Effect of a combined program of running exercise and environmental enrichment on memory function and neurogenesis markers in amyloid-beta-induced Alzheimer-like model.

Objectives: It is urgent to develop non-pharmacological interventions or multifactor combination approaches to combat Alzheimer's disease (AD). The effect of exercise (EX) combined with environmental enrichment (EE) on behavioral phenotypes and neurogenesis markers in an Alzheimer-like rat model was investigated. Materials and Methods: The groups consisted of AD, sham-operated, AD+EX, AD+EE, and AD+EX+EE. AD was produced by injection of amyloid-beta (1-42, 6 µg) intrahippocampally, and a daily treadmill for 3 consecutive weeks was used for EX animals. EE was a large cage (50× 50× 50 cm) containing differently shaped objects. Spatial learning and memory were evaluated in the Morris water maze (MWM), and a shuttle box was used to evaluate inhibitory avoidance memory. RT-PCR was performed to assess the expression of early neurogenesis markers, DCX, and Sox2 within the hippocampus. Results: Pretreatment with exercise and EE, both individually and in combination, could provide protection from memory impairments in AD rats. Combined treatment led to a significantly more pronounced improvement in memory deficits of AD rats than either paradigm alone. Combination therapy with exercise and EE could also reverse the passive avoidance memory impairment and hippocampal DCX expression of AD rats to the control levels. Conclusion: These data suggest that exercise in combination with cognitive engagement can provide a non-pharmacological and multidomain policy that may prevent or delay AD symptoms.

The effect of combination pretreatment of donepezil and environmental enrichment on memory deficits in amyloid-beta-induced Alzheimer-like rat model.

Alzheimer's disease (AD) is progressive neurodegeneration known as the most common cause of dementia, and it is the sixth leading cause of death in older people. Given the promising data on the additive effect of combination therapy with donepezil (Aricept), an acetylcholinesterase inhibitor (AChEI), and regarding the similar neuronal mechanisms through which donepezil (DON) and environmental enrichment (EE) exert their enhancing effects on cognition; we asked whether simultaneous treatment with two paradigms in amyloid-beta-induced AD rats may lead to greater protection against the cognitive impairments than either treatment individually. The experimental groups consisted of Alz, sham-operated, Alz + DON, Alz + EE, and Alz + DON + EE. AD was induced by intrahippocampal injection of amyloid-beta (1-42, 6 µg), and DON was orally administrated (4 mg/kg) for 21 days. Environmental enrichment consisted of housing animals in large cages (50 × 50 × 50 cm) containing a running wheel and differently shaped objects for 21 days. Spatial learning and memory were assessed in the Morris water maze (MWM) and Real-time PCR was performed to assess the expression of brain-derived neurotrophic factor (BDNF) and M1 muscarinic acetylcholine receptor (AchM1R) within the hippocampus. Spatial memory was impaired in Alz animals, and while neither pretreatment with DON nor EE alone could significantly restore spatial memory scores in Alz rats, combination therapy was effective. BDNF expression was suppressed in Alz rats and pretreatment with DON plus EE could increase it to the saline levels. The data suggest that a cholinesterase inhibitor and cognitive stimulation can be used effectively in combination to protect cognitive loss in an AD rat model. This additive protective effect may be in part due to the augmented influence of this combination on BDNF levels and cholinergic neuronal system within the hippocampus.

The role of astrocytes in epileptic disorders.

Epilepsy affects about 1% of the population and approximately 30% of epileptic patients are resistant to current antiepileptic drugs. As a hallmark in epileptic tissue, many of the epileptic patients show changes in glia morphology and function. There are characteristic changes in different types of glia in different epilepsy models. Some of these changes such as astrogliosis are enough to provoke epileptic seizures. Astrogliosis is well known in mesial temporal lobe epilepsy (MTLE), the most common form of refractory epilepsy. A better understanding of astrocytes alterations could lead to novel and efficient pharmacological approaches for epilepsy. In this review, we present the alterations of astrocyte morphology and function and present some instances of targeting astrocytes in seizure and epilepsy.

The beneficial effects of green tea on sleep deprivation-induced cognitive deficits in rats: the involvement of hippocampal antioxidant defense.

BACKGROUND: The weight of evidence suggests that sleep is essential for the processes of memory consolidation and sleep deprivation (SD) impairs the retention of long-term memory in both humans and experimental animals, which is associated with oxidative stress damage within the brain. Green tea polyphenols have revealed carcinogenic, antioxidant, anti-, and anti-mutagenic properties. We aimed to investigate the possible protective effect of green tea extract (GTE) and its main active catechin, epigallocatechin-3-gallate (EGCG), on post-training total sleep deprivation (TSD) -induced spatial memory deficits and oxidative stress profile in the hippocampus of the rat. METHODS: Male rats were treated with saline, GTE (100 and 200 mg/kg/day), and EGCG (50 mg/kg/day) intraperitoneally for 21 days and then trained in Morris water maze (MWM) in a single day protocol. Immediately after the end of MWM training, animals were sleep deprived for 6 h by the gentle handling method, and then evaluated for spatial memory. Hippocampal levels of malondialdehyde, (MDA), and thiol was assessed as oxidant and antioxidant markers. RESULTS: Spatial memory was impaired in the TSD group and GTE at the dose of 200 mg/kg/day as well as EGCG at the dose of 50 mg/kg/day could reverse the impairment to the saline-treated levels. Despite the unchanged MDA levels, hippocampal total thiol was significantly decreased after TSD and EGCG increased it to the basal levels. CONCLUSION: In conclusion, green tea and its main catechin, EGCG, could prevent memory impairments during 6 h of TSD; probably through normalizing the antioxidant thiol defense system which was impaired during TSD.

Combination effect of exercise and environmental enrichment on cognitive functions and hippocampal neurogenesis markers of rat.

OBJECTIVES: Cognitive decline is one of the most prevalent health problems and is associated with increased healthcare utilization and economic burden. Physical and cognitive training both have positive effects on cognition but have been less applied in combination. We hypothesized that simultaneous cognitive-physical components would yield greater cognitive benefits than single-domain interventions in rats. METHODS: A total of 40 male Wistar rats were divided into four treatment groups: the control, enriched environment (EE), exercise (EX), and EE + EX. Animals in EE groups housed in the large cages (50 × 50 × 50 cm) contained differently shaped objects for 3 weeks. EX animals were forced to run on a treadmill once daily for 3 consecutive weeks. Morris water maze test was used for the assessment of spatial learning and memory. Real-time PCR was performed to assess the expression of nestin, and Sox2 in the hippocampus. RESULTS: EX and EE animals separately did not show a significantly enhanced function in spatial memory in comparison with the control group. When animals were treated with EE and EX simultaneously, they exhibited significantly superior performance in spatial memory than control, EX, or EE groups separately. The hippocampal expression of Sox2 was significantly higher in EE + EX group than in the control, EX, and EE alone. CONCLUSIONS: These results may have clinical implications for behavioral interventions in conditions with cognitive deficiencies.

The next step of neurogenesis in the context of Alzheimer's disease.

Among different pathological mechanisms, neuronal loss and neurogenesis impairment in the hippocampus play important roles in cognitive decline in Alzheimer's disease (AD). AD is a progressive and complex neurodegenerative diseases, which is very debilitating. The purpose of this paper is to review recent research into neurogenesis and AD and discuss how pharmacological drugs and herbal active components have impacts on neurogenesis and consequently improve cognitive functions. To date, despite huge research, no effective treatment has been approved for AD. Therefore, an avenue for future research and drug discovery is stimulating adult hippocampal neurogenesis (AHN). Evidence suggests that neurogenesis is regulated by the pharmacological treatment that may be recommended as a part of prophylaxis and therapeutic options for AD. However, the underlying mechanisms of regulating neurogenesis in AD are not well understood. To this point, we highlight to achieve an efficient treatment in AD by manipulating neurogenesis, it's necessary to target all steps of neurogenesis.

Neuronal injury and death following focal mild brain injury: The role of network excitability and seizure.

OBJECTIVES: While traumatic brain injury (TBI) is a predisposing factor for development of post-traumatic epilepsy (PTE), the occurrence of seizures following brain trauma can infuriate adverse consequences of brain injury. However, the effect of seizures in epileptogenesis after mild TBI cannot yet be accurately confirmed. This study was designed to investigate the histopathological and molecular modifications induced by seizures on traumatized brain. MATERIALS AND METHODS: Using a new method, head was traumatized and seizures were evoked by sub-convulsive dose of pentylenetetrazole (PTZ) fifteen days after induction of focal mild TBI. Convulsion assessments were performed one hour after PTZ injection and was followed by histopathological and molecular evaluations. RESULTS: A significantly higher score and longer duration of seizure attacks as well as higher number of epileptiform discharges were observed in the TBI+PTZ group compared to sham and TBI groups. An elevated number of apoptotic cells was observed in the TBI+PTZ group compared to sham and TBI rats. Molecular investigations revealed higher levels of Bax/Bcl2 ratio, Caspase 3, and NF-κB in the TBI+PTZ group compared to the other animal groups. The value of Nrf2 did not change after mild TBI compared to sham and PTZ control groups. Occurrence of seizures after TBI, however, significantly decreased the level of Nrf2. CONCLUSION: Our data indicated that seizure occurrence following mild TBI aggravates cell injury and death via activation of neuroinflammatory processes and may increase the risk of PTE. Additionally, our results suggest a potential protective role of Nrf2 after chemically evoked PTE.

The Impact of Estradiol on Neurogenesis and Cognitive Functions in Alzheimer's Disease.

Alzheimer's disease (AD) is described as cognitive and memory impairments with a sex-related epidemiological profile, affecting two times more women than men. There is emerging evidence that alternations in the hippocampal neurogenesis occur at the early stage of AD. Therapies that may effectively slow, stop, or regenerate the dying neurons in AD are being extensively investigated in the last few decades, but none has yet been found to be effective. The regulation of endogenous neurogenesis is one of the main therapeutic targets for AD. Mounting evidence indicates that the neurosteroid estradiol (17ß-estradiol) plays a supporting role in neurogenesis, neuronal activity, and synaptic plasticity of AD. This effect may provide preventive and/or therapeutic approaches for AD. In this article, we discuss the molecular mechanism of potential estradiol modulatory action on endogenous neurogenesis, synaptic plasticity, and cognitive function in AD.

Progesterone modulates post-traumatic epileptogenesis through regulation of BDNF-TrkB signaling and cell survival-related pathways in the rat hippocampus.

Female sex hormone, progesterone, in addition to seizure modifying activity is also known as a potential protective agent against various brain injury conditions. Considering the predisposal role of traumatic brain injury (TBI) on developing post-traumatic epilepsy (PTE), the effect of progesterone on post-traumatic epileptogenesis is not investigated yet. Male Wistar rats were given a moderate focal weight drop injury (500 gr) or sham surgery and then progesterone (16 and 32mg/kg) was given daily for two consecutive weeks. On day 15 of injury, seizures were induced by administration of a GABAA receptor antagonist, pentylenetetrazole (PTZ, 30 mg/kg). Seizures were then assessed over a 1-h period using the Racine clinical rating scale. Traumatized animals that received 32 mg/kg progesterone had reduced score, duration of seizures and almost did not show tonic-clonic seizures during 60 min versus the untreated trauma group. In line with behavioral alterations, 32 mg/kg progesterone enhanced the amount of Nrf2 and HO-1 proteins and decreased the level of NF-kB, BDNF, Caspase 3 and ratio of Bax/Bcl-2 in the ipsilateral hippocampus. Additionally, the number of TUNEL-positive apoptotic cells, as well as injured dark neurons in the parietal cortex and hippocampal CA1 of 32 mg/kg-treated animals showed a significant reduction. Administration of 16 mg/kg progesterone elevated production of BDNF, Bax and Caspase 3 and decreased anti-apoptotic Bcl-2 protein. Taken together, an early administration of 32 mg/kg of progesterone after TBI for two weeks post-injury modified seizure activity. Our findings suggest that post-traumatic anti-epileptogenesis property of a high dose of progesterone partly occurs through the manipulation of BDNF-TrkB axis along with control of cell survival pathways.

Sex differences in sleep and sleep loss-induced cognitive deficits: The influence of gonadal hormones.

Males and females can respond differentially to the same environmental stimuli and experimental conditions. Chronic sleep loss is a frequent and growing problem in many modern societies and has a broad variety of negative outcomes for health and well-being. While much has been done to explore the deleterious effects of sleep deprivation (SD) on cognition in both human and animal studies over the last few decades, very little attention has been paid to the part played by sex differences and gonadal steroids in respect of changes in cognitive functions caused by sleep loss. The effects of gonadal hormones on sleep regulation and cognitive performances are well established. Reduced gonadal function in menopausal women and elderly men is associated with sleep disturbances and cognitive decline as well as dementia, which suggests that sex steroids play a key role in modulating these conditions. Finding out whether there are sex differences in respect of the effect of insufficient sleep on cognition, and how neuroendocrine mediators influence cognitive impairment induced by SD could provide valuable insights into the best therapies for each sex. In this review, we aim to highlight the involvement of sex differences and gonadal hormone status on the severity of cognitive deficits induced by sleep deficiency in both human and animal studies.

Naloxone Ameliorates Spatial Memory Deficits and Hyperthermia Induced by a Neurotoxic Methamphetamine Regimen in Male Rats.

BACKGROUND: Methamphetamine (METH) as a synthetic psychostimulant is being increasingly recognized as a worldwide problem, which may induce memory impairment. On the other hand, it is well established that naloxone, an opiate antagonist, has some beneficial effects on learning and memory. The present research aimed at evaluating naloxone effects on spatial learning and memory impairment triggered by a neurotoxic regimen of METH in male rats. MATERIALS AND METHODS: The animals received the subcutaneous (sc) regimen of METH (4×6 mg/kg at 2-h intervals), intraperitoneal (ip) naloxone (4×1 mg/kg at 2-h intervals), or normal saline at four events. The Nal-METH group of rats received four naloxone injections (1 mg/ kg, ip) 30 min before each METH injection (6 mg/kg, sc) at 2-h intervals. Seven days later, they were evaluated for spatial learning and memory in the Morris Water Maze (MWM) task. RESULTS: METH regimen induced hyperthermia, as well as a poor performance, in the acquisition and retention phases of the task, indicating spatial learning and memory impairment compared to the controls. Naloxone administration (1 mg/kg, ip) before each METH injection led to significant attenuations of both hyperthermia and METH adverse effects on the rat performance in the MWM task. CONCLUSION: The results revealed that pretreatment with the opiate antagonist naloxone could prevent METH adverse effects on body temperature and memory performance. It seems that the opioidergic system and hyperthermia may, at least partially, be involved in METH effects on spatial memory.

Peroxisome proliferator-activated receptor-γ activation attenuates harmaline-induced cognitive impairments in rats.

Cognitive and motor disturbances are serious concerns of the tremors induced by motor disorders. Despite the lack of effective clinical treatment, some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of tremor. Recent studies have shown that PPAR-γ agonists have neuroprotective effects. In the current study, the effects of pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma agonist, on harmaline-induced motor and cognitive impairment were studied. Male Wistar rats were divided into vehicle (normal saline), PIO (20 mg/kg i.p.), harmaline (10 mg/kg, i.p.) and PIO + harmaline (PIO injected 2 h before harmaline) groups. Open field, rotarod, wire grip, foot print and Morris water maze tests were used to evaluate the motor and cognitive performance. The results indicated that administration of PIO attenuated harmaline-induced locomotor, anxiety-like behaviors, and spatial learning and memory impairments, but it partially decreased the tremor score. The neuroprotective and anxiolytic effects of PIO demonstrated in the current study can offer the PPAR-γ receptor agonism as a potential therapeutic agent in the treatment of patients with tremor that manifest mental dysfunction.

Alterations in the intrinsic electrophysiological properties of Purkinje neurons in a rat model of hepatic encephalopathy: Relative preventing effect of PPARγ agonist.

Patients suffering from hepatic cirrhosis (HC) have been shown to have motor and cognitive impairments. The cerebellum, which controls coordinated and rapid movements, is a potential target for the deleterious effects of hyperammonemia induced by bile duct ligation. Therefore, the aim of this study was to determine the mechanisms of motor impairments observed in a rat model of HC and second objective of the current study was to evaluate the possible protective effect of pioglitazone (PIO) on these impairments. Male Wistar rats were used in the current study. Bile duct ligation (BDL) surgery was performed and pioglitazone administration was started two weeks after the surgery for the next four weeks. The effects of pioglitazone on BDL-induced electrophysiological changes of the Purkinje cerebellum neurons were evaluated by Whole-cell patch clamp recordings. Purkinje neurons from the BDL group exhibited significant changes in a number of electrophysiological properties and some alterations partially were counteracted by activation of peroxisome proliferator-activated receptor-γ. Purkinje cells from BDL groups showed a significant increase in the spontaneous firing frequency followed by a decrease in the action potential duration of half-amplitude and spike interval. Chronic administration of pioglitazone could contract this effect of BDL on event frequency and interevent interval, though the difference with the sham group was still significant in the duration of action potential. Results of the current study raise the possibility that BDL may profoundly affect the intrinsic membrane properties of the cerebellar Purkinje neurons and PIO administration can counteract some of these effects.

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.

Hippocampal receptor complexes paralleling LTP reinforcement in the spatial memory holeboard test in the rat.

The current study was designed to examine learning-induced transformation of early-LTP into late-LTP. Recording electrodes were implanted into the dentate gyrus of the hippocampus in male rats and early-LTP was induced by weak tetanic stimulation of the medial perforant path. Dorsal right hippocampi were removed, membrane proteins were extracted, separated by blue-native gel electrophoresis with subsequent immunoblotting using brain receptor antibodies. Spatial training resulted into reinforcement of LTP and the reinforced LTP was persistent for 6h. Receptor complex levels containing GluN1 and GluN2A of NMDARs, GluA1 and GluA2 of AMPARs, nAchα7R and the D(1A) dopamine receptor were significantly-elevated in rat hippocampi of animals underwent spatial learning, whilst levels of GluA3 and 5-HT1A receptor containing complexes were significantly reduced. Evidence for complex formation between GluN1 and D(1A) dopamine receptor was provided by antibody shift assay, co-immunoprecipitation and mass spectrometric analysis. Thus our results propose that behavioural stimuli like spatial learning reinforce early LTP into late LTP and this reinforced LTP is accompanied by changes in certain receptor levels in the membrane fraction of the rat hippocampus.

Prior regular exercise prevents synaptic plasticity impairment in sleep deprived female rats.

Previous studies have indicated that physical exercise plays a preventive role in synaptic plasticity deficits in the hippocampus of sleep-deprived male rats. The objective of the present study was to evaluate the effects of treadmill running on early long term potentiation (E-LTP) at the Cornu Ammonis (CA1) area of the hippocampus in sleep-deprived female rats. Intact and ovariectomiezed (OVX) female Wistar rats were used in the present study. The exercise protocol was four weeks treadmill running and the multiple platform method was applied to induce 72 h sleep deprivation (SD). We examine the effect of exercise and/or SD on synaptic plasticity using in vivo extracellular recording in the CA1 area of the hippocampus. The field excitatory post-synaptic potential (fEPSP) slope was measured before and 2h after high frequency stimulation (HFS) in the experimental groups. Field potential recording indicated that the induction and maintenance phase of E-LTP impaired in the sleep deprived animals compared to the other groups. After 72 h SD, E-LTP impairments were prevented by 4 weeks of regular treadmill exercise. In conclusion, the synaptic plasticity deficit in sleep-deprived female rats was improved by regular physical exercise. Further studies are suggested to evaluate the possible underlying mechanisms.

Single and repeated ultra-rapid detoxification prevents cognitive impairment in morphine addicted rats: a privilege for single detoxification.

BACKGROUND: Opioids have been shown to affect learning and memory processes. Different protocols of morphine withdrawal can substantially vary in their success to prevent opioid induced impairments of cognitive performance. In the present study, we report the effects of single and repetitive ultra-rapid detoxification (URD) on spatial learning and memory in morphine addicted rats. METHODS: Morphine (10 mg/kg) was intraperitoneally (IP) injected in male rats once a day over one week and after which they were detoxified with naloxone administration under anesthesia. For the repetitive procedure, a second one week morphine treatment with a second subsequent detoxification was performed. Control groups received an equivalent volume of saline injections. Spatial learning and memory was evaluated using the Morris water maze (MWM) task. FINDINGS: Both protocols of morphine administration resulted in a severe spatial memory impairment that could be significantly prevented by both single and repetitive URD. However, memory abilities in animals treated with repetitive URD were still significantly lower than in animals of the corresponding control group. Alterations in motor activity or sensory-motor coordination between morphine treated and control animals could be ruled out by comparing swimming speed and visible platform performances that were not different between groups. Thus, URD and, specifically single URD, can prevent the spatial memory impairments in addicted rats. CONCLUSION: As opioid addiction is an extending and serious concern in many societies, these findings may have clinical values and therapeutic implications for patients who experience multiple opioid relapses.

Susceptibility to life-threatening ventricular arrhythmias in an animal model of paradoxical sleep deprivation.

BACKGROUND: According to some reports regarding the increase of cardiac events following sleep deprivation, our study was conducted to clarify the effects of rapid eye movement (REM) sleep deprivation on susceptibility to lethal ventricular arrhythmias in rat. METHODS: The animal groups included the control group; the sham 48 and sham 72 groups (without sleep deprivation); and the test 48 and test 72 groups, who experienced REM sleep deprivation for 48h and 72h, respectively. For induction of cardiac arrhythmia, aconitine was infused via the tail vein of the animals. RESULTS: After 72h of REM sleep deprivation, the blood pressure (BP) levels and the QTc interval of the electrocardiogram (ECG) were significantly increased (P<.05 and P<.01, respectively). However, the sleep deprivation had no significant effect on the heart rate (HR), myocardial oxygen consumption index, and plasma corticosterone level. Furthermore, sleep deprivation increased the latency times of premature ventricular contraction (PVC), ventricular tachycardia (VT), and also the PVC number; however, it did not increase the number, duration, and severity of VT and ventricular fibrillation (VF). CONCLUSION: Our findings suggest that 72h of REM sleep deprivation is associated with increased risk for hypertension and QT interval prolongation under nonstressful conditions; however, it does not increase the susceptibility to lethal ventricular arrhythmia in rat.

Evaluation of destructive effects of exposure to cisplatin during developmental stage: no profound evidence for sex differences in impaired motor and memory performance.

We have elucidated the alteration in hippocampal and cerebellum function following chronic cisplatin treatment in male and female rats. Hippocampus and cerebellum related behavioral dysfunction in cisplatin-treated [intraperitoneally, 5 mg/(kg/week) for 5 weeks from 23-day-old] rats were analyzed using explorative, motor function, learning, and memory tasks (grasping, rotarod, open field, and Morris water maze tests). Exposure to cisplatin impaired the motor coordination in male and female rats. Exposure to cisplatin was reflected by a decrease in grasping time compared to vehicle-treated controls (saline) only in male rat while there were not any differences in female rats. When the rearing frequency, total distance moved and velocity of their recorded in open fieldtest, both males and females were dramatically affected by exposure to cisplatin. Compared to the saline, male and female rats trained 5 weeks after cisplatin injection showed significant memory deficits in the Morris water maze test. However, hippocampal and cerebellum functions of male and female rats were profoundly affected by exposure to cisplatin while no sex differences in the most variable were evident.