Acute Treatment with Bis Selenide, an Organic Compound Containing the Trace Element Selenium, Prevents Memory Deficits Induced by Reserpine in Rats

Taking into account the promising pharmacological actions of (Z)-2,3-bis(4-chlorophenylselanyl) prop-2-en-1-ol) (bis selenide), an organic compound containing the trace element selenium, and the constant search for drugs that improve the cognitive performance, the objective of the present study was to investigate whether bis selenide treatment ameliorates memory deficits induced by reserpine in rats. For this aim, male adult rats received a single subcutaneous injection of reserpine (1 mg/kg), a biogenic amine-depleting agent used to induce memory deficit. After 24 h, bis selenide at doses of 25 and 50 mg/kg was administered to rats by intragastric route, and 1 h later, the animals were submitted to behavior tasks. The effects of acute administration of bis selenide on memory were evaluated by social recognition, step-down passive avoidance, and object recognition paradigms. Exploratory and locomotor activities of rats were determined using the open-field test. Analysis of data revealed that the social memory disruption caused by reserpine was reversed by bis selenide at both doses. In addition, bis selenide, at the highest dose, prevented the memory deficit resulting from reserpine administration to rats in step-down passive avoidance and object recognition tasks. No significant alterations in locomotor and exploratory behaviors were found in animals treated with reserpine and/or bis selenide. Results obtained from distinct memory behavioral paradigms revealed that an acute treatment with bis selenide attenuated memory deficits induced by reserpine in rats.     

Differential Behavioral and Biochemical Responses to Caffeine in Male and Female Rats from a Validated Model of Attention Deficit and Hyperactivity Disorder

Epidemiological studies suggest sex differences in attention deficit and hyperactivity disorder (ADHD) symptomatology. The potential benefits of caffeine have been reported in the management of ADHD, but its effects were not properly addressed with respect to sex differences. The present study examined the effects of caffeine (0.3 g/L) administered since childhood in the behavior and brain-derived neurotrophic factor (BDNF) and its related proteins in both sexes of a rat model of ADHD (spontaneously hypertensive rats—SHR). Hyperlocomotion, recognition, and spatial memory disturbances were observed in adolescent SHR rats from both sexes. However, females showed lack of habituation and worsened spatial memory. Although caffeine was effective against recognition memory impairment in both sexes, spatial memory was recovered only in female SHR rats. Besides, female SHR rats showed exacerbated hyperlocomotion after caffeine treatment. SHR rats from both sexes presented increases in the BDNF, truncated and phospho-TrkB receptors and also phospho-CREB levels in the hippocampus. Caffeine normalized BDNF in males and truncated TrkB receptor at both sexes. These findings provide insight into the potential of caffeine against fully cognitive impairment displayed by females in the ADHD model. Besides, our data revealed that caffeine intake since childhood attenuated behavioral alterations in the ADHD model associated with changes in BDNF and TrkB receptors in the hippocampus.     

Long‐term consequences of neonatal fluoxetine exposure in adult rats

Serotonin (5‐HT) plays important roles during neural development. Administration of selective serotonin reuptake inhibitor (SSRI)‐type medication during gestation may influence the maturation of the fetal brain and subsequent brain functions. To mimic the condition of late‐gestation SSRI exposure, we administered fluoxetine (FLX) in neonatal rats during the first postnatal week, which roughly corresponds to the third trimester period of human gestation. FLX‐exposed adult male rats exhibited reduced locomotor activity and depression‐like behaviors. Furthermore, sensorimotor gating capacity was also impaired. Interestingly, increased social interaction was noticed in FLX‐exposed rats. When the levels of 5‐HT and tryptophan hydroxylase were examined, no significant changes were found in FLX rats compared to control (CON) rats. The behavioral phenotypes of FLX rats suggested malfunction of the limbic system. Dendritic architectures of neurons in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) were examined. Layer II/III mPFC pyramidal neurons in FLX rats had exuberant dendritic branches with elongated terminal segments compared to those in CON rats. In BLA pyramidal neurons, the dendritic profiles were comparable between the two groups. However, in FLX rats, the density of dendritic spines was reduced in both mPFC and BLA. Together, our results demonstrated the long‐lasting effects of early FLX treatment on emotional and social behaviors in adult rats in which impaired neuronal structure in the limbic system was also noticed. The risk of taking SSRI‐type antidepressants during pregnancy should be considered. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 74: 1038–1051, 2014     

Effect of losartan and enalapril on cognitive deficit caused by Goldblatt induced hypertension

The present study was designed to evaluate the learning and memory, in an altered physiological state associated with increased blood pressure and activated renin angiotensin system in Wistar rats. The role of angiotensin in cognitive function was assessed by treatment with angiotensin converting enzyme (ACE) inhibitor enalapril (2 mg/kg), angiotensin 1 receptor (AT(1)) antagonist losartan (5 mg/kg) and their combination. The experimental renal hypertension was induced by the method of Goldblatt. Learning and memory was assessed using the radial arm maze test. Acetylcholine esterase (AChE) levels in the pons medulla, hippocampus, striatum and frontal cortex were measured as a cholinergic marker of learning and memory. Results indicate that in comparison to normotensive rats, renal hypertensive rats committed significantly higher number of errors and took more trials and days to learn the radial arm maze learning and exhibited memory deficit in the radial arm maze retrieval after two weeks of retention interval, indicating impaired acquisition and memory. Treatment with enalapril, losartan and their combination attenuated the observed memory deficits indicating a possible role of renin angiotensin system in cognitive function. AChE level was reduced in hippocampus and frontal cortex of renal hypertensive rats which could be attributed to the observed memory deficit in hypertensive rats. It can be concluded that, renal hypertensive rats had a poor acquisition, retrieval of the learned behavior, perhaps a possible disturbance in memory consolidation process and that this state was reversed with ACE inhibitor enalapril and AT 1 receptor antagonist losartan.     

Chronic antidepressant treatments induce a time-dependent up-regulation of AMPA receptor subunit protein levels

Growing evidence suggests a pivotal role for glutamatergic neurotransmission in the pathophysiology of major depressive disorder and in the action of antidepressants. The main aim of this study was to elucidate the temporal profile of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors expression and their functional regulation in prefrontal/frontal cortex (P/FC) and hippocampus (HC) of rats chronically treated with two different antidepressants: fluoxetine (FLX) and reboxetine (RBX). Rat groups were treated for 1, 2 or 3 weeks with the two drugs and, in additional groups, the treatments were followed by 1 week of drug washout (3 + 1). We found that both drugs induced strong increases in AMPAR subunit protein expression that were time dependent and subunit specific. Especially in P/FC, FLX had the main effect on GluA2 and GluA4 subunits, reaching a 5-fold increase after the drug washout; RBX mostly affected GluA1 and GluA3, reaching a 4-fold increase at the end of the treatment. Furthermore, in HC, the two drugs induced a time specific increase in subunit protein levels, with GluA3 and GluA4 presenting the main changes, albeit with different kinetics. In addition, our data indicate that antidepressants might alter, though by small changes, the R/G editing levels for GluA2, mostly in P/FC, and in turn may induce fine-tuning of glutamate neurotransmission.Overall, we showed that antidepressant treatments induced marked changes in AMPA receptor subunits expression, with time-dependent effects that are consistent with the onset of therapeutic effect of these drugs. These data confirm the involvement of glutamate neurotransmission in the effects of these drugs and further suggest the targeting of AMPA receptors as a therapeutic approach for the treatment of depression.     

卵巢激素撤除诱发雌性小鼠抑郁样状态（英文）

目的：建立卵巢激素撤除诱发雌性小鼠抑郁样状态模型,并且探讨其可能的神经化学机制。方法：将小鼠分为假手术组,卵巢摘除组,己烯雌酚治疗组和氟西汀治疗组。动物行卵巢摘除术后开始给药,术后两周进行强迫游泳试验及悬尾试验以考察其抑郁样状态,并利用高效液相结合电化学检测测定下丘脑及海马中去甲肾上腺素（NE）、多巴胺（DA）以及五羟色胺（5-HT）的含量。结果：在强迫游泳试验及悬尾试验中,卵巢摘除小鼠较假手术组小鼠不动时间显著延长。神经递质测定显示,卵巢摘除小鼠下丘脑中NE与DA的含量显著降低,海马中NE与5-HT的含量显著降低。给予己烯雌酚或氟西汀治疗对抗了卵巢摘除所诱导的抑郁样状态,并且缓解了神经递质水平的下降。结论：双侧卵巢摘除诱发的小鼠抑郁样状态可以模拟妇女更年期抑郁的某些症状。本研究对于探讨卵巢激素撤除诱发抑郁状态的神经生化机制可能具有重要的意义。     

Fluoxetine exerts age-dependent effects on behavior and amygdala neuroplasticity in the rat

The selective serotonin reuptake inhibitor (SSRI) Prozac® (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg) at postnatal day (PND) 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7–14 days after the last injection when (nor)fluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (nor)fluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling) immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT_1A receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age-dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential fluoxetine-induced neuroplasticity in the amygdala.     

Prenatal SSRI alters the hormonal and behavioral responses to stress in female mice: Possible role for glucocorticoid resistance

Life time prevalence of major depression disorder (MDD) is higher in women compared to men especially during the period surrounding childbirth. Women suffering from MDD during pregnancy use antidepressant medications, particularly Selective Serotonin Reuptake Inhibitors (SSRI). These drugs readily cross the placental barrier and impact the developing fetal brain. The present study assessed the effects of prenatal exposure to fluoxetine (FLX), an SSRI antidepressant drug, on corticosterone and behavioral responses to stress in female mice. In young females, prenatal FLX significantly elevated corticosterone response to continuous stress. In adults, prenatal FLX augmented corticosterone response to acute stress and suppressed the response to continuous stress. Additionally, prenatal FLX significantly augmented stress-induced increase in locomotion and reduced anxiety- and depressive-like behaviors in adult, but not young mice. The dexamethasone suppression test revealed that prenatal FLX induced a state of glucocorticoid resistance in adult females, indicating that the negative feedback control of the hypothalamic-pituitary-adrenal axis response to stress was disrupted. These findings provide the first indication of altered hormonal and behavioral responses to continuous stress and suggest a role for the development of glucocorticoid resistance in these effects. According to these findings, prenatal environment may have implications for stress sensitivity and responsiveness to life challenges. Furthermore, this study may assist in understanding the limitations and precautions that should be taken in the use of SSRIs during pregnancy.     

Prenatal Effect of Fluoxetine on Nociceptive System Reactivity and Psychoemotional Behavior of Young Female and Male Rats

Reactivity of the nociceptive system, psychoemotional behavior and cognitive abilities in female and male rats born to mothers that were exposed to chronic injection of fluoxetine, a serotonin reuptake inhibitor, on days 9–20 of pregnancy were studied in a battery of behavioral tests during the prepubertal period. It was found that chronic injection of physiological saline to pregnant females evoked enhanced nociceptive responses in their offspring of both sexes while fluoxetine injection neutralized the effects of such an invasive intervention, demonstrating thereby the antinociceptive effect of this agent. Negative effects of maternal fluoxetine included a weight loss in the neonate offspring of both sexes and 25-day-old males, as well as the increased anxiety level in females only as detected in the elevated plus maze test. Fluoxetine had no effect on the level of depressive-like behavior in the forced swim test in rats of both sexes. The positive prenatal effect of fluoxetine manifested itself in males as an improved spatial learning ability in the Morris water maze; the anti-nociceptive effect of chronic fluoxetine injection, as compared to the pro-nociceptive effect of chronic saline injection, can also be considered as a positive effect of fluoxetine. Sex differences in the prenatal effect of fluoxetine were revealed in the anxiety level with more anxiety behavior in females.     

Effect of donepezil and lercanidipine on memory impairment induced by intracerebroventricular streptozotocin in rats

Intracerebroventricular (ICV) injection of streptozotocin (STZ) causes cognitive impairment in rats. ICV STZ is known to impair cholinergic neurotransmission by decreasing choline acetyltransferase (ChAT) levels, glucose and energy metabolism in brain and synthesis of acetyl CoA. However, no reports are available regarding the cholinesterase inhibitors in this model. In aging brain, reduced energy metabolism increases glutamate release, which is blocked by L-type calcium channel blockers. These calcium channel blockers have shown beneficial effects on learning and memory in various models of cognitive impairment. The present study was designed to investigate the influence of chronic administration of donepezil (cholinesterase inhibitor, 1 and 3 mg/kg) and lercanidipine (L-type calcium channel blocker, 0.3 and 1 mg/kg) on cognitive impairment in male Sprague-Dawley rats injected twice with ICV STZ (3 mg/kg) bilaterally on days 1 and 3. ICV STZ injected rats developed a severe deficit in learning and memory indicated by deficits in passive avoidance paradigm and elevated plus maze as compared to control rats. Cholinesterase activity in brain was significantly increased in ICV STZ injected rats. Donepezil dose-dependently inhibited cholinesterase activity and improved performance in memory tests at both the doses. Lercanidipine (0.3 mg/kg) showed significant improvement in memory. When administered together, the effect of combination of these two drugs on memory and cholinesterase activity was higher than that obtained with either of the drugs when used alone.     

Serotonin function is associated with behavioral response to a novel conspecific in marmosets

The function of the central nervous system neurotransmitter serotonin (5-HT) contributes to individual differences in impulsive behavior in humans and nonhuman primates. We investigated the relationship between 5-HT function and behavioral responses to a novel social scenario in marmosets. In the first study, marmosets (n=10) were treated orally with fluoxetine HCl (FLX) or vehicle for two trial periods and exposed to a novel conspecific for a 20-min trial following each treatment. Levels of behavioral inhibition in response to a novel conspecific were quantified. The animals exhibited less inhibition toward the novel conspecific following the 14-day FLX treatment than they did following the vehicle treatment. In the second study we first characterized the parameters of the marmoset peripheral 5-HT system and further assessed the relationship between natural variation in peripheral 5-HT and 5-HIAA levels with behavioral inhibition in response to a novel conspecific (n=14). Individual peripheral 5-HT and 5-HIAA levels were higher in animals that exhibited more inhibition in response toward the stranger. We conclude that serotonergic influences play a role in behavioral response to a novel conspecific in marmosets.     

Depression mediates impaired glucose tolerance and cognitive dysfunction: A neuromodulatory role of rosiglitazone

Comorbidity of depression and diabetes is a serious risk factor worsening the complications such as cognitive function and locomotion. Treatment under this condition becomes extremely complicated. Insulin signaling and autophagy pathways are involved in modulation of learning and memory. Rosiglitazone (ROSI) ameliorate cognitive deficit associated with depression and insulin resistance. In the present study, we investigated the effect of ROSI against chronic unpredictable stress (CUS) induced depression as a risk factor for diabetes and behavioral dysfunctions. Adult male Swiss albino mice were exposed to CUS alongside ROSI (5 mg/kg/day) treatment for 21 days. Thereafter, animals were subjected to different behavioral studies to assess depressive like behavior, cognition and locomotion. The effect of ROSI on insulin signaling, autophagy and apoptosis were evaluated in the hippocampus. CUS resulted in depressive like behavior, cognitive impairment and hypolocomotion associated with oxidative stress, impaired glucose tolerance and hypercorticosteronemia. CUS significantly impaired hippocampal insulin signaling, membrane translocation of glucose transporter type 4 (GLUT4) as well as decreased the expression of autophagy5, autophagy7, B-cell lymphoma 2 and apoptosis inhibitory protein 2. ROSI significantly reduced depressive like behavior, postprandial blood glucose, hypercorticosteronemia, oxidative and inflammatory stress, and apoptosis in stressed mice. Moreover, ROSI treatment effectively improved hippocampal insulin signaling, GLUT4 membrane translocation and cognitive performance in depressed mice. ROSI administration might prove to be effective for neurological disorders associated with depressive like behavior and impaired glucose tolerance.     

Resveratrol prevents alcohol-induced cognitive deficits and brain damage by blocking inflammatory signaling and cell death cascade in neonatal rat brain

Human prenatal ethanol exposure that occurs during a period of increased synaptogenesis known as the 'brain growth spurt' has been associated with significant impairments in attention, learning and memory. Recent studies have shown that administration of ethanol to infant rats during the synaptogenesis period (first 2 weeks after birth) triggers extensive apoptotic neurodegeneration throughout many regions of the developing brain and results in cognitive dysfunctions as the animal matures. The present study was designed with an aim to investigate the effect of resveratrol, a polyphenolic phytoalexin (trans-3,5,4-trihydroxy stilbene) present in red wine on alcohol-induced cognitive deficits and neuronal apoptosis in rat pups postnatally exposed to ethanol. Pups were administered ethanol (5 g/kg, 12% v/v) by intragastric intubation on postnatal days 7, 8, and 9. Ethanol-exposed pups showed impaired memory performance in both Morris water maze elevated plus maze task recorded by using computer tracking with EthoVision software. Behavioral deficit in ethanol-exposed pups was associated with enhanced acetylcholinesterase activity, increased oxidative-nitrosative stress, cytokine (TNF-α, IL-1β and TGF-β), nuclear factor kappa beta and caspase 3 levels in both cerebral cortex and hippocampus. Chronic treatment with resveratrol (10 and 20 mg/kg) significantly attenuated all the behavioral, biochemical and molecular changes in different brain regions of ethanol administered pups. The major finding of the study is that resveratrol blocks activation of nuclear factor kappa beta pathway and apoptotic signaling and prevents cognitive deficits in rats postnatally exposed to ethanol.     

Effects of citalopram on cognitive performance in passive avoidance, elevated plus-maze and three-panel runway tasks in naïve rats

Recent studies have shown that learning and memory capacity is disturbed in depressive patients, and it is important to reveal the effects of antidepressant drugs on cognitive function in depressive patients with memory problems. Citalopram, a selective serotonin reuptake inhibitor (SSRI), is one of the most widely used drugs for the treatment of disorders related to serotonergic dysfunction like depression and anxiety. Contradictory findings exist regarding the effects of SSRIs on memory. The aim of this study is to investigate whether citalopram affects memory in various models of learning and memory tasks in rats. Citalopram (at 20 and 50 mg/kg) significantly shortened the retention latency in the passive avoidance test and prolonged the transfer latency on the second day at 10 and 50 mg/kg doses in the elevated plus-maze test. Citalopram also significantly increased the number of errors (at the 10 mg/kg dose) and prolonged the latency values compared to the control group in both reference and working memory trials in the three-panel runway test. Citalopram also impaired reference memory trials of animals at the 20 mg/kg dose. In conclusion, citalopram impaired cognitive performance in passive avoidance, elevated plus-maze and three-panel runway tasks in naive rats. These effects might be related to serotonergic and nitrergic mechanisms, which need to be investigated in further studies.     

Neuroprotective effect of atypical antipsychotics in cognitive and non-cognitive behavioral impairment in animal models

Antipsychotic drugs are divided into two groups: typical and atypical. Recent clinical studies show atypical antipsychotics have advantages over typical antipsychotics in a wide variety of neuropsychiatric conditions, in terms of greater efficacy for positive and negative symptoms, beneficial effects on cognitive functioning, and fewer extra pyramidal side effects in treating schizophrenia. As such, atypical antipsychotics may be effective in the treatment of depressive symptoms associated with psychotic and mood disorders, posttraumatic stress disorder and psychosis in Alzheimer disease. In this paper, we describe the effects and potential neurochemical mechanisms of action of atypical antipsychotics in several animal models showing memory impairments and/or non-cognitive behavioral changes. The data provide new insights into the mechanisms of action of atypical antipsychotics that may broaden their clinical applications.Key words: atypical antipsychotics, neuroprotective effect, memory, anxiety-like behavior, neurotoxicity     

Fluoxetine counteracts the cognitive and cellular effects of 5-fluorouracil in the rat hippocampus by a mechanism of prevention rather than recovery

5-Fluorouracil (5-FU) is a cytostatic drug associated with chemotherapy-induced cognitive impairments that many cancer patients experience after treatment. Previous work in rodents has shown that 5-FU reduces hippocampal cell proliferation, a possible mechanism for the observed cognitive impairment, and that both effects can be reversed by co-administration of the antidepressant, fluoxetine. In the present study we investigate the optimum time for administration of fluoxetine to reverse or prevent the cognitive and cellular effects of 5-FU. Male Lister-hooded rats received 5 injections of 5-FU (25 mg/kg, i.p.) over 2 weeks. Some rats were co-administered with fluoxetine (10 mg/kg/day, in drinking water) for 3 weeks before and during (preventative) or after (recovery) 5-FU treatment or both time periods (throughout). Spatial memory was tested using the novel location recognition (NLR) test and proliferation and survival of hippocampal cells was quantified using immunohistochemistry. 5-FU-treated rats showed cognitive impairment in the NLR task and a reduction in cell proliferation and survival in the subgranular zone of the dentate gyrus, compared to saline treated controls. These impairments were still seen for rats administered fluoxetine after 5-FU treatment, but were not present when fluoxetine was administered both before and during 5-FU treatment. The results demonstrate that fluoxetine is able to prevent but not reverse the cognitive and cellular effects of 5-FU. This provides information on the mechanism by which fluoxetine acts to protect against 5-FU and indicates when it would be beneficial to administer the antidepressant to cancer patients.     

Impaired cognitive function and altered hippocampal synapse morphology in mice lacking Lrrtm1, a gene associated with schizophrenia

Recent genetic linkage analysis has shown that LRRTM1 (Leucine rich repeat transmembrane neuronal 1) is associated with schizophrenia. Here, we characterized Lrrtm1 knockout mice behaviorally and morphologically. Systematic behavioral analysis revealed reduced locomotor activity in the early dark phase, altered behavioral responses to novel environments (open-field box, light-dark box, elevated plus maze, and hole board), avoidance of approach to large inanimate objects, social discrimination deficit, and spatial memory deficit. Upon administration of the NMDA receptor antagonist MK-801, Lrrtm1 knockout mice showed both locomotive activities in the open-field box and responses to the inanimate object that were distinct from those of wild-type mice, suggesting that altered glutamatergic transmission underlay the behavioral abnormalities. Furthermore, administration of a selective serotonin reuptake inhibitor (fluoxetine) rescued the abnormality in the elevated plus maze. Morphologically, the brains of Lrrtm1 knockout mice showed reduction in total hippocampus size and reduced synaptic density. The hippocampal synapses were characterized by elongated spines and diffusely distributed synaptic vesicles, indicating the role of Lrrtm1 in maintaining synaptic integrity. Although the pharmacobehavioral phenotype was not entirely characteristic of those of schizophrenia model animals, the impaired cognitive function may warrant the further study of LRRTM1 in relevance to schizophrenia.     

推拿对慢性应激大鼠抑郁行为的影响及其机制

目的: 探讨推拿对慢性应激大鼠抑郁行为的影响及其作用机制。方法: 制备慢性轻度不可预见性的应激大鼠模型^[1-2],造模21 d后,进行推拿治疗14 d。分组:空白对照组、模型组、推拿组、氟西汀组,每组10只。每日推拿膀胱经重要穴位10 min(间隔2 min,共2次)。通过体质量检测、旷场、糖水消耗实验和水迷宫实验评价抑郁模型大鼠行为学改变情况;蛋白质免疫印迹法(Western blot)法检测大鼠海马及前额叶皮质组织中ERK/P-ERK、BDNF蛋白表达情况。结果: 模型组与空白组比较,大鼠的体质量、旷场、糖水消耗实验和水迷宫数据均显著下降(P＜0.01),P-ERK、BDNF蛋白含量均显著降低(P＜0.01);推拿组和氟西汀组与模型组比较,大鼠的体质量、旷场实验、糖水消耗实验和水迷宫实验数据均显著上升(P＜0.01),推拿组和氟西汀组大鼠海马及前额叶皮质组织中P-ERK、BDNF蛋白含量均显著升高(P＜0.05,P＜0.01),氟西汀组升高更为显著(P＜0.01)。结论: 推拿可上调大鼠海马及前额叶皮质组织中ERK蛋白的磷酸化水平,激活ERK信号通路,促进效应蛋白BDNF的表达,改善慢性应激大鼠的抑郁行为。     

Naringin and Sertraline Ameliorate Doxorubicin-Induced Behavioral Deficits Through Modulation of Serotonin Level and Mitochondrial Complexes Protection Pathway in Rat Hippocampus

The present study was designed to investigate the neuroprotective effect of naringin (NR) alone as well as its combination with sertraline (SRT) against doxorubicin (DOX)-induced neurobehavioral and neurochemical anomalies. DOX (15 mg/kg; i.p.) administration caused behavioral alterations, oxidative stress, neuroinflammation, mitochondrial dysfunction and monoamines alteration in male Wistar rats. NR (50 and 100 mg/kg; i.p.) and SRT (5 mg/kg; i.p.) treatment significantly attenuated DOX-induced anxiety and depressive-like behavior as evident from elevated plus maze (EPM) and modified forced swimming test (mFST), respectively. NR treatment significantly attenuated DOX-induced raised plasma corticosterone (CORT), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) levels in the hippocampus (HC). Furthermore, we found that combination of NR and SRT regimen ameliorated DOX-induced behavioral anomalies through modulation of the 5-HT level and mitochondrial complexes protection pathway along with alleviation of oxidative stress in the HC region. Therefore, NR treatment alone or in combination with SRT could be beneficial against DOX-induced neurotoxicity.