Chronic administration of harmine elicits antidepressant-like effects and increases BDNF levels in rat hippocampus

A growing body of evidence has pointed to the beta-carboline harmine as a potential therapeutic target for the treatment of major depression. The present study was aimed to evaluate behavioural and molecular effects of the chronic treatment with harmine and imipramine in rats. To this aim, rats were treated for 14 days once a day with harmine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and then subjected to the forced swimming and open-field tests. Harmine and imipramine, at all doses tested, reduced immobility time of rats compared with the saline group. Imipramine increased the swimming time at 20 and 30 mg/kg and harmine increased swimming time at all doses. The climbing time increased in rats treated with imipramine (10 and 30 mg/kg) and harmine (5 and 10 mg/kg), without affecting spontaneous locomotor activity. Brain-derived neurotrophic factor (BDNF) hippocampal levels were assessed in imipramine and harmine-treated rats by ELISA sandwich assay. Interestingly, chronic administration of harmine at the higher doses (10 and 15 mg/kg), but not imipramine, increased BDNF protein levels in rat hippocampus. Finally, these findings further support the hypothesis that harmine could bring about behavior and molecular effects, similar to antidepressants drugs.

Increased plasma levels of brain derived neurotrophic factor (BDNF) after multiple sclerosis relapse

Brain derived neurotrophic factor (BDNF) has been related to neuroprotection in a series of central nervous system diseases, although its role in multiple sclerosis (MS) was only partially investigated. In this work, we aimed to evaluate the plasma levels of BDNF from 29 MS patients and 24 control subjects. MS patients had decreased levels of BDNF in comparison with healthy controls. BDNF levels increased significantly after MS relapse. Our results provide some evidence for the involvement of BDNF in the pathogenesis of MS and suggest a role for this neurotrophin during the recovery of acute demyelinating inflammatory lesion. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Circulating levels of brain-derived neurotrophic factor: correlation with mood, cognition and motor function

Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the CNS, where it plays several pivotal roles in synaptic plasticity and neuronal survival. As a consequence, BDNF has become a key target in the physiopathology of several neurological and psychiatric diseases. Recent studies have consistently reported altered levels of BDNF in the circulation (i.e., serum or plasma) of patients with major depression, bipolar disorder, Alzheimer`s disease, Huntington`s disease and Parkinson`s disease. Correlations between serum BDNF levels and affective, cognitive and motor symptoms have also been described. BDNF appears to be an unspecific biomarker of neuropsychiatric disorders characterized by neurodegenerative changes.

Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment

Objectives. Abnormalities in neurotrophic systems have been reported in Alzheimer`s disease (AD), as shown by decreased serum brain-derived neurotrophic factor (BDNF) levels and association with BDNF genetic polymorphisms. In this study, we investigate whether these findings can be detected in patients with mild cognitive impairment (MCI), which is recognized as a high risk condition for AD. We also address the impact of these variables on the progression of cognitive deficits within the MCI-AD continuum. Methods. One hundred and sixty older adults with varying degrees of cognitive impairment (30 patients with AD, 71 with MCI, and 59 healthy controls) were longitudinally assessed for up to 60 months. Baseline serum BDNF levels were determined by sandwich ELISA, and the presence of polymorphisms of BDNF and apolipoprotein E (Val66Met and APOE*E4, respectively) was determined by allelic discrimination analysis on real time PCR. Modifications of cognitive state were ascertained for non-demented subjects. Results. Mean serum BDNF levels were reduced in patients with MCI and AD, as compared to controls (509.2 +/- 210.5; 581.9 +/- 379.4; and 777.5 +/- 467.8 pg/l respectively; P < 0.001). Baseline serum BDNF levels were not associated with the progression of cognitive impairment upon follow-up in patients with MCI (progressive MCI, 750.8 +/- 463.0; stable MCI, 724.0 +/- 343.4; P = 0.8), nor with the conversion to AD. Although Val66Met polymorphisms were not associated with the cross-sectional diagnoses of MCI or AD, the presence of Met-BDNF allele was associated with a higher risk of disease-progression in patients with MCI (OR = 3.0 CI(95%) [1.2-7.8], P = 0.02). We also found a significant interaction between the APOE*E4 and Met-BDNF allele increasing the risk of progression of cognitive impairment in MCI patients (OR = 4.4 CI(95%) [1.6-12.1], P = 0.004). Conclusion. Decreased neurotrophic support, as indicated by a reduced systemic availability of BDNF, may play role in the neurodegenerative processes that underlie the continuum from MCI to AD. The presence of Met-BDNF allele, particularly in association with APOE*E4, may predict a worse cognitive outcome in patients with MCI.

Administration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala

Objective: Cannabidiol is a chemical constituent from Cannabis sativa and it has multiple mechanisms of action, including antidepressant effects. The main objective of the present study was to evaluate behavioural and molecular effects induced by administration of cannabidiol and imipramine in rats. Methods: In the present study, rats were acutely or chronically treated for 14 days once a day with saline, cannabidiol (15, 30 and 60 mg/kg) or imipramine (30 mg/kg) and the animals behaviour was assessed in forced swimming and open-field tests. Afterwards, the prefrontal cortex, hippocampus and amygdala brain-derived neurotrophic factor (BDNF) levels were assessed by enzyme-linked immunosorbent sandwich assay. Results: We observed that both acute and chronic treatments with imipramine at the dose of 30 mg/kg and cannabidiol at the dose of 30 mg/kg reduced immobility time and increased swimming time; climbing time was increased only with imipramine at the dose of 30 mg/kg, without affecting locomotor activity. In addition, chronic treatment with cannabidiol at the dose of 15 mg/kg and imipramine at the dose of 30 mg/kg increased BDNF levels in the rat amygdala. Conclusion: In conclusion, our results indicate that cannabidiol has an antidepressant-like profile and could be a new pharmacological target for the treatment of major depression.

Striatum brain-derived neurotrophic factor levels are decreased in dystrophin-deficient mice

Brain dystrophin is enriched in the postsynaptic densities of pyramidal neurons specialized regions of the subsynaptic cytoskeletal network, which are critical for synaptic transmission and plasticity. Lack of dystrophin in brain structures have been involved with impaired cognitive functions. The brain-derived neurotrophic factor (BDNF) is a regulator of neuronal survival, fast synaptic transmission, and activity-dependent synaptic plasticity. The present study investigated BDNF protein levels by Elisa analysis in prefrontal cortex, cerebellum, hippocampus, striatum and cortex tissues from male dystrophic mdx (n = 5) and normal C57BL10 mouse (n = 5). We observed that the mdx mouse display diminution in BDNF levels in striatum (t = 6.073; df = 6; p = 0.001), while a tendency of decrease in BDNF levels was observed in the prefrontal cortex region (t = 1.962; df = 6; p = 0.096). The cerebellum (t = 1.258; df = 7; p = 0.249), hippocampus (t = 0.631; df = 7; p = 0.548) and cortex (t = 0.572; df = 7; p = 0.586) showed no significant alterations as compared to wt mouse. In conclusion, we demonstrate that only striatum decreased BDNF levels compared with wild-type (wt) mouse, differently to the other areas of the brain. This dystrophin deficiency may be affecting BDNF levels in striatum and contributing, in part, in memory storage and restoring. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Lithium increases plasma brain-derived neurotrophic factor in acute bipolar mania: A preliminary 4-week study

Several studies have suggested an important role for brain-derived neurotrophic factor (BDNF) in the pathophysiology and therapeutics of bipolar disorder (BPD). The mechanisms underlying the therapeutic effects of lithium in BPD seem to involve a direct regulation of neurotrophic cascades. However, no clinical study evaluated the specific effects of lithium on BDNF levels in subjects with BPD. This study aims to investigate the effects of lithium monotherapy on BDNF levels in acute mania. Ten subjects with bipolar I disorder in a manic episode were evaluated at baseline and after 28 days of lithium therapy. Changes in plasma BDNF levels and Young Mania Rating Scale (YMRS) scores were analyzed. A significant increase in plasma BDNF levels was observed after 28 days of therapy with lithium monotherapy (510.9 +/- 127.1 pg/mL) compared to pre-treatment (406.3 +/- 69.5 pg/mL) (p = 0.03). Although it was not found a significant association between BDNF levels and clinical improvement (YMRS), 87% of responders presented an increase in BDNF levels after treatment with lithium. These preliminary data showed lithium`s direct effects on BDNF levels in bipolar mania, suggesting that short-term lithium treatment may activate neurotrophic cascades. Further studies with larger samples and longer period may confirm whether this biological effect is involved in the therapeutic efficacy of lithium in BPD. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Serum brain-derived neurotrophic factor level is reduced in antidepressant-free patients with late-life depression

Objectives. The aim of the present study is to investigate serum BDNF levels in older depressed patients as compared to healthy elderly controls. Methods. Twenty-nine elderly subjects with major depression and 42 healthy older adults were enrolled to this study. All depressed patients were antidepressant-free for at least 1 month prior clinical and laboratorial assessments. Serum BDNF levels were determined by sandwich ELISA. Results. BDNF levels were lower in elderly depressed patients as compared to controls (P = 0.034). Patients with late-onset depression had the lowest BDNF level (median 478.5, interquartile range 373.5-740.9 pg/l) when compared to early-onset depression (median 620.7, interquartile range 366.1-971.9 pg/l) and healthy controls (median 711.3, interquartile range 534.7-1181.0 pg/l) (P < 0.03). Conclusions. Reduced serum BDNF level may be a state marker of late-life depression in non-medicated elderly patients. Our findings provide further evidences that reduced neurotrophic support may have an important role in the physiopathology of late-life depression.

Rapid antidepressant changes with sleep deprivation in major depressive disorder are associated with changes in vascular endothelial growth factor (VEGF): A pilot study

While conventional antidepressants benefit many patients with major depressive disorder (MDD), as much as eight to 12 weeks can elapse before significant improvements in depressive symptoms are seen. Treatments that act more rapidly in MDD are urgently needed. Sleep deprivation (SD) has been shown to produce a rapid antidepressant response within one day in 50-60% of patients with MDD; thus, identifying its antidepressant mechanism may contribute to the development of antidepressants that act more rapidly. The present study evaluated the effects of 39 h of SD on mood, as well as on plasma levels of brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in patients with MDD. After a drug-free period of at least two weeks, 11 patients (6 males, 5 females; ages 25-62) who met DSM-IV criteria for MDD underwent total SD. Plasma samples for BDNF and VEGF assays were collected on Days 1 (baseline) and 2. The six-item Hamilton Rating Scale for Depression (HAMD-6) was the primary outcome measure. HAMD-6 scores decreased significantly after SD (Day 2). SD was negatively correlated with change in HAMD-6 score and change in VEGF levels, indicating that as depression scores decreased following SD, VEGF plasma levels increased. In contrast, SD did not alter plasma BDNF concentrations, nor was an association found between BDNF levels and clinical improvement on the HAMD-6. These results suggest that SD is associated with mood-related changes in plasma VEGF levels, but not plasma BDNF levels. Further studies using larger sample sizes are needed to confirm these preliminary findings. Published by Elsevier Inc.

Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT(1A) receptors

Background and purpose: Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic- and antipsychotic-like effects in animal models. Effects of CBD may be mediated by the activation of 5-HT(1A) receptors. As 5-HT(1A) receptor activation may induce antidepressant-like effects, the aim of this work was to test the hypothesis that CBD would have antidepressant-like activity in mice as assessed by the forced swimming test. We also investigated if these responses depended on the activation of 5-HT(1A) receptors and on hippocampal expression of brain-derived neurotrophic factor (BDNF). Experimental approach: Male Swiss mice were given (i.p.) CBD (3, 10, 30, 100 mg.kg(-1)), imipramine (30 mg.kg(-1)) or vehicle and were submitted to the forced swimming test or to an open field arena, 30 min later. An additional group received WAY100635 (0.1 mg.kg(-1), i.p.), a 5-HT(1A) receptor antagonist, before CBD (30 mg.kg(-1)) and assessment by the forced swimming test. BDNF protein levels were measured in the hippocampus of another group of mice treated with CBD (30 mg.kg(-1)) and submitted to the forced swimming test. Key results: CBD (30 mg.kg(-1)) treatment reduced immobility time in the forced swimming test, as did the prototype antidepressant imipramine, without changing exploratory behaviour in the open field arena. WAY100635 pretreatment blocked CBD-induced effect in the forced swimming test. CBD (30 mg.kg(-1)) treatment did not change hippocampal BDNF levels. Conclusion and implications: CBD induces antidepressant-like effects comparable to those of imipramine. These effects of CBD were probably mediated by activation of 5-HT(1A) receptors. British Journal of Pharmacology (2010) 159, 122-128; doi:10.1111/j.1476-5381.2009.00521.x; published online 4 December 2009

Effects of cannabidiol on amphetamine-induced oxidative stress generation in an animal model of mania

Cannabidiol (CBD), a Cannabis sativa constituent, may present a pharmacological profile similar to mood stabilizing drugs, in addition to anti-oxidative and neuroprotective properties. The present study aims to directly investigate the effects of CBD in an animal model of mania induced by D-amphetamine (D-AMPH). In the first model (reversal treatment), rats received saline or D-AMPH (2 mg/kg) once daily intraperitoneal (i.p.) for 14 days, and from the 8th to the 14th day, they were treated with saline or CBD (15, 30 or 60 mg/kg) i.p. twice a day. In the second model (prevention treatment), rats were pretreated with saline or CBD (15, 30, or 60 mg/kg) regime i.p. twice a day, and from the 8th to the 14th day, they also received saline or D-AMPH i.p. once daily. In the hippocampus CBD (15 mg/kg) reversed the D-AMPH-induced damage and increased (30 mg/kg) brain-derived neurotrophic factor (BDNF) expression. In the second experiment, CBD (30 or 60 mg/kg) prevented the D-AMPH-induced formation of carbonyl group in the prefrontal cortex. In the hippocampus and striatum the D-AMPH-induced damage was prevented by CBD (15, 30 or 60 mg/kg). At both treatments CBD did not present any effect against D-AMPH-induced hyperactivity. In conclusion, we could not observe effects on locomotion, but CBD protect against D-AMPH-induced oxidative protein damage and increased BDNF levels in the reversal model and these effects vary depending on the brain regions evaluated and doses of CBD administered.

Effects of beta-carboline harmine on behavioral and physiological parameters observed in the chronic mild stress model: Further evidence of antidepressant properties

The chronic mild stress (CMS) model has been used as an animal model of depression which induces anhedonic behavior in rodents. The present study was aimed to evaluate the behavioral and physiological effects of administration of P-carboline harmine in rats exposed to CMS Procedure. To this aim, after 40 days of exposure to CMS procedure, rats were treated with harmine (15 mg/kg/day) for 7 days. In this study, sweet food consumption, adrenal gland weight, adrenocorticotrophin hormone (ACTH) levels, and hippocampal brain-derived-neurotrophic factor (BDNF) protein levels were assessed. Our findings demonstrated that chronic stressful situations induced anhedonia, hypertrophy of adrenal gland weight, increase ACTH circulating levels in rats and increase BDNF protein levels. Interestingly, treatment with harmine reversed anhedonia, the increase of adrenal gland weight, normalized ACTH circulating levels and BDNF protein levels. Finally, these findings further support the hypothesis that harmine could be a new pharmacological tool for the treatment of depression. (C) 2009 Elsevier Inc. All rights reserved.

Qualitative analysis of hippocampal plastic changes in rats with epilepsy supplemented with oral omega-3 fatty acids

Studies have provided evidence of the important effects of omega-3 fatty acid on the brain in neurological conditions, including epilepsy. Previous data have indicated that omega-3 fatty acids lead to prevention of status epilepticus-associated neuropathological changes in the hippocampal formation of rats with epilepsy. Omega-3 fatty acid supplementation has resulted in extensive preservation of GABAergic cells in animals with epilepsy. This study investigated the interplay of these effects with neurogenesis and brain-derived neurotrophic factor (BDNF). The results clearly showed a positive effect of long-term omega-3 fatty acid supplementation on brain plasticity in animals with epilepsy. Enhanced hippocampal neurogenesis and BDNF levels and preservation of interneurons expressing parvalbumin were observed. Parvalbumin-positive cells were identified as surviving instead of newly formed cells. Additional investigations are needed to determine the electrophysiological properties of the newly formed cells and to clarify whether the effects of omega-3 fatty acids on brain plasticity are accompanied by functional gain in animals with epilepsy. (C) 2009 Elsevier Inc. All rights reserved.

Sexually Dimorphic Effect of the Val66Met Polymorphism of BDNF on Susceptibility to Alzheimer`s Disease: New Data and Meta-Analysis

Conflicting results have been reported as to whether genetic variations (Val66Met and C270T) of the brain-derived neurotrophic factor gene (RDNF) confer susceptibility to Alzheimer`s disease (AD). We genotyped these polymorphisms in a Japanese sample of 657 patients with AD and 525 controls, and obtained weak evidence of association for Val66Met (P = 0.063), but not for C270T. After stratification by sex, we found a significant allelic association between Val66Met and AD in women (P = 0.017), but not in men. To confirm these observations, we collected genotyping data for each sex from 16 research centers worldwide (4,711 patients and 4,537 controls in total). The meta-analysis revealed that there was a clear sex difference in the allelic association; the Met66 allele confers susceptibility to AD in women (odds ratio = 1.14, 95% CI 1.05-1.24, P = 0.002), but not in men. Our results provide evidence that the Met66 allele of BDNF has a sexually dimorphic effect on susceptibility to AD. (C) 2009 Wiley-Liss, Inc.

Use of chewing gum containing 15% of xylitol and reduction in mutans streptococci salivary levels

Frequent use of Xylitol may decrease the S. mutans levels. However, very little is known about whether this effect on the levels of cariogenic bacteria is maintained after the interruption of short-term usage of xylitol. This study aimed at evaluating changes in mutans streptococci (MS) salivary levels after using a chewing gum containing xylitol. Twelve volunteers harboring > 10(5) CFU MS/ml saliva levels were asked to chew Happydent-xylit® for 5 minutes, 5 X/day, for 30 days. Saliva samples were collected at baseline, at 30 days after xylitol usage began, and at 30 days beyond its interruption. MS salivary levels were estimated. The average salivary levels of MS in the ten subjects who completed the study were 13.17 (NL-CFU) at baseline (A). After the 30 days experimental period (B), this average decreased to 9.45 (NL-CFU). Nine of ten subjects studied showed a reduction in MS salivary levels in relation to baseline, whereas salivary levels were maintained in the remaining subject. At thirty days beyond the interruption of xylitol usage (C), the average levels of MS were still reduced to 10.31 (NL-CFU). Multiple sample comparison using the Bonferroni test revealed that the decrease in MS levels observed from baseline (A) to the time immediately after 30 days of xylitol usage (B) was statistically significant (p < 0.05), and those levels were still decreased between baseline and 30 days beyond the interruption of xylitol usage (C). So, the use of xylitol induced a reduction in MS salivary levels after a short period of usage which persisted beyond its interruption.