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Zinc is known to have multiple beneficial effects including anti-inflammatory and antioxidant and anti-depressant actions. Data on the effects of zinc supplementation on biomarkers of inflammation, oxidative stress, and antidepressant-like effect among young women with premenstrual syndrome (PMS) are scarce. This study was a randomized, double-blind, placebo-controlled trial. Sixty women (18–30 years) with premenstrual syndrome diagnosed according to 30-item questionnaire were randomly assigned to receive either 30-mg zinc gluconate (group 1; n  = 30) and/or placebo (group 2; n  = 30) for 12 weeks. Premenstrual syndrome symptoms, total antioxidant capacity, high sensitivity reactive protein, and brain-derived neurotrophic factor were measured at study baseline and after 12-week intervention. After 12 weeks of intervention, PMS physical symptoms ( P  = 0.03) and psychological symptoms ( P  = 0.006) significantly decreased in zinc group compared to placebo group. We observed a significant increase in brain-derived neurotrophic factor ( P  = 0.01) and total antioxidant capacity ( P  ˂ 0.001) after 12 weeks of intervention with zinc compared to placebo. We failed to find any significant effect of zinc supplementation on high sensitivity reactive protein. Overall, zinc supplementation for 12 weeks among women with premenstrual syndrome had beneficial effects on physical and psychological symptoms of premenstrual syndrome, total antioxidant capacity, and brain-derived neurotrophic factor.

Background: Risperidone and paliperidone have been the mainstay treatment for schizophrenia and their potential role in neuroprotection could be associated with brain-derived neurotrophic factor (BDNF) and N400 (an event-related brain potential component). So far, different effects on both BDNF and N400 were reported in relation to various antipsychotic treatments. However, few studies have been conducted on the mechanism of risperidone and paliperidone on BDNF and N400. This study aimed to compare the effects of risperidone and paliperidone on BDNF and the N400 component of the event-related brain potential in patients with first-episode schizophrenia. Methods: Ninety-eight patients with first-episode schizophrenia were randomly divided into the risperidone and paliperidone groups and treated with risperidone and paliperidone, respectively, for 12 weeks. Serum BDNF level, the latency, and amplitude of the N400 event-related potential before and after the treatment and Positive and Negative Syndrome Scale (PANSS) scores were compared between the two groups. Results: A total of 94 patients were included in the final analysis (47 patients in each group). After the treatment, the serum BDNF levels in both groups increased (all P < 0.01), while no significant difference in serum BDNF level was found between the groups before and after the treatment (all P > 0.05). After the treatment, N400 amplitudes were increased (from 4.73 ± 2.86 μv and 4.51 ± 4.63 μv to 5.35 ± 4.18 μv and 5.52 ± 3.08 μv, respectively) under congruent condition in both risperidone and paliperidone groups (all P < 0.01). Under incongruent conditions, the N400 latencies were shortened in the paliperidone group (from 424.13 ± 110.42 ms to 4.7.41 ± 154.59 ms, P < 0.05), and the N400 amplitudes were increased in the risperidone group (from 5.80 ± 3.50 μv to 7.17 ± 5.51 μv, P < 0.01). After treatment, the total PANSS score in both groups decreased significantly (all P < 0.01), but the difference between the groups was not significant (P > 0.05). A negative correlation between the reduction rate of the PANSS score and the increase in serum BDNF level after the treatment was found in the paliperidone group but not in the risperidone group. Conclusions: Both risperidone and paliperidone could increase the serum BDNF levels in patients with first-episode schizophrenia and improve their cognitive function (N400 latency and amplitude), but their antipsychotic mechanisms might differ.

Alzheimer’s disease (AD) can be treated with inhibitors of the enzyme acetylcholinesterase (AChE). Recent pre-clinical and clinical studies gave evidence that AChE-inhibitors have neuroprotective effects and thereby a disease-modifying potential. The mechanism of this action is still discussed. In an animal model oral administration of an AChE-inhibitor lead to an increase of brain derived neurotrophic factor (BDNF) in hippocampus and cortex. Recent studies have found a decrease of BDNF in the serum and brain of AD patients with potentially consecutive lack of neurotrophic support and contribution to progressive neurodegeneration. BDNF serum concentrations were assessed by ELISA in 19 AD patients and 20 age-matched healthy controls at baseline and in the AD patients after 15 months of treatment with donepezil 10 mg per day (one patient received just 5 mg). Before treatment with donepezil we found in AD significantly decreased BDNF serum concentrations (19.2 ± 3.7 ng/ml) as compared to healthy controls (23.2 ± 6.0 ng/ml, P  = 0.015). After 15 months of treatment the BDNF serum concentration increased significantly in the AD patients (23.6 ± 7.0 ng/ml, P  = 0.001) showing no more difference to the healthy controls ( P  = 0.882). The results of the present study confirm data of prior investigations that a down-regulation of BDNF in serum and brain of AD patients seems to begin with the first clinical symptoms and to be persistent. A treatment with the AChE-inhibitor donepezil is accompanied with an increase of BDNF serum concentration in AD patients reaching the level of healthy controls. Thus, up-regulation of BDNF might be part of a neuroprotective effect of AChE-inhibitors. The molecular mechanism of this potentially disease-modifying mechanism of action of donepezil should be clarified.

Numerous studies have demonstrated that depression is associated with a decreased expression of brain-derived neurotrophic factor (BDNF). BDNF shows antidepressant-like effects in animal models. Therefore, we tested the hypothesis that BDNF might be a peripheral marker for the mechanism of action of antidepressant agents in humans. Thirty-two patients meeting the DSM-IV criteria for major depressive disorder and 50 normal control subjects were recruited for this study. Plasma BDNF levels and Hamilton Depression Rating Scales were measured at baseline and 6 weeks after antidepressant administration. At baseline, the mean plasma BDNF level was lower in the depressive patients (698.1 ± 537.7 pg/ml) than in the control subjects (830.7 ± 624.8 pg/ml), although the difference was not statistically significant (p = 0.33). The plasma BDNF levels in depressive patients significantly increased from 698.1 ± 537.7 to 1,028.9 ± 744.5 after 6 weeks of antidepressant treatment (p = 0.01). Moreover, plasma BDNF levels were significantly increased after 6 weeks of treatment in the responder group, while there was no statistically significant change in the unresponsive group. These results suggest that the therapeutic response after antidepressant administration might be attributable to the increase in BDNF levels. BDNF may play a critical role in the action mechanism of antidepressant drugs. Further studies with a larger number of subjects are needed to verify these findings.

Neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and other members of the neurotrophin family, are central mediators of the activity-dependent plasticity through which environmental experiences, such as sensory information are translated into the structure and function of neuronal networks. Synthesis, release and action of BDNF is regulated by neuronal activity and BDNF in turn leads to trophic effects such as formation, stabilization and potentiation of synapses through its high-affinity TrkB receptors. Several clinically available drugs activate neurotrophin signaling and neuronal plasticity. In particular, antidepressant drugs rapidly activate TrkB signaling and gradually increase BDNF expression, and the behavioral effects of antidepressants are mediated by and dependent on BDNF signaling through TrkB at least in rodents. These findings indicate that antidepressants, widely used drugs, effectively act as TrkB activators. They further imply that neuronal plasticity is a central mechanism in the action of antidepressant drugs. Indeed, it was recently discovered that antidepressants reactivate a state of plasticity in the adult cerebral cortex that closely resembles the enhanced plasticity normally observed during postnatal critical periods. This state of induced plasticity, known as iPlasticity, allows environmental stimuli to beneficially reorganize networks abnormally wired during early life. iPlasticity has been observed in cortical as well as subcortical networks and is induced by several pharmacological and non-pharmacological treatments. iPlasticity is a new pharmacological principle where drug treatment and rehabilitation cooperate; the drug acts permissively to enhance plasticity and rehabilitation provides activity to guide the appropriate wiring of the plastic network. Optimization of iPlastic drug treatment with novel means of rehabilitation may help improve the efficacy of available drug treatments and expand the use of currently existing drugs into new indications.

Currently available antidepressants have a substantial time lag to induce therapeutic response and a relatively low efficacy. The development of drugs that addresses these limitations is critical to improving public health. Cannabidiol (CBD), a non-psychotomimetic component of Cannabis sativa , is a promising compound since it shows large-spectrum therapeutic potential in preclinical models and humans. However, its antidepressant properties have not been completely investigated. Therefore, the aims of this study were to investigate in male rodents (i) whether CBD could induce rapid and sustained antidepressant-like effects after a single administration and (ii) whether such effects could be related to changes in synaptic proteins/function. Results showed that a single dose of CBD dose-dependently induced antidepressant-like effect (7–30 mg/kg) in Swiss mice submitted to the forced swim test (FST), 30 min (acute) or 7 days (sustained) following treatment. Similar effects were observed in the Flinders Sensitive and Flinders Resistant Line (FSL/FRL) rats and the learned helplessness (LH) paradigm using Wistar rats. The acute antidepressant effects (30 min) were associated with increased expression of synaptophysin and PSD95 in the medial prefrontal cortex (mPFC) and elevated BDNF levels in both mPFC and hippocampus (HPC). CBD also increased spine density in the mPFC after 30 min, but not 7 days later. Intracerebroventricular injection of the TrkB antagonist, K252a (0.05 nmol/μL), or the mTOR inhibitor, rapamycin (1 nmol/μL), abolished the behavioral effects of CBD. These results indicate that CBD induces fast and sustained antidepressant-like effect in distinct animal models relevant for depression. These effects may be related to rapid changes in synaptic plasticity in the mPFC through activation of the BDNF-TrkB signaling pathway. The data support a promising therapeutic profile for CBD as a new fast-acting antidepressant drug.

Selective serotonin reuptake inhibitors (SSRIs) represent the most common treatment for major depression. However, their efficacy is variable and incomplete. In order to elucidate the cause of such incomplete efficacy, we explored the hypothesis positing that SSRIs may not affect mood per se but, by enhancing neural plasticity, render the individual more susceptible to the influence of the environment. Consequently, SSRI administration in a favorable environment promotes a reduction of symptoms, whereas in a stressful environment leads to a worse prognosis. To test such hypothesis, we exposed C57BL/6 mice to chronic stress in order to induce a depression-like phenotype and, subsequently, to fluoxetine treatment (21 days), while being exposed to either an enriched or a stressful condition. We measured the most commonly investigated molecular, cellular and behavioral endophenotypes of depression and SSRI outcome, including depression-like behavior, neurogenesis, brain-derived neurotrophic factor levels, hypothalamic–pituitary–adrenal axis activity and long-term potentiation. Results showed that, in line with our hypothesis, the endophenotypes investigated were affected by the treatment according to the quality of the living environment. In particular, mice treated with fluoxetine in an enriched condition overall improved their depression-like phenotype compared with controls, whereas those treated in a stressful condition showed a distinct worsening. Our findings suggest that the effects of SSRI on the depression- like phenotype is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.

We demonstrate that exercise enables hippocampal-dependent learning in conditions that are normally subthreshold for encoding and memory formation, and depends on hippocampal induction of brain-derived neurotrophic factor (BDNF) as a key mechanism. Using a weak training paradigm in an object location memory (OLM) task, we show that sedentary mice are unable to discriminate 24 h later between familiar and novel object locations. In contrast, 3 weeks of prior voluntary exercise enables strong discrimination in the spatial memory task. Cognitive benefits of exercise match those attained with post-training sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitor previously shown to enable subthreshold learning. We demonstrate that the enabling effects of exercise and NaB on subthreshold OLM learning are dependent on hippocampal BDNF upregulation, and are blocked by hippocampal infusion of BDNF short-interfering RNA. Exercise and NaB increased bdnf transcripts I and IV, and the increases were associated with BDNF promoter acetylation on H4K8 but not H4K12. These data provide support for the concept that exercise engages epigenetic control mechanisms and serves as a natural stimulus that operates in part like NaB and potentially other HDAC inhibitors, placing the brain into a state of readiness for plasticity.

Conventional antidepressant medications, which act on monoaminergic systems, display significant limitations, including a time lag of weeks to months and low rates of therapeutic efficacy. GLYX-13 is a novel glutamatergic compound that acts as an N-methyl-d-aspartate (NMDA) modulator with glycine-like partial agonist properties; like the NMDA receptor antagonist ketamine GLYX-13 produces rapid antidepressant actions in depressed patients and in preclinical rodent models. However, the mechanisms underlying the antidepressant actions of GLYX-13 have not been characterized. Here we use a combination of neutralizing antibody (nAb), mutant mouse and pharmacological approaches to test the role of brain-derived neurotrophic factor-tropomyosin-related kinase B (BDNF-TrkB) signaling in the actions of GLYX-13. The results demonstrate that the antidepressant effects of GLYX-13 are blocked by intra-medial prefrontal cortex (intra-mPFC) infusion of an anti-BDNF nAb or in mice with a knock-in of the BDNF Val66Met allele, which blocks the processing and activity-dependent release of BDNF. We also demonstrate that pharmacological inhibitors of BDNF-TrkB signaling or of l-type voltage-dependent Ca2+ channels (VDCCs) block the antidepressant behavioral actions of GLYX-13. Finally, we examined the role of the Rho GTPase proteins by injecting a selective inhibitor into the mPFC and found that activation of Rac1 but not RhoA is involved in the antidepressant effects of GLYX-13. Together, these findings indicate that enhanced release of BDNF through exocytosis caused by activation of VDCCs and subsequent TrkB-Rac1 signaling is required for the rapid and sustained antidepressant effects of GLYX-13.

Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)–TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R -ketamine showed a greater potency and longer-lasting antidepressant effect than S -ketamine (esketamine). Furthermore, R -ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF–TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S -ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S -ketamine, but not R -ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S -ketamine, but not R -ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S -ketamine, R -ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF–TrkB signaling and synaptogenesis in the PFC, DG and CA3. R -ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S -ketamine, as R -ketamine appears to be free of psychotomimetic side effects and abuse liability.