Increased BDNF Levels Research Articles

Cannabidiol prevents lipopolysaccharide-induced sickness behavior and alters cytokine and neurotrophic factor levels in the brain.

BackgroundMajor depressive disorder (MDD) affects millions of people worldwide. While the exact pathogenesis is yet to be elucidated, the role of neuro-immune signaling has recently emerged. Despite major advances in pharmacotherapy, antidepressant use is marred by limited efficacy and potential side effects. Cannabidiol (CBD), a phytocannabinoid, exerts antidepressant-like effects in experimental animals. This study investigated the impact of CBD on sickness behavior (SB), a measure of depressive-like response, and neuro-immune changes induced by lipopolysaccharides (LPS) in mice.MethodsSocially isolated rodents were administered with LPS to trigger SB. and treated with CBD or its vehicle. Animals were submitted to forced swimming test, to evaluate depressive-like behavior, and to open field test, to evaluate locomotory activity. Immediately after behavioral analyses, animals were euthanized and had their hypothalamus, prefrontal cortex and hippocampus dissected, to proceed neurotrophins and cytokines analyses. ELISA was used to detect IL-1β, BDNF and NGF; and cytometric beads array to measure IL-2, IL-4, IL-6, IFN-γ, TNF-α and IL-10 levels.ResultsCBD effectively prevented SB-induced changes in the forced swim test without altering spontaneous locomotion. This phytocannabinoid also partially reversed LPS-evoked IL-6 increase in both the hypothalamus and hippocampus. In addition, CBD prevented endotoxin-induced increase in BDNF and NGF levels in the hippocampus of SB animals.ConclusionsApparently, CBD prevents both behavioral and neuro-immunological changes associated with LPS-induced SB, which reinforces its potential use as an antidepressant which modulates neuroinflammation. This opens up potentially new therapeutic avenues in MDD.Supplementary InformationThe online version contains supplementary material available at 10.1007/s43440-021-00301-8.

Chronic AdipoRon Treatment Mimics the Effects of Physical Exercise on Restoring Hippocampal Neuroplasticity in Diabetic Mice

Administration of exercise mimetic drugs could be a novel therapeutic approach to combat comorbid neurodegeneration and metabolic syndromes. Adiponectin is an adipocyte-secreted hormone. In addition to its antidiabetic effect, adiponectin mediates the antidepressant effect of physical exercise associated with adult hippocampal neurogenesis. The antidiabetic effect of the adiponectin receptor agonist AdipoRon has been demonstrated, but its potential pro-cognitive and neurotrophic effects in the hippocampus under diabetic condition are still unclear. This study reported that chronic AdipoRon treatment for 2 weeks improved hippocampal-dependent spatial recognition memory in streptozotocin-induced diabetic mice. Besides, AdipoRon treatment increased progenitor cell proliferation and neuronal differentiation in the hippocampal dentate gyrus (DG) of diabetic mice. Furthermore, AdipoRon treatment significantly increased dendritic complexity, spine density, and N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) in the dentate region, and increased BDNF levels in the DG of diabetic mice. AdipoRon treatment activated AMPK/PGC-1α signalling in the DG, whereas increases in cell proliferation and LTP were not observed when PGC-1α signalling was pharmacologically inhibited. In sum, chronic AdipoRon treatment partially mimics the benefits of physical exercise for learning and memory and hippocampal neuroplasticity in the diabetic brain. The results suggested that AdipoRon could be a potential physical exercise mimetic to improve hippocampal plasticity and hence rescue learning and memory impairment typically associated with diabetes.

The role of pre-pubertal training history on hippocampal neurotrophic factors and glucocorticoid receptor protein levels in adult male rats

Neurotrophic factors play an integral role in hippocampal plasticity, and interaction with HPA axis components, especially glucocorticoid receptors (GR), can mediate the structural and functional changes. In the present work, we investigated the long-term effects of combined exercise training (CET) and voluntary physical activity in an enriched environment (EE) in the pre-pubertal period on hippocampal neurotrophic factors and GR. For this purpose, a longitudinal study was designed. After three weeks, all rats were kept in the standard cages without any interventions until adulthood. Western blot analysis revealed a significant increase in hippocampal BDNF and VEGF protein levels in both EE and CET groups (P < 0.001), along with an increase in GR protein levels. In addition, EE decreased serum corticosterone levels compared to CET (P < 0.05). Serum insulin-like growth factor-1 (IGF-1) levels did not demonstrate remarkable changes between groups. Training interventions during sensitive developmental periods may produce profound and long-lasting effects on the hippocampus, at least in part by interactive effects of neurotrophic factors cascades and GR.

Exposure of R6/2 mice in an enriched environment augments P42 therapy efficacy on Huntington's disease progression

Huntington's disease (HD) is due to a mutation in the gene encoding for Huntingtin protein generating polyQ domain extension. Mutant Htt (mHtt) leads to important dysfunction of the BDNF/TrkB signaling. We previously described the 23aa Htt fragment P42, that attenuated the pathological phenotypes induced by mHtt. We reported that, in the R6/2 mouse model of HD, P42 rescued striatal TrkB level but marginally increased cortical BDNF. In the present study, our aim was to address P42 neuroprotection in presence of an external input of BDNF. We combined P42 administration with environmental enrichment (EE), induced by training in the Hamlet test. We examined the consequences of P42 + EE combination on different phenotypes in R6/2 HD mice: motor and cognitive performances, recorded at early and late pathological stages, and analyzed aggregated mHtt and BDNF levels in forebrain structures. Hamlet exploration (i.e., entries in Run, Hide, Eat, Drink and Interact houses) was gradually impaired in R6/2 mice, but maintained by P42 treatment until week 8. Topographic memory alteration measured at week 7 was attenuated by P42. Motor performances (rotarod) were significantly ameliorated by the P42 + EE combination until late stage (week 12). The P42 + EE combination also significantly decreased aggregated Htt levels in the hippocampus, striatum and cortex, and increased BDNF levels in the cortex and striatum. We concluded that combination between P42 treatment, known to increase TrkB striatal expression, and a BDNF-enhancing therapy such as EE efficiently delayed HD pathology in R6/2 mice. Use of dual therapies might be a pertinent strategy to fight neurodegeneration in HD.

Microinjection of the BDNF receptor antagonist ANA-12 into the nucleus accumbens and medial-prefrontal cortex attenuates morphine-induced reward memory, and alterations of BDNF levels and apoptotic cells in rats

This study was designed to examine the effects of intra- nucleus accumbens (NAc) of BDNF receptor antagonist ANA-12 on the acquisition and expression and intra- medial-prefrontal cortex (mPFC) of ANA-12 on the extinction and reinstatement of morphine-induced conditioned place preference (CPP) and also BDNF levels and apoptotic neurons in the NAc and mPFC of rats. In this study, adult male Wistar rats (200–250 g) were used. Two separate cannulas were inserted bilaterally into the NAc and/or mPFC. ANA-12 (3 μg/0.5 μl/side) was injected into the NAc and/or mPFC to evaluate the rewarding effects of morphine using a CPP paradigm. Then, the levels of BDNF and apoptotic in the NAc and mPFC were assessed at the end of each treatment phase using ELISA and TUNEL methods, respectively. All of vehicle-treated rats following morphine CPP showed the increase of BDNF levels and apoptotic neurons in the NAc and mPFC. ANA-12 significantly attenuated the acquisition and expression of morphine-induced CPP, BDNF levels and apoptotic neurons in the NAc during the acquisition, but not the expression phase. Also, ANA-12 significantly facilitated the extinction, but no effect on reinstatement of morphine CPP, and decreased BDNF levels and apoptotic neurons in the mPFC during the extinction, but not the reinstatement. We conclude that blocking TrkB with ANA-12 showed therapeutic effects on morphine-associated reward memory and neuronal death in the NAc and mPFC induced by morphine CPP. Thus, the BDNF–TrkB signaling may be important in the acquisition, expression, extinction, but not the reinstatement of morphine CPP.

Potential antidepressant-like effect of piperazine derivative LQFM212 in mice: Role of monoaminergic pathway and brain-derived neurotrophic factor

Major depression disorder (MDD) is one of the most widespread and debilitating psychiatric diseases and may be associated with other mental disorders such as anxiety. Despite advances in neurobiology studies, currently no established mechanism can explain all facets of MDD, and available drugs often show therapeutic delay for clinical effectiveness and response rates in patients are around 50 %. Previous activities of piperazine derivatives on CNS are indicators of its therapeutic potential for treating mental disorders. In this regard, we have previously shown that the piperazine derivative 2,6-di-tert-butyl-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenol (LQFM212) has anxiolytic-like activity which involves serotonergic pathway, nicotinic receptors and BZD-site of GABAA receptor, without cognitive impairments. Herein, was evaluated the potential antidepressant-like effect of LQFM212 on forced swimming test (FST) after a single dose of 54 μmol/kg and after repeated treatment for 15 days in mice. Pretreatment with WAY-100635, PCPA, prazosin, SCH-23390, sulpiride or AMPT reversed the antidepressant-like effect on FST, suggesting that monoaminergic pathway contributes for effects of LQFM212. Furthermore, repeated treatment with LQFM212 increased hippocampal BDNF levels dosed by ELISA kit. In assessment of possible adverse effects, repeated treatment with LQFM212 did not alter the body weight of the animals, glutathione levels in the liver, and serum levels of AST, ALT, urea, and creatinine. Taken together, the results showed that LQFM212 has an antidepressant-like effect that involves monoaminergic pathway and increased BDNF levels. This compound represents promising candidate for prototype of psychoactive drugs for treatment of anxiety and depression disorders since these pathological conditions may exist in comorbidities.

Diabetes mellitus, cognitive deficits and serum BDNF levels in chronic patients with schizophrenia: A case-control study

The relationship between serum BDNF levels and cognitive dysfunction in schizophrenia (SCZ) patients comorbid with type 2 diabetes mellitus (T2DM) has not been reported. Hence, this study aimed to explore whether and how the changes of serum BDNF levels were correlated with cognitive impairment in SCZ patients comorbid with T2DM. We recruited 472 inpatients with chronic SCZ (54 T2DM and 418 non-T2DM), and 225 healthy controls. Serum BDNF levels and routine biochemical parameters were measured. Psychopathological symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS) and cognitive function was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). SCZ patients with T2DM had significantly higher serum BDNF levels than SCZ patients without T2DM (F = 11.31, p = 0.001). SCZ patients with T2DM scored higher in delayed memory than SCZ patients without T2DM (77.17 ± 18.44 vs.66.24 ± 19.51, p = 0.000), and still showed significance after controlling for confounders. Further stepwise multiple regression analysis identified serum BDNF as an independent contributor to the RBANS attention of SCZ patients with T2DM (β = 0.30, t = 2.09, p = 0.042). The increase of BDNF levels and better cognitive performance, especially delayed memory, may be related to the pathophysiological process of T2DM in chronic SCZ patients.

Protection against acute cerebral ischemia/reperfusion injury by Leonuri Herba Total Alkali via modulation of BDNF-TrKB-PI3K/Akt signaling pathway in rats

ObjectiveTo observe the brain protective effect of Leonuri Herba Total Alkali (LHA) on cerebral ischemia reperfusion injury in rats, so as to provide basis for clinical research. MethodsAdult male SD rats were randomly assigned into sham group, middle cerebral artery occlusion/reperfusion (MCAO/R) group, and LHA + MCAO/R group (25 mg/kg, 50 mg/kg, and 100 mg/kg). Fourteen days before MCAO/R surgery, the rats in treatment groups were orally administered with LHA in ultrapure water once daily for 14 days, while rats in the sham and MCAO groups were given the same amount of saline in advance. After 1 h of administration on the 14th day, MCAO surgery was subjected. The neurological deficits, brain infarct volume, histopathology, immunofluorescence, inflammation indicators and the gene/protein expressions of BDNF-TrKB-PI3K/Akt signaling pathway in the rat brain tissue were evaluated 24 h after the MCAO/R-injury. ResultsIt was found that rats in LHA pre-administration group showed significantly reduced neurological deficit scores, infarction volume, the serum levels of NSE and S100β. Meanwhile, the content of Evans Blue (EB) in brain tissue from LHA group was decreased, as well as the levels of inflammatory cytokines and their gene levels. Moreover, LHA pre-administration inhibited the expression of CD44, GFAP, FOXO1 and promoted the expression of BDNF and NeuN. In addition, LHA pre-administration could up-regulate the protein expression of TrkB, p-PI3K, p-Akt, Bcl-2, and down-regulate the protein expression of Bax, and increase the level of Bcl-2/Bax. ConclusionsThe study demonstrated that LHA pre-administration could regulate the PI3K/Akt pathway by increasing BDNF levels, and play a neuroprotective role in cerebral ischemia-reperfusion injury.

The Effects of Exercise on BDNF Levels in Adolescents: A Systematic Review with Meta-Analysis.

The aim of this study was to analyze the evidence available in the literature about the effects of exercise on brain-derived neurotrophic factor levels in adolescents. The literature searches were conducted in PubMed, Embase, Scopus, ScienceDirect, Web of Science, SportDiscus, the Cochrane Central Register of Controlled Trials (CENTRAL) and CINAHL. Randomized controlled trials and non-randomized controlled trials performed with adolescents (10–19 years) who underwent different exercise programs and who evaluated BDNF levels before and after the intervention were included. We included six studies, four RCTs and two non-RCTs in the systematic review with a total of 407 adolescents. In two randomized trials and one non-RCT, the intervention groups showed significant improvements in BDNF levels compared with the control group. The results presented in the meta-analysis indicate that despite the positive effect in favor of the intervention, there were no significant differences (standardized mean difference 0.28 ng/mL, 95% confidence interval −0.28 to 0.85; p = 0.32, I² = 0%). The results presented in our review indicate that aerobic exercise programs practiced in moderate- or high-intensity are promising strategies to increase BDNF levels in adolescents. However, further studies are required to support this finding.

Balneotherapy decreases mechanical hyperalgesia by reversing BDNF and NOS2 immunocontent in spinal cord of mice with neuropathic pain

In the last decades, balneotherapy or thermalism has been used for health promotion and in the treatment of inflammatory and chronic processes. We found that balneotherapy reduced mechanical hyperalgesia, as well the increase of BDNF and NOS2 levels in the spinal cord, while increased BDNF and NOS1 in the paw. The data presented herein demonstrated for the first time in a murine model of neuropathic pain, the analgesic effect of balneotherapy with the water from the natural springs of Santo Amaro da Imperatriz-Brazil. Nevertheless, future clinical trials should be conducted to test the effectiveness of balneotherapy in neuropathic pain patients.

☆Protective effects of ginseng on memory and learning and prevention of hippocampal oxidative damage in streptozotocin-induced Alzheimer's in a rat model

BackgroundIn the etiology of Alzheimer's disease, the free radicals and Brain cholinergic system function, play a key role. The antioxidant compounds may well be effective in improving this disease. Hence, this study aimed to investigate the effects of ginseng on the treatment and prevention of Alzheimer’s disease in a rat model. Methods56 male Wistar rats were randomly divided into four groups: (1) control, (2) Alzheimer’s without treatment, (3) Alzheimer’s under post-treatment (ginseng, 200 mg/kg/day) for three weeks, and (4) Alzheimer's under pre and post-treatment from one week before induction of Alzheimer's to three weeks after that. To induce Alzheimer's disease 1.5 mg/kg of streptozotocin was injected into both lateral ventricles of the brain. Three weeks after induction, the rats' behavioral tests were applied in all groups. Glutathione peroxidase, Glutathione reductase, Total antioxidant capacity, Malondialdehyde, and Brain-derived neurotrophic factor were measured using commercial kits. Data were analyzed using one-way ANOVA and Bonferroni post hoc test. ResultsLearning and memory, antioxidant defenses, and BDNF showed a significant decrease after the onset of Alzheimer's induction compared with the control group (p < 0.05). Pre and post-treatment of the Alzheimer animals with ginseng significantly improved their learning and memory, antioxidant defenses, and BDNF levels (p < 0.05) compared with the Alzheimer animals without treatment. ConclusionBased on our results, pre and post-treatment with ginseng have protective effects against Alzheimer -induced learning and memory impairment. The effects of ginseng may be mediated through an increase in BDNF and antioxidants levels in the hippocampus region of the brain.

Enriched environment ameliorates memory impairments in rats after postsurgery sleep deprivation

Postsurgery sleep deprivation is a common complication that severely deteriorates the quality of life of patients. Here we aim to investigate the effects and mechanism of enriched environment in ameliorating sleep deprivation and memory impairments. Hernia repair surgery was performed on rats to induce sleep deprivation. Enriched environment (EE) was used to treat rats with sleep deprivation, and open field and Y-maze tests were performed to compare behavioral parameters of sleep deprivation rats with or without EE treatments to those of normal rats. To understand the mechanism, neurotrophic and growth factors including BDNF, NGF, NT-3 and GDNF were analyzed using enzyme-linked immunosorbent assay (ELISA). AMPAR subunits, including GluA1-A3, and GABAA receptor α1 subunit expression in hippocampus tissues were assessed using western blot. EE restored normal levels of anxiety index and freezing behavior in open field test and level of alternation in Y-maze test, suggesting the reduction of anxiolytic effects and spatial memory impairment induced by sleep deprivation. EE increased BDNF levels and reduced NT-3 levels in sleep deprivation rats. GluA1/GluA2 ratio was increased by EE. GABAA receptor α1 subunit expression was decreased by EE. EE is effective in ameliorating the detrimental effects of sleep deprivation in spatial memory impairment, and restoring normal levels of neurotrophic factors, which are potentially mediated by attenuating the changes in AMPAR subunit expression and reducing GABAA receptor α1 subunit expression. These data provide supporting evidences for the use of EE to treat adverse outcomes of sleep deprivation induced by surgery.

Plasma BDNF Levels Following Transcranial Direct Current Stimulation Allow Prediction of Synaptic Plasticity and Memory Deficits in 3×Tg-AD Mice.

Early diagnosis of Alzheimer’s disease (AD) supposedly increases the effectiveness of therapeutic interventions. However, presently available diagnostic procedures are either invasive or require complex and expensive technologies, which cannot be applied at a larger scale to screen populations at risk of AD. We were looking for a biomarker allowing to unveil a dysfunction of molecular mechanisms, which underly synaptic plasticity and memory, before the AD phenotype is manifested and investigated the effects of transcranial direct current stimulation (tDCS) in 3×Tg-AD mice, an experimental model of AD which does not exhibit any long-term potentiation (LTP) and memory deficits at the age of 3 months (3×Tg-AD-3M). Our results demonstrated that tDCS differentially affected 3×Tg-AD-3M and age-matched wild-type (WT) mice. While tDCS increased LTP at CA3-CA1 synapses and memory in WT mice, it failed to elicit these effects in 3×Tg-AD-3M mice. Remarkably, 3×Tg-AD-3M mice did not show the tDCS-dependent increases in pCREBSer133 and pCaMKIIThr286, which were found in WT mice. Of relevance, tDCS induced a significant increase of plasma BDNF levels in WT mice, which was not found in 3×Tg-AD-3M mice. Collectively, our results showed that plasticity mechanisms are resistant to tDCS effects in the pre-AD stage. In particular, the lack of BDNF responsiveness to tDCS in 3×Tg-AD-3M mice suggests that combining tDCS with dosages of plasma BDNF levels may provide an easy-to-detect and low-cost biomarker of covert impairment of synaptic plasticity mechanisms underlying memory, which could be clinically applicable. Testing proposed here might be useful to identify AD in its preclinical stage, allowing timely and, hopefully, more effective disease-modifying interventions.

A valepotriate-enriched fraction from Valeriana glechomifolia decreases DNA methylation and up-regulate TrkB receptors in the hippocampus of mice.

DNA methylation, an epigenetic modification that mediates gene silencing, has been shown to play a role in the neurobiology of major depression. Studies suggested that terpenes inhibit DNA methylation and increase gene expression. The present study investigated the involvement of DNA methylation in the antidepressant-like activity of diene valepotriates, non-glicosilated carbocyclic iridoids that comprise a family of terpenes obtained from Valeriana glechomifolia. The antidepressant-like effect of diene valepotriates acute administration (5 mg/kg, p.o.) in mice submitted to the forced swimming test was followed by a decrease in global DNA methylation in animals' hippocampus (but not in the pre-frontal cortex). Mice pretreatment with anysomicin (a protein synthesis inhibitor) and K252a (an inhibitor of Trk receptors) attenuated diene valepotriates-induced antidepressant-like effect in the forced swimming test. Diene valepotriates elicited an upregulation in the TrkB receptor and a tendency to increase BDNF levels in mice hippocampus. These results demonstrate that DNA methylation could be an in vivo molecular target of diene valepotriates. The diene valepotriates-triggered reduction in hippocampal DNA methylation is accompanied by increased protein synthesis, which is involved in its antidepressant-like activity. Furthermore, BDNF-mediated TrkB signaling may contribute for diene valepotriates antidepressant-like effect.

Brain Vitalization Gymnastics Improved Cognitive Function Marked by Increased BDNF, Decreased Serum Interleukin-6 and Decreased S-100β Expression among Elderly in West Denpasar Primary Health Clinic.

BACKGROUND:Brain vitalisation gymnastics (BVG) is a form of physical exercise which attempts to synchronise bodily movements with cognition within the same time frame.AIM:This study aims to prove BVG can improve cognitive function among the elderly.METHODS:The impact of BVG was evaluated as opposed to elderly gymnastics (regarded as a control group) for a 4-week study period. Outcomes measured were improvements of cognitive function assessed by MoCA-Ina questionnaire, as well as the difference in serum levels of BDNF, IL-6, and S100β. An experimental pretest-posttest control design was applied to evaluate BDNF and IL-6 levels, while the post-test only designed to evaluate S100β levels. Parametric data were tested for normality before being proceeded into either parametric (independent student’ t) or non-parametric (Mann Whitney) test.RESULTS:BVG significantly improved cognitive function better than elderly gymnastics with MoCA-Ina score of 1.53 ± 1.58 dan 0.11 ± 2.54, respectively (p ≤ 0.047). BVG group also had increased BDNF levels when compared with control (-6020.58 ± 7857.22 dan 0.11 ± 2.54; p = 0.027). Whereas BVG had lower IL-6 levels as opposed to the control group (median pre-test IL-6: 2212, median post-test IL-6: 3197.50; p = 0.004). Meanwhile, S100β levels were found lower among BVG when compared with the control group, although statistically insignificant (p = 0.40).CONCLUSION:BVG programme for 4 weeks improved: (1) brain plasticity as shown by increased serum BDNF and S100β levels (although the latter was statistically not-significant), as well as marked decrease of IL-6 levels, (2) cognitive function as proven by an increase of MoCA-Ina score when compared with elderly gymnastics.

The potential effects of anticonvulsant drugs on neuropeptides and neurotrophins in pentylenetetrazol kindled seizures in the rat

Purpose: Neuropeptides and neurotrophic factors are thought to be involved in epileptogenesis. This study aims to investigate the potential effects of anticonvulsant drugs on neuropeptides (galanin and neuropeptide Y) and neurotrophic factors (BDNF and NGF) in pentylenetetrazol (PTZ)-kindled seizures in the rat.Methods: Forty-eight adult male Sprague–Dawley rats were included in the study. The animals were divided into 8 groups of six rats. Group 1 was defined as naïve control, and received no medication. Group 2 (PTZ + saline) was treated with sub-convulsive doses of PTZ (35 mg/kg) and saline i.p. for 14 days. For anticonvulsant treatments, Groups 3–8 were treated with 200 mg/kg levetiracetam (PTZ + LEV), 1 mg/kg midazolam (PTZ + MDZ), 80 mg/kg phenytoin (PTZ + PHT), 80 mg/kg topiramate (PTZ + TPR), 40 mg/kg lamotrigine (PTZ + LMT) and 50 mg/kg sodium valproate (PTZ + SV), respectively. All anticonvulsant drugs were injected 30 min prior to PTZ injection throughout 14 days. Following treatment period, behavioral, biochemical and immunohistochemical studies were performed.Results: PTZ + saline group revealed significantly decreased galanin, NPY, BDNF and NGF levels compared to control. PTZ + MDZ group had significantly increased galanin, BDNF and NGF levels compared to saline group. Also, PTZ + LEV group showed increased BDNF levels. PTZ + saline group revealed significantly lower neuron count and higher GFAP (+) cells in hippocampal CA1–CA3 regions. All anticonvulsants significantly reduced hippocampal astrogliosis whereas only midazolam, levetiracetam, sodium valproate and lamotrigine prevented neuronal loss.Conclusion: Our results suggested that anticonvulsant drugs may reduce the severity of seizures, and exert neuroprotective effects by altering the expression of neuropeptides and neurotrophins in the epileptogenic hippocampus.

Forced Physical Training Increases Neuronal Proliferation and Maturation with Their Integration into Normal Circuits in Pilocarpine Induced Status Epilepticus Mice.

Increased number of newly-born neurons produced at latent stage after status epilepticus (SE) contribute to aberrant rewiring of hippocampus and are hypothesized to promote epileptogenesis. Although physical training (PT) was reported to cause further increase in neurogenesis after SE, how PT affect their integration pattern is still elusive, whether they integrate into normal circuits or increase aberrant integrations is yet to be determined. To understand this basic mechanism by which PT effects SE and to elaborate the possible role of neuronal integrations in prognosis of SE, we evaluated the effect of 4weeks of treadmill PT in adult male mice after pilocarpine-induced SE on behavioral and aberrant integrations' parameters. Changes in BDNF gene methylation and its protein level in hippocampus was also measured at latent stage (2-weeks) to explore underlying pathways involved in increasing neurogenesis. Our results demonstrated that although PT increased proliferation and maturation of neurons in dentate gyrus, they showed reduced aberrant integrations into hippocampal circuitry assessed through a decrease in the number of ectopic granular cells, hilar basal dendrites and mossy fiber sprouting as compared to non-exercised SE mice. While SE decreased the percentage methylation of specific CpGs of BDNF gene's promoter, PT did not yield any significant difference in methylation of BDNF CpGs as compared to non-exercised SE mice. In conclusion, PT increases hippocampal neurogenesis through increasing BDNF levels by some pathways other than demethylating BDNF CpGs and causes post SE newly-born neurons to integrate into normal circuits thus resulting in decreased spontaneous recurrent seizures and enhanced spatial memory.

Neuroprotection and immunomodulation of progesterone in the gut of a mouse model of Parkinson's disease.

Gastrointestinal symptoms appear in Parkinson's disease patients many years before motor symptoms, suggesting the implication of dopaminergic neurones of the gut myenteric plexus. Inflammation is also known to be increased in PD. We previously reported neuroprotection with progesterone in the brain of mice lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and hypothesised that it also has neuroprotective and immunomodulatory activities in the gut. To test this hypothesis, we investigated progesterone administered to adult male C57BL/6 mice for 10days and treated with MPTP on day 5. In an additional experiment, progesterone was administered for 5days following MPTP treatment. Ilea were collected on day 10 of treatment and microdissected to isolate the myenteric plexus. Dopaminergic neurones were reduced by approximately 60% and pro-inflammatory macrophages were increased by approximately 50% in MPTP mice compared to intact controls. These changes were completely prevented by progesterone administered before and after MPTP treatment and were normalised by 8mgkg-1 progesterone administered after MPTP. In the brain of MPTP mice, brain-derived neurotrophic peptide (BDNF) and glial fibrillary acidic protein (GFAP) were associated with progesterone neuroprotection. In the myenteric plexus, increased BDNF levels compared to controls were measured in MPTP mice treated with 8mgkg-1 progesterone started post MPTP, whereas GFAP levels remained unchanged. In conclusion, the results obtained in the present study show neuroprotective and anti-inflammatory effects of progesterone in the myenteric plexus of MPTP mice that are similar to our previous findings in the brain. Progesterone is non-feminising and could be used for both men and women in the pre-symptomatic stages of the disease.

An increase in plasma brain derived neurotrophic factor levels is related to n-3 polyunsaturated fatty acid efficacy in first episode schizophrenia: secondary outcome analysis of the OFFER randomized clinical trial

RationaleN−3 polyunsaturated fatty acids (n−3 PUFA) influence multiple biochemical mechanisms postulated in the pathogenesis of schizophrenia that may influence BDNF synthesis.ObjectivesA randomized placebo-controlled study was designed to compare the efficacy of a 26-week intervention composed of either 2.2 g/day of n−3 PUFA or olive oil placebo, with regard to symptom severity in first-episode schizophrenia patients. The secondary outcome measure of the study was to describe the association between n−3 PUFA clinical effect and changes in peripheral BDNF levels.MethodsSeventy-one patients aged 16–35 were enrolled in the study and randomly assigned to the following study arms: 36 to the EPA + DHA group and 35 to the placebo group. Plasma BDNF levels were assessed three times, at baseline and at weeks 8 and 26 of the intervention. BDNF levels were determined in plasma samples using Quantikine Human BDNF ELISA kit. Plasma BDNF level changes were further correlated with changes in the severity of symptoms in different clinical domains.ResultsA significantly greater increase in plasma BDNF levels was observed in the intervention compared to the placebo group (Cohen’s d = 1.54). Changes of BDNF levels inversely correlated with change in depressive symptoms assessed using the Calgary Depression Rating Scale in Schizophrenia (Pearson’s r = − 0.195; p = 0.018).ConclusionsThe efficacy of a six-month intervention with n−3 PUFA observed in first-episode schizophrenia may be related to an increase in BDNF levels, which may be triggered by the activation of intracellular signaling pathways including transcription factors such as cAMP-reactive element binding protein.

Leptin Prevents Lipopolysaccharide-Induced Depressive-Like Behaviors in Mice: Involvement of Dopamine Receptors

Depression is a chronic and recurrent disorder, associated with high morbidity and risk of suicide. Leptin was firstly described as an anti-obesity hormone, but several actions of leptin in CNS have been reported. In fact, leptin regulates dopaminergic neurotransmission in mesolimbic areas and has antidepressant-like properties in stress-based models. In the present study, we investigated, for the first time, putative antidepressant-like effects of leptin in an animal model of depressive-like behaviors induced by lipopolysaccharide (LPS), and the potential involvement of dopamine receptors as mediators of those behavioral effects. Mice were injected leptin (1.5 mg/kg, IP) or imipramine prior to LPS administration. To evaluate the involvement of dopamine receptors, different experimental groups were pretreated with either the dopaminergic antagonist SCH23390, for D1 receptors or raclopride, for D2/D3 receptors, prior to leptin injection. Twenty-four hours post-LPS, mice were submitted to the forced swimming and sucrose preference tests. In addition, IL-1β levels were determined in the prefrontal cortex (PFC), hippocampus and striatum. BDNF levels were measured in the hippocampus. Our results showed that leptin, similarly to imipramine, prevented the core behavioral alterations induced by LPS (despair-like behavior and anhedonia), without altering locomotion. In neurochemical analysis, leptin restored LPS-induced changes in IL-1β levels in the PFC and striatum, and increased BDNF levels in the hippocampus. The blockade of dopamine D1 and D2/D3 receptors inhibited leptin's antidepressant-like effects, whilst only the blockade of D1-like receptors blunted leptin-induced increments in prefrontal IL-1β levels. Our results indicate that leptin has antidepressant-like effects in an inflammatory model of depression with the contribution, at least partial, of dopamine receptors.