Cardiac and hepatic side effects of fluoxetine in male and female adolescent rats.

BACKGROUND: Fluoxetine (FLX) is widely prescribed as an antidepressant medicine in the juvenile population. OBJECTIVES: Although some adverse effects of FLX have been reported in adults, the present study aimed to investigate the side effects of FLX treatment during adolescence on the cardiac and hepatic systems. METHODS: Male and female rats were gavaged with FLX (5 mg/kg/day) on postnatal days (PND) 21 to PND 60. Following treatment, blood samples were collected and hepatic enzymes were evaluated. The specimens of the liver and heart of animals were subjected to histopathological assessment. RESULTS: Fluoxetine significantly raised serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in males, whereas the aspartate aminotransferase (AST) level increased in both male and female animals. In the histopathological study, hepatic plates were more seriously affected, and the sinusoids were irregular in adolescent male rats. Degenerative changes were observed especially in the first and second hepatic zones of FLX-treated male rats. Signs of inflammation and accumulation of lymphoid groups were frequently observed in the portal triad of the hepatic lobules. These alterations were more severe in male livers. Minimum or nearly normal changes were observed in female liver slides. In addition, the histological assessment indicated that treatment with FLX during adolescence also increased the heart's weight and the wall thickness of the right and left ventricles (hypertrophy) in male and especially female animals. CONCLUSION: Our findings may provide new insights into the cardiac and hepatic adverse effects of FLX.

Beneficial effects of enriched environment on behavior, cognitive functions, and hippocampal brain-derived neurotrophic factor level following postnatal serotonin depletion in male rats.

The neurotransmitter serotonin (5-HT) is one of the most important modulators of neural circuitry and has a critical role in neural development and functions. Previous studies indicated that changes in serotonergic system signaling in early life critically impact mental health, behavior, the morphology of hippocampal neurons, and cognitive functions across the lifespan. The enriched environment (EE) has indicated beneficial effects on behavior and cognitive functions in the developmental period of life, but its impacts on cognitive impairments and behavioral changes following postnatal serotonin depletion are unknown. Therefore, the present study aimed to evaluate the influences of the EE housing (postnatal days [PNDs] 21-60) following postnatal serotonin depletion (by para-chlorophenylalanine [PCPA], 100 mg/kg, s.c, in PNDs 10-20) on anxiety-related behaviors, cognitive functions, and brain-derived neurotrophic factor (BDNF) mRNA expression in the hippocampus of male rats. Memory and behavioral parameters were examined in early adulthood and after that, the hippocampi of rats were removed to determine the BDNF mRNA expression by PCR (PNDs 60-70). The findings of the present work indicated that adolescent EE exposure alleviated memory impairment, decreased BDNF levels, and anxiety disorders induced by experimental depletion of serotonin. Overall, these results indicate that serotonergic system dysregulation during the developmental periods can be alleviated by adolescent EE exposure.

Early life GABAA blockade alters the synaptic plasticity and cognitive functions in male and female rats.

Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in adults, has a critical contribution to balanced excitatory-inhibitory networks in the brain. Alteration in depolarizing action of GABA during early life is connected to a wide variety of neurodevelopmental disorders. Additionally, the effects of postnatal GABA blockade on neuronal synaptic plasticity are not known and therefore, we set out to determine whether postnatal exposure to bicuculline, a competitive antagonist of GABAA receptors, affects electrophysiologic changes in hippocampal CA1 neurons later on. To this end, male and female Wistar rats received vehicle or bicuculline (300 µg/kg) on postnatal days (PNDs) 7, 9 and 11, and then underwent different behavioral and electrophysiological examinations in adulthood. Postnatal exposure to bicuculline did not affect basic synaptic transmission but led to a pronounced decrease in paired-pulse facilitation (PPF) in CA1 pyramidal neurons. Bicuculline treatment also attenuated the long-term potentiation (LTP) and long-term depression (LTD) of CA1 neurons accompanied by decreased theta-burst responses in male and female adult rats. These electrophysiology findings together with the reduced brain-derived neurotrophic factor (BDNF) levels in the hippocampus and prefrontal cortex reliably explain the disturbance in spatial reference and working memories of bicuculline-treated animals. This study suggests that postnatal GABAA blockade deteriorates short- and long-term synaptic plasticity of hippocampal CA1 neurons and related encoding of spatial memory in adulthood.

Postnatal depletion of serotonin affects the morphology of neurons and the function of the hippocampus in male rats.

Serotonin (5-HT) is an essential neurotransmitter for the refined organization of the cerebral cortex. Studies have suggested that altered serotonin signaling contributes to cognitive impairment and psychiatric disorders. However, the exact role of this neurotransmitter on the development of hippocampal neurons is not recognized. Here we aimed to examine the effects of the para-chlorophenylalanine (PCPA; 100 mg/kg/daily, s.c. during the postnatal days 10-20), a reversible inhibitor of 5-HT synthesis, on the serotonin level of the hippocampal and prefrontal cortex. We also focused on the morphology of the neurons in the hippocampus and spatial learning and memory. Our results indicated that the administration of PCPA led to a decrease in serotonin levels in the hippocampus and prefrontal cortex. Postnatal serotonin depletion also induced subtle alterations in the neuronal populations of the hippocampus and impaired spatial memory in the adulthood period of life. We found that critical developmental periods of serotonin depletion caused degeneration and swelling of neurons as well as significant neuronal loss in the hippocampal CA1, CA3, and dentate gyrus (DG) areas. Thus, serotonin, a strikingly important neurotransmitter, can affect neuronal morphology, development, and hippocampal-dependent memory.

Calcitriol supplementation attenuates cisplatin-induced behavioral and cognitive impairments through up-regulation of BDNF in male rats.

Chemotherapy-induced cognitive impairment such as memory impairment and concentration problems are now extensively recognized as side effects of chemotherapy. These problems reduce the quality of life in patients. Therefore, the present study aims to examine the effects of calcitriol supplementation (100 ng/kg /day for five weeks) on cognitive impairment, behavioral deficits, and hippocampal brain-derived neurotrophic factor (BDNF) changes following cisplatin treatment (5 mg/kg/ once a week for five weeks). We also determined the impact of cisplatin and calcitriol administration on reaction time against the thermal stimulus and muscle strength. Our findings showed that cisplatin administration resulted in a significant increase in anxiety-like behaviors. Treatment of rats with cisplatin also impaired performance in the passive avoidance and novel object recognition tasks which are indicating cognitive deficits. Co-administration of calcitriol prevented the cisplatin-induced behavioral and cognitive impairments. Cisplatin exposure also resulted in enhanced reaction time to the thermal stimulus and decreased muscle ability. Besides, hippocampal BDNF levels were reduced in cisplatin-treated rats; however, calcitriol alleviated these effects of cisplatin and up-regulated BDNF mRNA in the hippocampus. In addition, calcitriol alone indicated a significant change in BDNF level compared to the control group. We conclude that increased hippocampal BDNF mediates the beneficial effects of calcitriol against neurotoxicity in cisplatin-exposed rats. However, further studies are required to explore the other mechanisms that mediate the beneficial effect of calcitriol.

Combined effects of royal jelly and environmental enrichment against stress-induced cognitive and behavioral alterations in male rats: behavioral and molecular studies.

BACKGROUND: Exposure to chronic stress has detrimental effects on cognitive and emotional processing. Also, the neuroprotective influences of environmental enrichment (EE) and royal jelly (RJ) have been indicated in previous studies. AIMS: To our knowledge, to date, there are no studies about the synergistic effects of EE and RJ on cognitive changes induced by stress. Therefore, this study aimed to investigate the protective effects of RJ, and EE on anxiety-like behaviors, cognitive functions, and expression of hippocampal and also prefrontal cortex (PFC) brain-derived neurotrophic factor (BDNF) levels in stressed rats. METHODS: By using restraint and cold temperature, rats were exposed to stressful situations and then subjected to treatment with RJ or/ and EE for 14 days. Stress induction was done 14 days before treatments by placing the rats in the restrainer under 4°C. Following the interventions, anxiety-like behaviors, novel object recognition memory (NORM), inhibitive avoidance performance, hippocampal, and PFC BDNF expression were examined. The plasma corticosterone level of all groups was also evaluated. RESULTS: Results showed increased plasma corticosterone levels, stress-induced deficits in the NORM and IA tests, and increased anxiety-like behaviors. EE and RJ improved these deficits with a decline in serum corticosterone and also increased BDNF levels in the hippocampus and PFC in stressed ones. CONCLUSION: The EE and the RJ prevented the detrimental effects of stress on anxiety-like behaviors and memory processes. These treatments can protect susceptible brain areas against chronic stress via improvement in behavioral and cognitive impairments through mediating BDNF expression.

Adolescent enriched environment exposure alleviates cognitive impairments in sleep-deprived male rats: Role of hippocampal brain-derived neurotrophic factor.

Developmental life experience has long-lasting influences on the brain and behavior. The present study aims to examine the long-term effects of the enriched environment (EE), which was imposed during the adolescence period of life, on their passive avoidance and recognition memories as well as anxiety-like behaviors and hippocampal brain-derived neurotrophic factor (BDNF) levels, in sleep-deprived male rats. In the present study, the male pups were separated from their mothers in postnatal day 21 (PND21) and were housed in the standard or EE for 40 days. In PND 61, the rats were allocated in four groups: control, SD (sleep deprivation), EE, and EE + SD groups. SD was induced in rats by a modified multiple platform model for 24 h. Open field, novel object recognition memory, and passive avoidance memory tests were used to examine behavior and cognitive ability. The expression of hippocampal BDNF levels was determined by PCR. The results revealed that SD increased anxiety-like behaviors and impaired cognitive ability, while adolescent EE housing alleviated these changes. In addition, EE reversed SD-induced changes in hippocampal BDNF level. We also demonstrated that EE not only has beneficial effects on the cognitive functions of normal rats but also declined memory deficits induced by SD. In conclusion, our results suggest that housing in EE during the adolescence period of life reduces cognitive impairment induced by SD. The increase of the BDNF level in the hippocampus is a possible mechanism to alleviate cognitive performance in sleep-deprived rats.

Alterations in the behavior, cognitive function, and BDNF level in adult male rats following neonatal blockade of GABA-A receptors.

Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the mature brain. At an early developmental period, it acts in an excitatory manner that influences many processes of proliferation, migration, and differentiation of the neurons. Previous evidence indicated that manipulation of the GABAergic system function by activation or blockade of its receptors during developmental periods leads to behavioral and cognitive abnormality in adulthood. Therefore, we examined the effects of neonatal blockade of GABA-A receptors by bicuculline on behavior, cognitive function, and hippocampal and prefrontal cortex (PFC) brain-derived neurotrophic factors level (BDNF) in adulthood. As a result, neonatal rats were treated with either bicuculline (75,150, and 300 µg/kg) or DMSO on postnatal days 7,9, and 11. These groups underwent the behavioral (open field, elevated plus maze, and hot plate) and learning and memory (passive avoidance learning and memory) tests in postnatal days (PNDs) 61-70. After the ending of the behavioral tests, the rats were sacrificed under deep anesthesia and the hippocampi and prefrontal cortex (PFC) of the brain were removed for assessing the BDNF mRNA expression. Our results indicated that neonatal administration of bicuculline at the highest dose increased passive avoidance memory and hippocampal BDNF level. Meanwhile, this drug at a low dose impaired this type of memory and increased PFC BDNF level. Besides, treatment with bicuculline during postnatal days increased anxiety and pain sensitivity in a dose-dependent manner. Taken together, these findings confirmed the notion that GABA-A receptors during the developmental period are important for programming neurobehavioral phenotypes in adult life.

Serotonin depletion during the postnatal developmental period causes behavioral and cognitive alterations and decreases BDNF level in the brain of rats.

A survey of the literature indicates that the developmental disruptions in serotonin (5-HT) levels can influence the brain development and the function. To the best of our knowledge, so far, there are a few studies about the effects of developmental period 5-HT depletion on cognition and behavior of adult male and female rats. Therefore, in the present study, we examined the effects of postnatal days (PND 10-20) administration of para-chlorophenylalanine (PCPA, 100 mg/kg, s.c) a 5-HT synthesis inhibitor, on anxiety-related behaviors, pain sensitivity, short-term recognition memory, and hippocampal and prefrontal cortex (PFC) brain-derived neurotrophic factor (BDNF) mRNA expression in adult male and female rats. Novel object recognition memory (NORM) and behavioral parameters (anxiety-like behaviors and pain sensitivity) were evaluated in early adulthood and after that, the hippocampi and PFC of the rat's brain were removed for the determination of BDNF mRNA expression. Our results indicated that the postnatal period administration of PCPA impaired short-term NORM. The postnatal developmental period treatment with PCPA also increased anxiety-like behaviors in the open field and elevated plus maze (EPM) tests. Postnatal PCPA treatment increased pain sensitivity in the hot plate test in both male and female rats, especially in female animals. In addition, postnatal days serotonin depletion decreased BDNF level in the hippocampus and PFC of both male and female rats. These findings demonstrate that serotonin plays the main role in neurodevelopment, cognitive functions, and behavior. Therefore, serotonergic system dysregulation during the developmental periods may have more adverse influences on the brain development of rats.

The Neuroprotective Effect of Mesna on Cisplatin-Induced Neurotoxicity: Behavioral, Electrophysiological, and Molecular Studies.

Peripheral neuropathy and cognitive impairments following cisplatin administration may interfere with the clinical usage of the drug. Mesna is a chemoprotective agent with anti-inflammatory and anti-oxidant effects. Our study aimed to investigate the protective effects of mesna against cisplatin-induced neurotoxicity. Neurotoxicity was induced by the administration of 2.5 mg/kg cisplatin twice a week for four consecutive weeks in male Wistar rats. The neuroprotective effect of mesna (150 mg/kg/day) was evaluated through behavioral, electrophysiological, and molecular studies. Cisplatin treatment caused passive avoidance memory impairment, increased anxiety-like behaviors, altered thermal sensitivity, and decreased muscle strength in a grip strength test. Our electrophysiological studies indicated that administration of cisplatin induced peripheral sensory neuropathy and decreased the amplitudes of the compound action potential of sensory nerves. Cisplatin administration increased MDA and 4-HNE levels and decreased anti-oxidant (SOD and GPx) enzymes. Proinflammatory cytokines (IL-1ß and TNF-α) and metalloproteinase-2 and 9 (MMP-2/9) were increased by cisplatin treatment. Morphological alterations were observed in the dorsal root ganglion (DRG) of cisplatin-treated rats. Cognitive impairments, anxiety, muscle strength, and thermal sensitivity changes induced by cisplatin were improved with mesna treatment. The reduced conduction velocity in sensory nerves was recovered in the cisplatin + mesna group. Mesna partially alleviated redox imbalance, reduced the proinflammatory cytokines, and MMP-2/9 levels. Mesna administration also relieved the morphological changes in DRG of cisplatin-treated rats. In conclusion, our results revealed that mesna can alleviate cisplatin-induced central and peripheral nervous system toxicity. These results support the concept that chemotherapy-induced neuropathy can be partially inhibited via mesna.

Effects of adolescent administration of fluoxetine on novel object recognition memory, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor level.

AIMS: Fluoxetine (FLX) is a common selective serotonin reuptake inhibitor, which is used in adolescents with psychiatric disorders. Controversial results have been obtained in different studies about the effects of FLX on cognitive functions. The present study was designed to examine the effects of chronic FLX exposure during adolescence on cognitive function, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression among adult male and female rats. MAIN METHODS: The sex-dependent effects of FLX chronic administration during adolescence (5 mg/kg/day, gavage) on short-term novel object recognition memory (NORM), anxiety-like behaviors, and BDNF mRNA expression in the hippocampus were examined. NORM and anxiety-like behaviors were assessed by novel object recognition, open field, and elevated plus-maze (EPM) tests, respectively. The expression of BDNF mRNA was also evaluated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). KEY FINDINGS: The present findings revealed the dysfunction of short-term NORM among the adolescent male and female rats exposed to FLX, while the mRNA expression of BDNF was significantly higher among the males. Moreover, adolescent FLX administration had different effects on the anxiety-like behaviors of the male and female rats. Adolescent FLX treatment also decreased the body weight of the male animals. SIGNIFICANCE: In conclusion, adolescent FLX treatment impairs cognitive functions in both sexes and increases BDNF mRNA expression in the hippocampus of the male animals. FLX administration during adolescence has sex-dependent effects on anxiety-like behaviors. These findings indicate that the impairment of cognitive functions can occur following the adolescent manipulation of the serotonergic system. Therefore, the side effects of chronic FLX administration during adolescence should be more considered.

Effects of exposure to enriched environment during adolescence on passive avoidance memory, nociception, and prefrontal BDNF level in adult male and female rats.

Previous studies demonstrated that an enriched environment (EE) exposure improves cognitive functions, synaptic plasticity, neurogenesis, and induction of brain-derived neurotrophic factor (BDNF) in multiple brain regions of laboratory animal models. Also, studies on the sex-dependent effects of exposure to EE during adolescence on adult cognitive functions are less. Therefore, the present experiment was aimed to assess the effects of EE during adolescence on passive avoidance learning and memory, nociception, and prefrontal cortex (PFC) BDNF mRNA levels in the adult male and female rats. Our results indicated that housing in the EE during adolescence improves passive avoidance memory and increases nociceptive response against thermal stimulus in both sexes. Findings of our study also showed an increased BDNF level in the PFC of female animals. As a result, sex differences can affect the expression of BDNF mRNA in the PFC. Further research concerning the precise mechanisms underlying sex hormone-dependent production of BDNF in PFC is critical.

Sex-dependent effects of postweaning exposure to an enriched environment on novel objective recognition memory and anxiety-like behaviors: The role of hippocampal BDNF level.

Exposure to enriched environment (EE) has been indicated to enhance cognitive functions, hippocampal neural plasticity, neurogenesis, long-term potentiation, and levels of the brain-derived neurotrophic factor (BDNF) in laboratory animals. Also, studies on the sex-dependent effects of exposure to EE during adolescence on adult cognitive functions are less. This is important because the beneficial effects of EE may be predominant in the adolescence stage. Therefore, the present study was designed to compare the effects of EE during adolescence (PND21-PND60) on novel objective recognition memory (NORM), anxiety-like behaviors, and hippocampal BDNF mRNA level in the adult male and female rats. Assessment of NORM and anxiety-like behaviors has been done by novel objective recognition task, open field (OF), and elevated plus maze (EPM), respectively. The expression of BDNF mRNA level was also evaluated by quantitative RT-PCR. Our findings demonstrated that housing in the EE during adolescence improves NORM in adult male rats. Also, exposure to EE during adolescence had a different effect on anxiety-like behaviors in both sexes. Additionally, our results indicated an augmented BDNF level in the hippocampus of male and female rats. In conclusion, adolescent exposure to EE has sex-dependent effects on cognitive functions and anxiety-like behaviors and increases BDNF mRNA expression in the hippocampus of both male and female rats; thus, BDNF is an important factor that can mediate the beneficial effects of EE and running exercise on cognitive functions and psychiatric traits.

The compensatory effect of regular exercise on long-term memory impairment in sleep deprived female rats.

Previous studies have been shown that exercise can improve short-term spatial learning, memory and synaptic plasticity impairments in sleep deprived female rats. The aim of the present study was to investigate the effects of treadmill exercise on sleep deprivation (SD) induced impairment in hippocampal dependent long-term memory in female rats. Intact and ovariectomized female rats were used in the current study. Exercise protocol was 4 weeks treadmill running. Twenty four hour SD was induced by using multiple platform apparatus after learning phase. Spatial learning and long-term memory was examined by using the Morris Water Maze (MWM) test. Our results indicated that sleep deprivation impaired long term memory in the intact and ovariectomized female rats, regardless of reproductive status (p<0.05) and treadmill exercise compensated this impairment (p<0.05). In conclusion the results of the current study confirmed the negative effect of SD on cognitive functions and regular exercise seems to protect rats from these factors, however more investigations need to be done.

Effect of castration on the susceptibility of male rats to the sleep deprivation-induced impairment of behavioral and synaptic plasticity.

In both human and animal studies, the effect of sleep deficiency on cognitive performances has mostly been studied during adulthood in males, but very little data exist concerning the effects of poor sleep in gonadal hormones-depleted status, such as aging or gonadectomized (GDX) male animal models. The present study investigated the potential modulatory effects of the endogenous male sex hormones on the 48h REM sleep deprivation (SD)-induced cognitive and synaptic impairments by comparing the gonadally intact with castrated male rats, a rodent model of androgen-deprived male animals. The multiple platform method was used for inducing REM-SD and spatial performances were evaluated using Morris water maze (MWM) task. Early long-term potentiation (E-LTP) was measured in area CA1 of the hippocampus and PCR and western blotting assays were employed to assess brain derived neurotrophic factor (BDNF) gene and protein expression in the hippocampus. To reveal any influence of sleep loss on stress level, we also evaluated the plasma corticosterone levels of animals. Regardless of reproductive status, REM-SD significantly disrupted short-term memory and LTP, as well as hippocampal BDNF expression. The corticosterone levels were not significantly changed following REM-SD neither in intact nor in GDX male rats. These findings suggest that depletion of male sex steroid hormones by castration does not lead to any heightened sensitivity of male animals to the deleterious effects of 48h REM-SD on cognitive and synaptic performances.

Ovariectomy does not exacerbate the negative effects of sleep deprivation on synaptic plasticity in rats.

In our previous work, we found that female rats showed more cognitive impairment than male rats following 72h sleep deprivation (SD). Here, we compared the intact female with ovariectomized (OVX) rats to assess the potential modulatory effects of endogenous female sex hormones against the 48h SD-induced cognitive and synaptic modulations. The multiple platform method was applied for SD induction and spatial performances were determined using Morris water maze (MWM) task. Early longterm potentiation (E-LTP) was evaluated in area CA1 of the hippocampus and PCR and western blotting assays were employed to assess hippocampal BDNF gene and protein expression. To reveal any influence of sleep loss on stress level, we also measured the plasma corticosterone levels of animals. Regardless of reproductive status, SD significantly impaired short-term memory and LTP, but did not significantly change the BDNF expression in the hippocampus. The corticosterone levels were decreased in both intact and OVX female rats following SD. These findings suggest that depletion of female sex steroid hormones does not lead to any heightened responsivity of female animals to the negative effects of SD on cognitive and synaptic functions.

Exercise improves learning and memory impairments in sleep deprived female rats.

Inadequate sleep is a common problem in modern societies. It has been previously shown that female rats are more vulnerable to the deleterious effects of sleep deprivation on cognitive functions. Physical exercise has been suggested to attenuate the cognitive impairments induced by sleep deprivation in male rats. The objective of the current study was to investigate the effects of physical exercise on cognitive functions of female rats following paradoxical sleep deprivation. Intact and ovariectomized (OVX) female Wistar rats were used in the present study. The exercise protocol was 4 weeks of treadmill running. The multiple platform method was applied for the induction of 72h paradoxical sleep deprivation and the cognitive function was evaluated using Morris water maze (MWM). Plasma corticosterone level was evaluated in separate groups of study. ANOVA and repeated measures were used to analyze the data and P<0.05 was considered statistically significant. Throughout the investigation, significant learning impairment was observed in sleep-deprived OVX rats compared to the intact and the other OVX groups. Short term memory impairment was observed in both sleep-deprived OVX and intact groups. Physical exercise alleviated the PSD-induced learning and memory impairments in both intact and OVX groups. Corticosterone levels were not statistically significant among the different groups. The results of our study confirmed the negative effects of PSD on cognitive functions in female rats and regular physical exercise seems to protect rats from these effects. Further studies are suggested to be carried out in order to evaluate the possible underlying mechanisms, and also to evaluate the possible interactions between sex hormones and PSD-induced cognitive impairments.

Prior regular exercise reverses the decreased effects of sleep deprivation on brain-derived neurotrophic factor levels in the hippocampus of ovariectomized female rats.

Previous studies indicated that brain-derived neurotrophic factor (BDNF) is the main candidate to mediate the beneficial effects of exercise on cognitive function in sleep deprived male rats. In addition, our previous findings demonstrate that female rats are more vulnerable to the deleterious effects of sleep deprivation on cognitive performance and synaptic plasticity. Therefore, the current study was designed to investigate the effects of treadmill exercise and/or sleep deprivation (SD) on the levels of BDNF mRNA and protein in the hippocampus of female rats. Intact and ovariectomized (OVX) female Wistar rats were used in the present experiment. The exercise protocol was four weeks treadmill running and sleep deprivation was accomplished using the multiple platform method. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblot analysis were used to evaluate the level of BDNF mRNA and protein in the rat hippocampus respectively. Our results showed that protein and mRNA expression of BDNF was significantly (p<0.05) decreased after 72 h SD in OVX rats in compared with other groups. Furthermore, sleep deprived OVX rats under exercise conditions had a significant (p<0.05) up-regulation of the BDNF protein and mRNA in the hippocampus. These findings suggest that regular exercise can exert a protective effect against hippocampus-related functions and impairments induced by sleep deprivation probably by inducing BDNF expression.