in the hippocampus. These effects were prevented with LIG treatment (p<0.01 vs. vehicle-treated group). LIG also significantly reduced malondialdehyde levels and increased superoxide dismutase activity in ischemic brain tissue (p<0.05 and p<0.01 vs. vehicle-treated group). In addition, LIG significantly increased choline acetyltransferase activity and inhibited acetylcholinesterase activity in ischemic brain tissues (p<0.05 and p<0.01 vs. vehicle-treated group). The present data demonstrate that LIG significantly prevented chronically hypoperfused cognitive deficits and brain damage at least partly through an antioxidant effect and improved cholinergic activity. The present findings suggest that LIG may have therapeutic potential in treating vascular dementia and cerebrovascular insufficiency.