Hippocampal Brain-derived Neurotrophic Factor Levels Research Articles

The Effect of Memantine Administration on Anxiety Maintenance in Stressed Male Wistar Rats

Background: Anxiety is considered as a chronic stress complication. The role of N-methyl-D-aspartate (NMDA) glutamate receptors located in basolateral amygdala (BLA) in stress-induced anxiety is hypothesized. Objectives: It is unknown how NMDA glutamate receptors located in BLA affect maintenance of chronic stress-induced anxiety. This study investigated the role of these receptors in maintaining anxiety induced by electric foot shock in male Wistar rats. Methods: Animals were subjected to stress based on the following protocol: Seven days after bilateral cannulation in BLA, they experienced seven sessions of stress (one session/day). Before each stress session, the animals received different doses of memantine (1, 2.5, and 5 mg/kg) peripherally, or (0.1, 1 and 5 μg/kg) in BLA. Six days after stress termination, the animals were tested for maintenance of anxiety using an open field paradigm. Moreover, the animals’ brains were removed for further assessment of brain-derived neurotrophic factor (BDNF) levels in the hippocampus. Results: The stressed animals showed anxiety six days after stress termination. Moreover, chronic peripheral and central memantine injection by itself showed both anxiolytic and anxiogenic properties six days after drug administration termination in the non-stressed animals. Memantine preadministration, both peripherally and centrally, reduced the stress-induced maintenance of anxiety in the stressed animals. The BDNF assessment revealed that stress and memantine did not change hippocampal BDNF level six days after drug or stress termination. Conclusions: Inhibition of NMDA receptors in BLA can inhibit maintenance of stress-induced anxiety, which is not related to hippocampal BDNF level. In addition, chronic memantine injection induces anxiety.

Effect of vitamin D supplementation on CREB-TrkB-BDNF pathway in the hippocampus of diabetic rats.

Objective(s):Cyclic AMP (adenosine monophosphate) response element-binding protein (CREB) and Brain-derived neurotrophic factor (BDNF) are reported to broadly involve in learning capacity and memory. BDNF exerts its functions via tropomyosin receptor kinase B (TrkB). BDNF transcription is regulated by stimulating CREB phosphorylation. The CREB-TrkB-BDNF pathway is reported to be affected by diabetes, which may contribute to its cognitive deficits. This study was conducted to investigate the effect of vitamin D supplementation on the hippocampal fraction of this pathway in an animal model of type-1 diabetes mellitus (T1DM). Materials and Methods:Thirty-six adult male Sprague-Dawley rats were randomly divided into 4 groups as follows: Group 1: normal healthy rats (n=8); group 2: normal healthy rats receiving sesame oil supplementation as placebo (n=8); Group 3: diabetic rats receiving sesame oil (n=10); and Group 4: diabetic rats treated with 4300 IU/kg/week vitamin D dissolved in sesame oil (n=10). Diabetes was induced by intraperitoneal (IP) injection of streptozotocin. Blood and hippocampal samples were acquired at the end of the experiment. RNA was extracted from the hippocampus, and real-time PCR (polymerase chain reaction) was performed for BDNF and TrkB gene expression. Results:Administration of vitamin D (4300 IU/kg/week) in a T1DM animal model increased CREB phosphorylation in the hippocampus, but the serum and hippocampal BDNF levels and TrkB and BDNF gene expression did not change significantly.Conclusion:Vitamin D increased hippocampal CREB phosphorylation in a T1DM animal model. Our findings showed that vitamin D might be protective against central nervous system complications in diabetes. However, future studies are warranted.

Crocin acts as a neuroprotective mediator against methylphenidate-induced neurobehavioral and neurochemical sequelae: Possible role of the CREB-BDNF signaling pathway

Methylphenidate (MPH) abuse causes adverse neurobehavioral and neurochemical effects. Some herbal components such as crocin have shown neuroprotective properties. The current study evaluates the potential role of the cyclic AMP response element binding protein (CREB)‑brain‑derived neurotrophic factor (BDNF) signaling pathway in mediating the neuroprotective effects of crocin against MPH‑induced neurotoxicity in rats. Seventy adult male rats were randomly divided into seven groups. Group 1 and 2 received 0.7 ml/rat of normal saline and 10 mg/kg of MPH, respectively. Groups 3, 4, 5, and 6 were treated simultaneously with MPH (10 mg/kg) and crocin (10, 20, 40, and 80 mg/kg, respectively) for 21 days. Group 7 was treated with crocin (80 mg/kg) alone for 21 days. The Morris water maze (MWM) and open field test were used to assess cognitive and locomotor activities. Hippocampal neurotoxicity parameters and levels of BDNF and CREB were evaluated. Simultaneous treatment with various doses of crocin reduced the MPH‑induced cognition disturbances and hyperlocomotion. In addition, lipid peroxidation increased with MPH treatment and levels of the oxidized forms of glutathione (GSSG), interleukin 1 beta (IL‑1β), tumor necrosis factor alpha (TNF‑α), and Bax increased. MPH treatment decreased levels of the reduced form of glutathione (GSH), P‑CREB, Bcl‑2, and BDNF in the hippocampus. MPH also reduced activity of superoxide dismutase, glutathione peroxidase, and glutathione reductase in the hippocampus. In contrast, crocin attenuated MPH‑induced oxidative stress, inflammation, and apoptosis, and increased levels of P‑CREB and BDNF. Thus, crocin - likely via stimulation of the P‑CREB/BDNF signaling pathway - displayed neuroprotection against MPH‑induced neurotoxicity.

Memory Impairment Induced by Chronic Psychosocial Stress Is Prevented by L-Carnitine.

IntroductionPsychosocial stress (STS) negatively influences memory. This might be associated to oxidative stress-induced progressive destruction of numerous brain structures and functions. L-carnitine (L-CAR) is a widely used antioxidant compound that is endogenously made in mammalian species. The current study investigated the effect of L-CAR on STS-induced memory impairment in the rat hippocampus.MethodsThe STS was induced using intruder model, where two rats were randomly switched from each one cage to another, once/day for 6 weeks. Concurrently, L-CAR (300mg/kg/day) was intraperitoneally administered for 6 weeks. After that, radial arm water maze (RAWM) was used to assess spatial learning memory in rats. Hippocampal biomarkers of oxidative stress, including thiobarbituric acid reactive substance (TBARs), oxidized glutathione (GSSG), reduced glutathione (GSH), glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD), and Brain-derived neurotrophic factor (BDNF) were examined.ResultsThe results showed impairment of short-term memory (P < 0.05) during STS, whereas L-CAR treatment protected against this effect. Furthermore, while no change was observed in GSH, GSSG, GPx, catalase, and SOD, L-carnitine normalized STS-induced reduction in the hippocampal BDNF levels and increase in TBARS levels.DiscussionChronic psychosocial stress-induced memory impairment was prevented via L-CAR administration, which could have been achieved via normalizing changes in lipid peroxidation (TBARs) and BDNF levels in the hippocampus.

Voluntary exercise and estradiol reverse ovariectomy-induced spatial learning and memory deficits and reduction in hippocampal brain-derived neurotrophic factor in rats

Ample evidences have demonstrated the beneficial effects of physical exercise on cognitive functions such as learning and memory. It is well established that female sex hormones have an important role in regulating learning and memory. This study was designed to investigate the effects of voluntary exercise and estrogen replacement on learning and memory deficits and reduction in hippocampal brain derived neurotrophic factor (BDNF) levels induced by ovariectomy. Ovariectomized rats were given daily vehicle or 17 β-estradiol (20 μg/kg) and allowed to freely exercise in a running wheel over the course of 2 weeks. After this period, they were trained and tested on a water-maze spatial task for 5 consecutive days, followed by a probe test one day later. At the end of the behavioral tests, all animals were decapitated and their hippocampal levels of BDNF were measured. Ovariectomy impaired spatial learning and memory and reduced hippocampal BDNF levels. Exercise significantly improved performance during both training and the retention of the water-maze task and increased hippocampal BDNF. Exercise, 17 β-estradiol and their combination recovered the impairing effects of ovariectomy on learning and memory performance. The combined treatment did not produce stronger effect than either exercise or 17 β-estradiol alone. Our findings provide an important evidence about positive influences of regular exercise and estrogen treatment against cognitive and BDNF deficits induced in ovariectomized rats, an experimental model of menopause.

Effect of continuous environmental enrichment and aerobic exercise on rat plasma and hippocampal brain-derived neurotrophic factor

Objective: Environmental enrichment (EE) or exercise can positively affect memory function through increased long-term potentiation and neurogenesis, which is facilitated by brain-derived neurotrophic factor (BDNF). BDNF promotes blood vessel growth, angiogenesis linked to adult neurogenesis, and neuronal survival. Here, we investigated the effects of EE, aerobic exercise, and their combination on plasma and hippocampal BDNF levels. Materials and Methods: Twenty-four 7-month-old adult male Wistar rats weighing 300–400 g were randomly assigned to the following four groups: control (C), aerobic exercise (A), EE, and combined EE and aerobic exercise (EEA). Interventions were given for 8 weeks, and plasma and hippocampal BDNF levels were measured using enzyme-linked immunosorbent assay. Results: A combination of aerobic exercise and continuous EE produced the largest increase in hippocampal and plasma BDNF levels in adult rats. A positive correlation (r = 0.686, P = 0.002, n = 24) was observed between plasma and hippocampal BDNF levels in adult rats. Conclusion: We conclude that a combination of aerobic exercise and continuous EE increases plasma and hippocampal BDNF in adult rats.

Vitamin E attenuates alterations in learning, memory and BDNF levels caused by perinatal ethanol exposure

ABSTRACT Objective: Alcohol exposure during pregnancy affects the developing fetus and causes a variety of physical and neurological abnormalities. Here we aim to study the effects of vitamin E on spatial learning and memory deficits and on changes in hippocampal brain-derived neurotrophic factor (BDNF) levels following perinatal ethanol exposure in rats. Method: Pregnant Wistar rats received ethanol (4 g/kg) and vitamin E (doses of 100, 200, and 400 mg/kg) on day 0 of gestation (GD) until weaning (28 days). On postnatal days (PND) 29, the performance of spatial learning and memory of rats were measured using the Morris water maze (MWM). The expression of BDNF protein levels in the hippocampus was assayed using BDNF ELISA kits. Results: Ethanol exposed group showed higher escape latency during training, reduced time spent in the target quadrant, higher escape location latency and average proximity in probe test. Vitamin E with doses of 100, 200 and 400 mg/kg significantly reduced escape latency during training. Also, vitamin E (400 mg/kg) significantly increased time spent in target quadrant, decreased escape location latency and average proximity in probe test. Maternal ethanol treatment significantly reduced the expression of BDNF protein in the hippocampus of offspring, whereas administration of vitamin E (400 mg/kg) significantly increased hippocampal BDNF in ethanol-treated rats. Discussion: Vitamin E administration dose-dependently ameliorate learning and memory deficits induced by perinatal ethanol exposure and increased hippocampal BDNF levels. BDNF may be implicated in the beneficial effects of vitamin E on learning and memory in the perinatal ethanol-exposed rat.

Antidepressant effects of moxidectin, an antiparasitic drug, in a rat model of depression

Substantial data indicate that an imbalance in gut microbiome (GM), also referred to as dysbiosis, may play an important role in depression. Moreover, drugs that normalize GM can result in an antidepressant-like effect. It was reported recently that moxidectin (MOX), an antiparasitic drug commonly used in veterinary medicine, has a positive influence on microbiota implicated in mood regulation. We undertook this study to determine whether MOX would actually show antidepressant-like properties in an animal model of depression and whether it would affect the hippocampal and frontal cortex levels of brain-derived neurotrophic factor (BDNF) or tumor necrosis factor (TNF)-alpha, peptides that have been implicated in pathogenesis of depression and effectiveness of various antidepressants. Adult male Wistar-Kyoto rats, a putative animal model of depression, were treated with a single dose of MOX (2.5 mg/kg, i.p.) and their performance in the open field locomotor activity (OFLA) as well as in the forced swim test (FST) was evaluated at 24 h, one week and two weeks after the single injection. A separate group of rats were injected with 2.5 mg/kg MOX and sacrificed 24 h later for neurochemical evaluations. MOX resulted in a decrease in immobility score after 24 h, whereas OFLA was not affected. Concomitant with the 24 h behavioral effects, the levels of hippocampal and frontal cortical BDNF were significantly increased, whereas the levels of TNF-alpha in both these areas were significantly decreased. The decrease in immobility scores was still evident after one week, but not 2 weeks of rest. These results indicate long lasting antidepressant effects of a single MOX dose and suggest potential utility of this drug in treatment-resistant depression.

Obese mice exposed to psychosocial stress display cardiac and hippocampal dysfunction associated with local brain-derived neurotrophic factor depletion.

IntroductionObesity and psychosocial stress (PS) co-exist in individuals of Western society. Nevertheless, how PS impacts cardiac and hippocampal phenotype in obese subjects is still unknown. Nor is it clear whether changes in local brain-derived neurotrophic factor (BDNF) account, at least in part, for myocardial and behavioral abnormalities in obese experiencing PS.MethodsIn adult male WT mice, obesity was induced via a high-fat diet (HFD). The resident-intruder paradigm was superimposed to trigger PS. In vivo left ventricular (LV) performance was evaluated by echocardiography and pressure-volume loops. Behaviour was indagated by elevated plus maze (EPM) and Y-maze. LV myocardium was assayed for apoptosis, fibrosis, vessel density and oxidative stress. Hippocampus was analyzed for volume, neurogenesis, GABAergic markers and astrogliosis. Cardiac and hippocampal BDNF and TrkB levels were measured by ELISA and WB. We investigated the pathogenetic role played by BDNF signaling in additional cardiac-selective TrkB (cTrkB) KO mice.FindingsWhen combined, obesity and PS jeopardized LV performance, causing prominent apoptosis, fibrosis, oxidative stress and remodeling of the larger coronary branches, along with lower BDNF and TrkB levels. HFD/PS weakened LV function similarly in WT and cTrkB KO mice. The latter exhibited elevated LV ROS emission already at baseline. Obesity/PS augmented anxiety-like behaviour and impaired spatial memory. These changes were coupled to reduced hippocampal volume, neurogenesis, local BDNF and TrkB content and augmented astrogliosis.InterpretationPS and obesity synergistically deteriorate myocardial structure and function by depleting cardiac BDNF/TrkB content, leading to augmented oxidative stress. This comorbidity triggers behavioral deficits and induces hippocampal remodeling, potentially via lower BDNF and TrkB levels.FundJ.A. was in part supported by Rotary Foundation Global Study Scholarship. G.K. was supported by T32 National Institute of Health (NIH) training grant under award number 1T32AG058527. S.C. was funded by American Heart Association Career Development Award (19CDA34760185). G.A.R.C. was funded by NIH (K01HL133368-01). APB was funded by a Grant from the Friuli Venezia Giulia Region entitled: “Heart failure as the Alzheimer disease of the heart; therapeutic and diagnostic opportunities”. M.C. was supported by PRONAT project (CNR). N.P. was funded by NIH (R01 HL136918) and by the Magic-That-Matters fund (JHU). V.L. was in part supported by institutional funds from Scuola Superiore Sant'Anna (Pisa, Italy), by the TIM-Telecom Italia (WHITE Lab, Pisa, Italy), by a research grant from Pastificio Attilio Mastromauro Granoro s.r.l. (Corato, Italy) and in part by ETHERNA project (Prog. n. 161/16, Fondazione Pisa, Italy). Funding source had no such involvement in study design, in the collection, analysis, interpretation of data, in the writing of the report; and in the decision to submit the paper for publication.

Antidepressant effects of C-Terminal domain of the heavy chain of tetanus toxin in a rat model of depression

The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) may be of therapeutic potential in motor impairments associated with Parkinson disease (PD). Since depression is a common co-morbid condition with PD, we undertook this study to determine whether Hc-TeTx might also show antidepressant-like properties and whether central brain-derived neurotrophic factor (BDNF) and/or tumor necrosis factor (TNF)-alpha are also affected by it. Adult male Wistar-Kyoto rats, a putative animal model of depression, were treated with various doses of Hc-TeTx (0, 20, 40 and 60 μg/kg, IM) and their performance in the open field locomotor activity (OFLA) as well as in the forced swim test (FST) was evaluated at 24 h, one week and two weeks after the single injection. A separate group of rats were injected with 60 μg/kg Hc-TeTx and sacrificed 24 h later for neurochemical evaluations. Hc-TeTx resulted in a dose-dependent decrease in immobility score after 24 h, whereas OFLA was not affected. Concomitant with the 24 h behavioral effects, the levels of hippocampal and frontal cortical BDNF were significantly increased, whereas the levels of TNF-alpha in both these areas were significantly decreased. The decrease in immobility scores following higher doses of Hc-TeTx were still evident after one week, but not 2 weeks of rest. These results indicate long lasting antidepressant effects of a single Hc-TeTx dose and suggest potential utility of Hc-TeTx in PD-depression co-morbidity.

Branched-chain amino acids mediate resilience to chronic social defeat stress by activating BDNF/TRKB signaling

How individuals respond to chronic stress varies. Susceptible individuals ultimately develop depression; whereas resilient individuals live normally. In this study, our objective was to examine the effect of branched-chain amino acids (BCAA), commonly used by athletes, on susceptibility to stress. Male C57BL/6 mice were subjected to daily defeat sessions by a CD1 aggressor, for 10 days. On day11, the behavior of mice was assessed using the social interaction test, elevated plus maze and open field. Mice received the BCAA leucine, isoleucine or valine before each defeat session. Furthermore, we examined whether BCAA regulate brain derived neurotrophic factor (BDNF) signaling by using a brain-permeable tropomyosin receptor kinase B (TRKB) inhibitor, ANA-12. We also tested the effect of voluntary exercise and high protein diets on susceptibility to stress. Mice exposed to chronic stress displayed increased susceptibility and social avoidance. BCAA promoted resilience to chronic stress, rescued social avoidance behaviors and increased hippocampal BDNF levels and TRKB activation. Inhibition of TRKB signaling abolished the ability of BCAA to promote resilience to stress and to rescue social avoidance. Interestingly, we found that BCAA activate the exercise-regulated PGC1a/FNDC5 pathway known to induce hippocampal BDNF signaling. Although both voluntary exercise and BCAA promoted resilience to stress, combining them did not yield synergistic effects confirming that they affect similar pathways. We also discovered that high protein diets mimic the effect of BCAA by rescuing social deficits induced by chronic stress and increase Bdnf expression in the hippocampus. Our data indicate that BCAA, exercise and high protein diets rescue susceptibility to stress by activating the hippocampal BDNF/TRKB signaling.

Social isolation and social support at adulthood affect epigenetic mechanisms, brain-derived neurotrophic factor levels and behavior of chronically stressed rats

Epigenetic modulation of brain-derived neurotrophic factor (BDNF) provides one possible explanation for the dysfunctions induced by stress, such as psychiatric disorders and cognitive decline. Interestingly, social support can be protective against some of these effects, but the mechanisms of social buffering are poorly understood. Conversely, early isolation exacerbates the responses to stressors, although its effects in adulthood remain unclear. This study investigated the effects of social isolation and social buffering on hippocampal epigenetic mechanisms, BDNF levels and behavioral responses of chronically stressed young adult rats. Male Wistar rats (3 months) were assigned to accompanied (paired) or isolated housing. After one-month half of each group was submitted to a chronic unpredictable stress (CUS) protocol for 18 days. Among accompanied animals, only one was exposed to stress. Behavioral analysis encompassed the Open field, plus maze and inhibitory avoidance tasks. Hippocampal H3K9 and H4K12 acetylation, HDAC5 expression and BDNF levels were evaluated. Isolated housing increased HDAC5 expression, decreased H3K9 and H4K12 acetylation, reduced BDNF levels, and impaired long-term memory. Stress affected weight gain, induced anxiety-like behavior and decreased AcK9H3 levels. Interactions between housing conditions and social stress were seen only for HDAC5 expression, which showed a further increase in the isolated + CUS group but remained constant in accompanied animals. In conclusion, social isolation at adulthood induced epigenetic alterations and exacerbated the effects of chronic stress on HDAC5. Notwithstanding, social support counteracted the adverse effects of stress on HDAC5 expression.

What is the combined effect of intense intermittent exercise and Ginkgo biloba plant on the brain neurotrophic factors levels, and learning and memory in young rats?

The present study was conducted to investigate the effect of intense intermittent exercise and Ginkgo biloba on the hippocampal levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) and also memory and learning in young rats. Forty two eight-week-old rats were randomly divided into six groups including control, low dose of Ginkgo biloba (65 mg/kg), high dose of Ginkgo biloba (100 mg/kg), exercise, exercise + low dose of Ginkgo biloba, exercise + high dose of Ginkgo biloba. The exercise protocol or Ginkgo biloba administration was six days a week for six weeks. The hippocampal levels of BDNF and NT-4 were measured by ELISA method, and learning and memory were evaluated by Morris water maze test in all groups. Data were analyzed using SPSS software. Increase in hippocampal levels of BDNF and NT-4 appeared following exercise (p < 0.01). The levels do not change following exercise + Ginkgo biloba administration. However, the NT-4 level decreased in the high dose of Ginkgo biloba group (p < 0.01). Disorder in learning and memory was indicated following the use of low dose of Ginkgo biloba or exercise + low dose Ginkgo biloba administration (p < 0.001). Learning elevated in the exercise group (p < 0.05). Exercise in young rats may increase brain neurotrophin levels and lead to improved learning. The preventative or protective role of Ginkgo biloba against some diseases has been suggested, but its consumption in young athletes is recommended with caution.

Modulation of Phospho-CREB by Systemically Administered Recombinant BDNF in the Hippocampus of the R6/2 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease due to an expansion of a trinucleotide repeats in IT15 gene encoding for the protein huntingtin. Motor dysfunction, cognitive decline, and psychiatric disorder are typical clinical signs of HD. In HD, mutated huntingtin causes a major loss of brain derived neurotrophic factor (BDNF), causing striatal atrophy. Moreover, a key involvement of BDNF was observed in the synaptic plasticity that controls the acquisition and/or consolidation of certain forms of memory. We studied changes in hippocampal BDNF and in CREB in the R6/2 mouse model of HD. Moreover, we investigated if the beneficial effects of systemically administered recombinant BDNF observed in the striatum and cortex had an effect also on the hippocampus. Osmotic minipumps that chronically released recombinant BDNF or saline solution from 4 weeks of age until euthanasia were implanted into R6/2 and wild type mice. Our data show that BDNF is severely decreased in the hippocampus of R6/2 mice, while BDNF treatment restored its physiological levels. Moreover, the chronic administration of recombinant BDNF promoted the increment of phosphorylated CREB protein. Our study demonstrates the involvement of hippocampus in the pathology of R6/2 model of HD and correlates the beneficial effects of BDNF administration with increased hippocampal levels of BDNF and pCREB.

Hippocampal BDNF signaling is required for the antidepressant effects of perillaldehyde

Perillaldehyde is one of the main components in perilla. Previous studies have shown that perillaldehyde exerted an antidepressant effect in mice, some of which is mediated through regulation of the anti-inflammatory system and the monoamine system. The primary objective of this study was to investigate the possible effects of perillaldehyde on the neurotrophic system and to elucidate whether its antidepressant effect requires brain-derived neurotrophic factor (BDNF) signaling. Mice were exposed to chronic unpredictable mild stress (CUMS) and orally administrated with perillaldehyde for 4 weeks for behavioral testing. Perillaldehyde not only reversed the decrease in sucrose preference but also attenuated the increase in feeding latency. In addition, perillaldehyde can attenuate the reduction of CUMS-induced hippocampal BDNF levels. Our further study found that the BDNF receptor tropomyosin receptor kinase B (TrkB) antagonist K252a completely blocked the antidepressant effect of perillaldehyde in mice. Biochemical analysis showed that K252a pretreatment completely prevented the improvement of BDNF, extracellular signal-regulated kinase (ERK) phosphorylation and synaptic protein. These results indicated that activation of BDNF-ERK signaling in the hippocampus was required, at least in part for the antidepressant effects of perillaldehyde.

Effects of escitalopram and ibuprofen on a depression-like phenotype induced by chronic stress in rats

Clinical and preclinical studies have reported that co-administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and antidepressant drugs are effective in patients with depression and in animal models of depression. However, several studies have suggested that NSAIDs inhibit the antidepressant effects of selective serotonin reuptake inhibitors in humans and mice. The present study investigated the effects of escitalopram (ESC) and ibuprofen (IBU), alone or in combination, on the stress-induced behavior and expression of brain-derived neurotrophic factor (BDNF) and p11, markers of depression and antidepressant action, in chronically stressed rats. Rats were subjected to chronic restraint stress (CRS) for 3 weeks and administered the following drugs: single administration of ESC or IBU or co-administration of ESC and IBU (ESC + IBU). Immobility time was measured by the forced swimming test (FST), and hippocampal BDNF and p11 levels were analyzed by quantitative real-time polymerase chain reaction and Western blotting. CRS increased immobility time on the FST. Administration of ESC, IBU, or ESC + IBU significantly attenuated the stress-induced increase in immobility time. CRS also significantly increased plasma corticosterone concentration by 169%. This effect was significantly recovered by administering ESC, IBU, or ESC + IBU. The levels of BDNF and p11 in the hippocampus decreased significantly in response to CRS. These decreases were prevented by administering ESC, IBU, or ESC + IBU. These findings suggest that both single and co-administration of ESC and IBU exerts antidepressant effects. These effects were associated with upregulation of BDNF and p11 expression.

Changes in brain metabolites related to stress resilience: Metabolomic analysis of the hippocampus in a rat model of depression

The ability to cope successfully with stress is known as ‘resilience’, and those with resilience are not prone to developing depression. One preclinical animal model for depression is the chronic mild stress (CMS) model. There are CMS-resilient (do not manifest anhedonia) and CMS-susceptible (manifest anhedonia) rats. This study aimed to investigate the differences in the profiles of hippocampal metabolites between susceptible and resilient rats, and to identify a biomarker that can distinguish the two. We divided stress-loaded rats into susceptible and resilient types based on their sucrose preference values. We then conducted brain-derived neurotrophic factor (BDNF) quantification and metabolomic analysis in the hippocampus. Compared to the controls, no significant differences were observed in the hippocampal BDNF levels of susceptible and resilient rats. However, the control rats were clearly distinguishable from the susceptible rats in terms of their brain metabolite profiles; the control rats were difficult to distinguish from the resilient rats. CMS model rats showed an increase in the levels of N-acetylaspartate and glutamate, and a decrease in the levels of aspartate and γ-aminobutyric acid in the hippocampus. Of the 12 metabolites measured in the present study, N-acetylaspartate was the only one that could differentiate the three types (control, susceptible, and resilient) of rats. Thus, brain metabolomic analyses can not only distinguish CMS model rats from control rats, but also indicate stress susceptibility. The variation in the levels of N-acetylaspartate in the hippocampus of control, resilient, and susceptible rats demonstrated that it could be a biomarker for stress susceptibility.

In vitro cytotoxicity assessments of persistent organic pollutants using cetacean fibroblasts

The serotonin reuptake inhibitor antidepressant fluoxetine (FLX) has been widely prescribed for the treatment of some diseases during pregnancy and/or lactation. Despite possible adverse effects observed in the progeny after maternal exposure to FLX, it is recognized that not treating a mother who has clinical indication for antidepressants may also impact negatively her well being and the fetal/newborn development. The present study investigated if two supplements already used by pregnant women, i.e., folic acid (FA) and fish oil (FO) could minimize effects in pubertal rats induced by maternal exposure to FLX during pregnancy and lactation. Evaluations included two behavioral tests (elevated plus maze and novelty-induced suppressed feeding) and quantification of brain derived neurotrophic factor (BDNF) in the hippocampus. Wistar rats were gavaged with FLX (5 mg/kg) or tap water associated or not with FA (3 mg/kg) or FO (1.3 mg/kg) during pregnancy and lactation. Pups exposed to FLX presented anxiety-like behavior and decreased hippocampal BDNF levels that were not influenced by co-exposure with FA or FO. FO exposure resulted in anxiety-like behavior, decreased BDNF levels and eating behavior whereas FA exposure increased BDNF and induced hyperactivity in the elevated plus maze. In conclusion, this study suggests that reduced hippocampal BDNF may play a role in the developmental neurotoxicity of FLX. FA and FO were not effective as employed in the present study but the search for alternatives to manage the risk of antidepressant exposure during pregnancy and/or lactation is likely to continue.

Agomelatine-induced modulation of brain-derived neurotrophic factor (BDNF) in the rat hippocampus

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that serves as a survival factor for neurons. Agomelatine is a novel antidepressant as well as a potent agonist of melatonin (MT), MT1 and MT2 receptor types and an antagonist of the serotonin (5HT), 5-HT2C receptor. The study herein established whether treatment with agomelatine alters hippocampal BDNF protein expression under chronic unpredictable mild stress (CUMS) condition. Twenty-one day treatment with agomelatine, fluoxetine or vehicle was assessed in 52 Sprague-Dawley rats undergoing CUMS. Ten naïve control rats were also evaluated after 21 days. The behavioral effects of treatments were studied using the open field test (OFT) on day 0, 7 and 21 and sucrose preference test on day 21. Hippocampal BDNF protein expression was measured using immunohistochemistry. The effect of the interventions on hippocampal neurons was histologically examined after H&E staining. Agomelatine mitigated the reduction in rearing behavior by CUMS in the OFT on day 7 as well as sucrose preference on day 21. The mean optical density value of BDNF was significantly higher in the CUMS + agomelatine group than the CUMS and CUMS + fluoxetine groups. The CUMS + agomelatine group had a significantly higher number of BDNF positive cells compared to naïve controls and CUMS group. Histology showed that hippocampal neurons in the CUMS + agomelatine and CUMS + fluoxetine groups were intact and few of them demonstrated karyopyknosis. Agomelatine–a novel antidepressant, but not fluoxetine, increased hippocampal BDNF level and of BDNF positive neurons in rats subject to CUMS.

Iron chelator deferiprone rescues memory deficits, hippocampal BDNF levels and antioxidant defenses in an experimental model of memory impairment

Brain-derived neurotrophic factor (BDNF) plays a key role in neural development and physiology, as well as in pathological states. Post-mortem studies demonstrate that BDNF is reduced in the brains of patients affected by neurodegenerative diseases. Iron accumulation has also been associated to the pathogenesis of neurodegenerative diseases. In rats, iron overload induces persistent memory deficits, increases oxidative stress and apoptotic markers, and decreases the expression of the synaptic marker, synaptophysin. Deferiprone (DFP) is an oral iron chelator used for the treatment of systemic iron overload disorders, and has recently been tested for Parkinson's disease. Here, we investigated the effects of iron overload on BDNF levels and on mRNA expression of genes encoding TrkB, p75NTR, catalase (CAT) and NQO1. We also aimed at investigating the effects of DFP on iron-induced impairments. Rats received iron or vehicle at postnatal days 12-14 and when adults, received chronic DFP or water (vehicle). Recognition memory was tested 19days after the beginning of chelation therapy. BDNF measurements and expression analyses in the hippocampus were performed 24h after the last day of DFP treatment. DFP restored memory and increased hippocampal BDNF levels, ameliorating iron-induced effects. Iron overload in the neonatal period reduced, while treatment with DFP was able to rescue, the expression of antioxidant enzymes CAT and NQO1.