Edaravone improves the post-traumatic brain injury dysfunction in learning and memory by modulating Nrf2/are signal pathway

OBJECTIVES: To investigate the molecular mechanism of edaravone (EDA) in improving the post-traumatic brain injury (TBI) dysfunction in learning and memory. METHODS: In vitro and in vivo TBI models were established using hydrogen peroxide (H2O2) treatment for hippocampal nerve stem cells (NSCs) and surgery for rats, followed by EDA treatment. WST 1 measurement, methylthiazol tetrazolium assay, and flow cytometry were performed to determine the activity, proliferation, and apoptosis of NSCs, and malondialdehyde (MDA), lactic dehydrogenase (LDH), and reactive oxygen species (ROS) detection kits were used to analyze the oxides in NSCs. RESULTS: Following EDA pretreatment, NSCs presented with promising resistance to H2O2-induced oxidative stress, whereas NSCs manifested significant increases in activity and proliferation and a decrease in apoptosis. Meanwhile, for NSCs, EDA pretreatment reduced the levels of MDA, LDH, and ROS, with a significant upregulation of Nrf2/antioxidant response element (ARE) signaling pathway, whereas for EDA-treated TBI rats, a significant reduction was observed in the trauma area and injury to the hippocampus, with improvement in memory and learning performance and upregulation of Nrf2/ARE signaling pathway. CONCLUSIONS: EDA, by regulating the activity of Nrf2/ARE signal pathway, can improve the TBI-induced injury to NSCs and learning and memory dysfunction in rats.

Effects of gallic acid and physical exercise on passive avoidance memory in male rat

Learning and memory play main roles in daily life of human, and memory represents the basis of all trainings and learning. The aim of the current study is to investigate the effects of gallic acid and physical exercise on the levels of passive avoidance memory in rat. In this experimental study, 46 rats weighing 200-300 g were randomLy divided to six groups of eight each: including control group, groups treated with 10 and 20 mg/kg gallic acid, group undergoing physical exercise alone, and groups both undergoing physical exercise and treated with 10 and 20 mg/kg gallic acid. The interventions continued for 10 days. After the intervention, passive avoidance memory was measured by shuttle box, blood samples were taken, and serum and brain antioxidant capacity and malondialdehyde (MDA) levels were measured. Secondary latency in shuttle box significantly increased in groups undergoing treadmill exercise and undergoing treadmill exercise + treating 10 and 20 mg/kg gallic acid. In groups treated with 10 and 20 mg/kg gallic acid alone, secondary latency increased significantly. Results confirmed the effects of gallic acid and physical exercise, either alone or combined, in improving memory.

Hyperbaric Oxygen Pretreatment Improves Cognition and Reduces Hippocampal Damage Via p38 Mitogen-Activated Protein Kinase in a Rat Model

PURPOSE: To investigate the effects of hyperbaric oxygen (HBO) pretreatment on cognitive decline and neuronal damage in an Alzheimer’s disease (AD) rat model. MATERIALS AND METHODS: Rats were divided into three groups: normal saline (NS), AD, and HBO+AD. In the AD group, amyloid β peptide (Aβ)₁₋₄₀ was injected into the hippocampal CA1 region of the brain. NS rats received NS injection. In the HBO+AD group, rats received 5 days of daily HBO therapy following Aβ₁₋₄₀ injection. Learning and memory capabilities were examined using the Morris water maze task. Neuronal damage and astrocyte activation were evaluated by hematoxylin-eosin staining and immunohistochemistry, respectively. Dendritic spine density was determined by Golgi-Cox staining. Tumor necrosis factor-α, interleukin-1β, and interleukin-10 production was assessed by enzyme-linked immunosorbent assay. Neuron apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Protein expression was examined by western blotting. RESULTS: Learning and memory dysfunction was ameliorated in the HBO+AD group, as shown by significantly lower swimming distances and escape latency, compared to the AD group. Lower rates of neuronal damage, astrocyte activation, dendritic spine loss, and hippocampal neuron apoptosis were seen in the HBO+AD than in the AD group. A lower rate of hippocampal p38 mitogen-activated protein kinase (MAPK) phosphorylation was observed in the HBO+AD than in the AD group. CONCLUSION: HBO pretreatment improves cognition and reduces hippocampal damage via p38 MAPK in AD rats.

Possible roles of COX-1 in learning and memory impairment induced by traumatic brain injury in mice

People who suffer from traumatic brain injury (TBI) often experience cognitive deficits in spatial reference and working memory. The possible roles of cyclooxygenase-1 (COX-1) in learning and memory impairment in mice with TBI are far from well known. Adult mice subjected to TBI were treated with the COX-1 selective inhibitor SC560. Performance in the open field and on the beam walk was then used to assess motor and behavioral function 1, 3, 7, 14, and 21 days following injury. Acquisition of spatial learning and memory retention was assessed using the Morris water maze on day 15 post-TBI. The expressions of COX-1, prostaglandin E2 (PGE2), interleukin (IL)-6, brain-derived neurotrophic factor (BDNF), platelet-derived growth factor BB (PDGF-BB), synapsin-I, and synaptophysin were detected in TBI mice. Administration of SC560 improved performance of beam walk tasks as well as spatial learning and memory after TBI. SC560 also reduced expressions of inflammatory markers IL-6 and PGE2, and reversed the expressions of COX-1, BDNF, PDGF-BB, synapsin-I, and synaptophysin in TBI mice. The present findings demonstrated that COX-1 might play an important role in cognitive deficits after TBI and that selective COX-1 inhibition should be further investigated as a potential therapeutic approach for TBI.

Learning and memory promoting effects of crude garlic extract.

Chronic administration of aged garlic extract has been shown to prevent memory impairment in mice. Acute and chronic (21 days) effects of marketed formulation of crude garlic extract (Lasuna) were evaluated on learning and memory in mice using step down latency (SDL) by passive avoidance response and transfer latency (TL) using elevated plus maze. Scopolamine (0.4 mg/kg, ip) was used to induce amnesia in mice and piracetam (200 mg/kg, ip) served as positive control. In the acute study, Lasuna (65 mg/kg, po) partially reversed the scopolamine-induced amnesia but failed to improve learning and memory in untreated animals. Chronic administration of Lasuna (40 mg/kg/day for 21 days) significantly improved learning both in control and scopolamine induced amnesic animals. Influence of Lasuna on central cholinergic activity and its antioxidant properties were also studied by estimating the cortical acetylcholinesterase (AchE) activity and reduced glutathione (GSH) levels respectively. Chronic administration of Lasuna inhibited AchE, while increasing GSH levels. Thus the results indicate that long-term administration of crude garlic extract may improve learning and memory in mice while the underlying mechanism of action may be attributed to the anti-AchE activity and anti-oxidant property of garlic.

[Interaction between vitamin A and pilocarpine on memory retention in adult male rats]

Several studies have reported that retinoic acid administration and/or consumption of a vitamin A-enriched diet could repair the aging induced memory deficits, decreased hippocampal long term potentiation [LTP]. Vitamin A deficiency impairs learning ability and hippocampal LTP in mice. In the present study, the effects of the vitamin A and pilocarpine [a muscarinic agonist] on memory retention in adult male rats were investigated. Post-training intracerebroventricular injections were carried out in all experiments. Memory retention was evaluated by using a step-through passive avoidance paradigm in adult male rats. Vitamin A [1000 and 2000 IU/rat] and pilocarpine [1 microg/rat] increased memory retention. The acetylcholine receptor agonist [pilocarpine] increased the response to vitamin A. The response to vitamin A was potentiated by pilocarpine. It is concluded that vitamin A elicits an interaction with the cholinergic system in memory retention

[Effects of pioglitazone injection into hippocampal CA1 area on spatial learning and memory deficits in rats]

Pioglitazone from thiazolidinediones generation, represent a new antidiabetic drugs that have been introduced in the world recently. Thiazolidinediones can improve insulin resistance by activating the nuclear peroxoxisome proliferator activated receptor-gamma [PPAR-gamma] and increasing insulin sensitivity in their receptors. Insulin and its receptors are found in specific areas of CNS with a variety of region-specific functions. The effects of insulin in CNS are different from its direct glucose regulation in the periphery. Hippocampus and cerebral cortex distributed insulin/insulin receptor have been shown to be involved in brain cognitive functions. In the present study, the effect of pioglitazone microinjection into CA1 region of rat hippocampus using Morris water maze performance has been investigated. In this experimental study, male N-MRI rats were randomly divided into control, DMF [dimethyl formamide] and pioglitazone groups [0.001, 0.01, 0.1, 1, 10 microg/rat]. Drugs were injected [1 microl/rat] into CA1 region bilaterly during 1 min. Thirty minutes after the intrahippocampal injection of drugs, water maze training was started. Pioglitazone had a dose dependent effect. The spatial learning and memory didn't change with lower dose of pioglitazone, but improved with intermediate doses, while they impaired with higher dose. These results suggest that intrahippocampal injection of pioglitazone may have a dose-dependent effect on spatial learning and memory in rats in range of 0.001 to 1 microg/rat

[ effect of sodium salicylate injection on spatial learning and memory of rat]

Cyclooxygenase [COX] enzyme known as a regulatory factor in synaptic plasticity. It has been reported that synaptic plasticity is one of the mechanisms involved in learning and memory processes. In the current study peripheral injection's effects of sodium salicylate [as a non selective COX inhibitor] on spatial learning and memory have been investigated. Four groups of male rats received different doses of sodium salicylate [0, 200, 300, 400 mg/kg; i.p.]. Studies were performed using Morris Water Maze [MWM]. Spatial learning and memory parameters were subjected to the one- and two-way analyses of variance [ANOVAs] followed by Tukey's post hoc test. Data showed that intraperitoneal injection of sodium salicylate had not significant effect on spatial learning parameters [including escape latency and traveled distance to hidden platform in training days]; but administration of high dose of the drug [400 mg/kg] significantly increased the percentage of time that animals spent in the target quadrant in probe trial testing. Peripheral injection of the COX inhibitor has no significant effect on spatial learning; but potentiates spatial memory consolidation using MWM

Effects of isoflavone on the learning and memory of women in menopause: a double-blind placebo-controlled study

Hormone decline is common to all women during aging and, associated with other factors, leads to cognitive impairment. Its replacement enhances cognitive performance, but not all women present a clinical and family or personal history that justifies its use, mainly women with a history of cancer. The aim of this study was to determine whether a daily oral dose of 80 mg of isoflavone extract for 4 months can produce benefits in women with low hormone levels, contributing to improvement in cognitive aspects. The sample comprised 50- to 65-year-old women whose menstruation had ceased at least 1 year before and who had not undergone hormone replacement. The volunteers were allocated to two groups of 19 individuals each, i.e., isoflavone and placebo. There was a weak correlation between menopause duration and low performance in the capacity to manipulate information (central executive). We observed an increase in the capacity to integrate information in the group treated with isoflavone, but no improvement in the capacity to form new memories. We did not observe differences between groups in terms of signs and symptoms suggestive of depression according to the Geriatric Depression Scale. Our results point to a possible beneficial effect of isoflavone on some abilities of the central executive. These effects could also contribute to minimizing the impact of memory impairment. Further research based on controlled clinical trials is necessary to reach consistent conclusions.

[ effect of silymarin on learning and histological changes of hippocampal regions of rats]

Silymarin, an extract from seeds of milk thistle [Silybum marianum], is known to have hepato-protective, anticarcinogenic, antioxidant and estrogenic effects. The aim of the present study was to test the effect of silymarin on passive avoidance learning in rats. This was an experimental study carried on Wistar rats in Arak Unviersity, Iran. The animals were provided with silymarin [from day 7 of gestational age to 4 weeks after birth] at 2 doses of 180 mg/kg in the experimental group 1 [Exp 1] and 90mg/kg in the experimental group 2 [Exp 2] while the sham group received saline and the control group with regular food and water. The memory retention and duration of step-through latency in male offsprings was determined by passive avoidance apparatus. Neuronal density in hippocampus was established by histopathological value less than 0.05 was considered as significant. Both experimental groups showed significantly longer step-through latency compared to control group [p<0.05]. The average number of pyramidal cells in hippocampal CA1 and granular cells in the hippocampal DG were remarkably higher in Exp 1 and Exp 2 groups compared to control group. The difference between Exp 1 and Exp2 for pyramidal cells was found to be significant [p<0.01 and p<0.05, respectively]. Silymarin produced a significant increase in learning and memory. Also, our results indicate that silymarin is a dose dependent component. These data may lay a background for application of silybin in treatment of memory impairment diseases

[ effect of low concentration of lead acetate on learning ability and memory of rats during infancy and adulthood]

Numerous observations in clinical and preclinical studies indicate that the developing brain is particularly sensitive to lead [PB]'s pernicious effects. The effects of low concentrations of lead on neurodevelopment are complicated. Lead acetate can disrupt both the CNS activity and neurons development. The present study was carried out to assess the effect of low level lead exposure on learning and memory by active avoidance learning. This experimental study was conducted at the Islamic Azad University of Parand in 2008. Eight groups of NMRI rats [9 rats in each group] [weight 220 +/- 30 gr] consisting of six experimental groups [3 after infancy and 3 adult groups] were exposed to low concentrations of lead for 45 days. The drinking water of the experimental groups was replaced by 0.05%, 0.1% and 0.2% of lead acetate solution whereas the two control groups received distilled water. The results were analyzed using the SPSS software and student t-test. In this study, the learning and memory tests showed no significant differences between experimental groups [infancy and adulthood] and infancy control and adult control in number of shocks for 0.05% concentration of lead acetate. The memory test showed an increase in number of shocks for 0.1% and 0.2% concentration of lead acetate in adult groups and an increase in number of shocks for 0.2% concentration of lead acetate in infancy groups [P<0.05]. The learning test showed an increase in number of shocks for 0.2% concentration of lead acetate in infancy groups [P<0.05]. Mechanisms of lead poisoning in the CNS are not clear; and it as been suggested that lead exposure during life alters the granule cell neurogenesis and morphology in the hippocampus of infant or young adult rats

[ effects of chronic use of imatinib on wistar rat fetuses]

Imatinib mesylate selectively inhibits bcr/abl and other non-specific tyrosine kinases and represents a model of targeted therapy for chronic myeloid leukaemia [CML] as well as gastrointestinal stromal tumors [GIST]. This study was designed to evaluate effects of imatinib on pregnancy and development of fetus. In this experimental study, imatinib was administrated orally at doses of 7, 12, 22, 50 and 100 mg/kg/day and control groups received sterile water. The pregnant rats were subdivided into 2 groups. In group one, the pregnant rats were sacrificed on day 18 of gestation and the number alive and dead of foetuses were checked. The brain of fetuses were fixed in formalin and embedded in paraffin for histological studies. Selected slides were stained with hematoxylin and eosin [H and E]. In group two, the fetuses were allowed to become mature. The effect of drug on learning and memory were assessed by a passive avoidance method using shuttle box apparatus. Histological studies revealed no evidence of teratogenic effects of imatinib on development of frontal and parietal bones. Imatinib given in 100 mg/kg dose caused weight decrease [p<0.001] and increase mortality in fetuses [p<0.01]. Administration of imatinib in 7, 12, 22 and 50 mg/kg doses showed statistically significant reduction in learning and memory of fetuses [p<0.05]. Imatinib can decrease development, learning and memory of fetuses. So, it is recommended that women treated with imatinib avoid becoming pregnant

[Role of melatonin receptors in spatial learning of rats exposed to continuous light]

During critical period of mammal's CNS development, interaction of genetic and experience driven processes affects almost their all behaviors in adolescence. The aim of this study was to assess interaction of melatonin and its antagonist, Luzindole on the spatial learning and memory of the rats [Morris Water Maze [MWM]] exposed to continuous light. This experimental study included sixty 45-day-old male rats which were randomly allocated in two groups; control group went through cycles of 12 hours in light/12 hours in dark from birth to the end of the study and the light exposed group was reared in light. Each group also, had 3 subgroups: control, receiving melatonin and receiving luzindole [n=10 for every group]. Using MWM, the animals learning and memory was tested for 5 days. Our results indicated that in the learning phase, the light exposed animals spent more time to find the hidden platform than the control group. Luzindole improved the learning ability in light exposed animals. Melatonin also, slackens the spatial learning of the control animals. luzindole improved spatial learning of the light exposed rats. Light exposure and melatonin had no effect on the memory of these animals. Luzindole only caused a disturbance in spatial memory of the rats in the control group. Light exposure and melatonin impair rat's spatial learning. Non of these two interventions influenced spatial learning of the rats

[ effect of oral and intraperitoneal administration of acorus calamus l. extract on learning and memory in male rats]

Learning and memory impairment during aging mind have a disturbance role in human life. Regarding to the defect mechanisms for prevention or treatment of memory loss, the new strategies were recommended for study on it. Importance of herbal medicine treatment encouraged us to examine the effect of a candidate plant Acorus calamus for improvement of learning and memory. Male rats were randomly divided to control and treatment groups. In treatment group the plant were applied to animals in oral [plant/ food ratio =% 6.25] for two weeks and in injected groups the plant extract were applied [i.p] to rat in 25, 50 and 100 mg/kg]. Finally, all experimental animal groups were conducted to Y maze and shuttle box tests in order to obtain spatial recognition and acquisition - recalling data, respectively. The step through latency [STL] time resulted from oral and 100 mg/kg injected dose groups show a significant difference with control animals. Also, alternation behavior [%] obtained from Y maze test data was marked than control rats. The present study show that oral and intraperitoneal administration of the extract in higher dose could have increase spatial recognition and recalling the data

[Effects boswellia carterii gum resin fractions on intact memory and hyoscine-induced learning impairments in rats performing the morris water maze task]

In traditional medicine, a gum resin obtained from Boswellia carterii, has been used as an agent for enhancing memory and learning abilities. In the present research, the effect of fractions obtained from gum resin of Boswellia carterii was assessed on enhancement of memory in intact and on memory impairments induced in rats by hyoscine using the Morris water maze task. The ethyl acetate [0.1 mg/kg] and N-butanol [0.1 mg/kg] fractions were injected intraperitoneally to rats 1 h before training for 5 consecutive days. During the training period, four trials were carried out each day. On the 5th day of the experiment, the locomotor activity was assessed using open field test. The effect of ethyl acetate fractions was evaluated on memory impairment induced by hyoscine [0.5 mg/kg]. The ethyl acetate [0.1 mg/kg] and N-butanol [0.1 mg/kg] fractions showed significant effects in enhancing the memory ability in intact rats. This effect was much significant with ethyl acetate fraction [p<0.001]. The ethyl acetate [0.1 mg/kg] fraction reduced the deficit effect of hyoscine on memory [p<0.001]. The N-butanol and ethyl acetate fractions [0.1 g/kg] have no effect on locomotor activity. On the basis of these results, B. carterii gum resin improved intact memory and the hyoscine impaired acquisition/performance activity. This effect may be mediated via cholinergic system

Effects of a cognitive modulator in the theta and alpha asymmetry during a typewriting task: a sensorimotor integration perspective / Efeitos de um modulador cognitivo na assimetria de teta e alfa durante uma tarefa de datilografia: uma perspectiva da integração sensório-motora

This study aimed to elucidate cortical mechanisms and to identify the areas where occur such mechanisms due to interaction between bromazepam and motor learning. The sample was composed of 45 healthy subjects randomly distributed in 3 groups: placebo (n=15), bromazepam 3 mg (n=15) or bromazepam 6 mg (n=15). To perform the experimental task, subjects sat comfortably at a distance of approximately 20 cm from the typewriter. The typewriter keyboard was covered with a wooden box to avoid visual information about the hands' position. The typewriting task was performed concomitantly with EEG recording. ANOVA two-way results indicated a decreased asymmetry in sensorimotor areas in the experimental groups. Our interpretation is that moderate doses of bromazepam may improve performance on tasks with predictable elements to promote stability of psychomotor functions, but may also impair performance on tasks executed in unpredictable environments.

O objetivo do estudo foi elucidar mecanismos corticais e identificar as áreas onde estas ocorrem tais mecanismos devido à interação entre bromazepam e aprendizagem motora. A amostra compreendeu 45 sujeitos hígidos distribuídos randomicamente em 3 grupos: placebo (n=15), bromazepam 3 mg (n=15) ou bromazepam 6 mg (n=15). Para a realização da tarefa experimental, sujeitos sentaram-se confortavelmente a uma distância de aproximadamente 20 cm da máquina de escrever. O teclado da máquina foi coberto com uma caixa de madeira para evitar informações visuais sobre a posição das mãos. O registro do EEGq ocorreu simultaneamente à tarefa de datilografia. Os resultados da ANOVA two-way indicaram menor assimetria em áreas sensório-motoras nos grupos experimentais. Nossa interpretação é que doses moderadas de bromazepam podem melhorar o desempenho em tarefas previsíveis por promover estabilidade das funções psicomotoras, mas pode prejudicar o desempenho em tarefas realizadas em ambientes imprevisíveis.

[Influence of basolateral amygdala lesion on the inhibitory effects of propranolol on voluntary exercise- induced enhancement of learning and memory

The beneficial effects of physical activity and exercise on brain functions such as improvement in learning and memory are well documented. In a recent study, we have found that blockade of beta-adrenergic receptors by propranolol attenuates an improvement of learning and memory by exercise. However, the anatomical sites of propranolol actions are not known. The aim of this study was to determine the role of Basolateral amygdala [BLA] in the inhibitory effects of propranolol on the beneficial effects of exercise on learning and memory. In order to block the beta-adrenergic receptors, male mice were received the beta-antagonist propranolol [10 mg/kg], before each night of five consecutive nights of exercise. The BLA lesion was made by electrolytic lesion [2mA, 2 s]. Learning and memory were tested on the Morris water maze task using a two-trials-per-day for five consecutive days. A probe trial was performed two days after the last training day. Our results showed that propranolol reversed the exercise-induced improvement in learning and memory in rat. This effect was not blocked by the BLA lesion. However, lesion of the BLA alone blocked exercise-induced enhancement of learning and memory. These findings indicate beta-adrenergic receptors located outside the BLA may mediate the effects of exercise on learning and memory. Also, the BLA play an important role in the mediating the effects of physical activity on learning and memory

[Effect of aspirin on learning and memory impaired by pentylenetetrazole kindling in male rat]

In recent years many studies have reported that aspirin could have beneficial effect on learning and memory in different diseases of central nervous system. The objective of present study was to explore the effect of aspirin on learning and memory of Rats in pentylenetetrazole kindling model. In this experimental study Rats were divided randomly into six groups [n=8]. Animals in three groups received aspirin [15 and 30 mg/kg, orally] and saline, one week before and during induction of kindling, respectivley. Kindling was induced in these groups by administration of pentylenetetrazole [PTZ: 40 mg/kg, ip]. Two groups of animals received only aspirin 25 and 30 microg/kg orally. Other group received only saline throughout the study and served as health control group. After induction of kindling the learning and memory of Rats was tested in shuttle box. Study was divided to three stages of adaptation, acquisition and retention test. Initial Latency [IL] time before electrical shock and Step through latency [STL] time, 20 min or 24h after acquisition was evaluated as learning and memory index. Locomotor activity was also evaluated in open filed test. PTZ kindling significantly decreased Initial Latency and Step through latency time, 20 min or also 24h after acquisition, and aspirin significantly increased these times in kindled animals [p<0.05]. Aspirin also had no significant effect on locomotor activity of animals. This study showed that the administration of aspirin to kindled Rats improved learning and memory impairments induced by pentylenetetrazole kindling

[ effects of prenatal morphine exposure on spatial learning]

Drug abuse during pregnancy is a growing problem in all developed countries worldwide. Maternal drug abuse affects the developing systems and the associated long-term effects can persist untill adulthood, decreasing the rate of their maturation. To determine the effects of prenatal morphine exposure on spatial learning Eighteen pregnant rats were divided into morphine, saline, and control groups. Morphine or saline was administrated [S.C] to female rats twice a day [at 12-hr intervals] during the days 11-18 of their gestational period [5 mg/kg morphine for the first 3 days and 10 mg/kg for further 5 days]. Pups [P90, n=6] were trained in an 8-arm radial maze apparatus.The data were analyzed statistically using Chi-square test. The results indicated that prenatal morphine exposure causes a reduction in the time needed to learn these trials however, they needed more time to complete regular trials. Prenatal morphine exposure impairs normal spatial learning