BDNF Release Is Required for the Behavioral Actions of Ketamine

Background:

Recent studies demonstrate that the rapid antidepressant ketamine increases spine number and function in the medial prefrontal cortex (mPFC), and that these effects are dependent on activation of glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and brain-derived neurotrophic factor (BDNF). In vitro studies also show that activation of AMPA receptors stimulates BNDF release via activation of L-type voltage-dependent calcium channels (VDCC).

Methods:

Based on this evidence, we examined the role of BDNF release and the impact of L-type VDCCs on the behavioral actions of ketamine.

Results:

The results demonstrate that infusion of a neutralizing BDNF antibody into the mPFC blocks the behavioral effects of ketamine in the forced swim test (FST). In addition, we show that pretreatment with nifedipine or verapamil, two structurally-different L-type calcium channel antagonists, blocks the behavioral effects of ketamine in the FST. Finally, we show that ketamine treatment stimulates BDNF release in primary cortical neurons and that this effect is blocked by inhibition of AMPA receptors or L-type VDCCs.

Conclusions:

Taken together, these results indicate that the antidepressant effects of ketamine are mediated by activation of L-type VDCCs and the release of BDNF. They further elucidate the cellular mechanisms underlying this novel rapid-acting antidepressant.     

The Mood Stabilizer Lithium Potentiates the Antidepressant-Like Effects and Ameliorates Oxidative Stress Induced by Acute Ketamine in a Mouse Model of Stress

Background:

Evidence suggests that mammalian target of rapamycin activation mediates ketamine’s rapid but transient antidepressant effects and that glycogen synthase kinase-3β inhibits this pathway. However, ketamine has associated psychotomimetic effects and a high risk of abuse. The mood stabilizer lithium is a glycogen synthase kinase-3 inhibitor with strong antisuicidal properties. Here, we used a mouse stress model to investigate whether adjunct lithium treatment would potentiate ketamine’s antidepressant-like effects.

Methods:

Mice received chronic restraint stress and long-term pre- or postketamine lithium treatment in drinking water. The effects of lithium on ketamine-induced antidepressant-like effects, activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways, oxidative stress, and dendritic spine density in the brain of mice were investigated.

Results:

Subtherapeutic (600mg/L) lithium-pretreated mice exhibited an antidepressant-like response to an ineffective ketamine (2.5mg/kg, intraperitoneally) challenge in the forced swim test. Both the antidepressant-like effects and restoration of dendritic spine density in the medial prefrontal cortex of stressed mice induced by a single ketamine (50mg/kg) injection were sustained by postketamine treatment with 1200mg/L of lithium for at least 2 weeks. These benefits of lithium treatments were associated with activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways in the prefrontal cortex. Acute ketamine (50mg/kg) injection also significantly increased lipid peroxidation, catalase activity, and oxidized glutathione levels in stressed mice. Notably, these oxidative stress markers were completely abolished by pretreatment with 1200mg/L of lithium.

Conclusions:

Our results suggest a novel therapeutic strategy and justify the use of lithium in patients who benefit from ketamine.     

女性不同性激素水平下脑源性神经营养因子的变化

目的:观察女性不同性激素水平下脑源性神经营养因子(brain-derived neurotrophic factor,BD-NF)的变化.方法:临床纳入62例围绝经期及绝经后妇女,根据STRAW分期以及绝经年限长短进行分组,同时纳入16例健康育龄妇女作为对照组.分别采集所有入组者的血液标本,检测血清雌二醇(E2)、睾酮(T)、卵泡刺激素(FSH)以及BDNF的水平.结果:围绝经期组以及绝经后的妇女,血清BD-NF水平明显低于健康育龄妇女,BDNF水平与E2水平有明显相关性(r=0.302,P=0.016).结论:血清BDNF水平与脑源性雌激素水平有着密切的联系.     

缺血性脑卒中后抑郁患者血浆Hcy和BDNF水平变化的观察

目的:观察缺血性脑卒中后抑郁(PSD)患者血浆Hcy和BDNF的水平变化与其在PSD发病中的作用。方法:选取80例缺血性PSD患者,根据是否发生抑郁分为对照组和观察组,每组各40例。对照组患者缺血性脑卒中后未发生抑郁,观察组患者缺血性脑卒中后发生抑郁。测定两组患者治疗前、治疗2周和4周3个时间点血浆中Hcy和BDNF的水平。结果:观察组患者血浆Hcy水平显著高于对照组(P<0.05);治疗前、治疗14d和4周,观察组患者血浆BDNF水平均显著低于对照组(P<0.05);Hcy水平与BNDF水平呈负相关(P<0.05)。结论:PSD患者血浆中Hcy水平显著升高,BDNF水平显著降低,二者可能参与了PSD的发生。     

Diet-Induced Cognitive Deficits: The Role of Fat and Sugar,Potential Mechanisms and Nutritional Interventions

It is of vital importance to understand how the foods which are making us fat also act to impair cognition. In this review, we compare the effects of acute and chronic exposure to high-energy diets on cognition and examine the relative contributions of fat (saturated and polyunsaturated) and sugar to these deficits. Hippocampal-dependent memory appears to be particularly vulnerable to the effects of high-energy diets and these deficits can occur rapidly and prior to weight gain. More chronic diet exposure seems necessary however to impair other sorts of memory. Many potential mechanisms have been proposed to underlie diet-induced cognitive decline and we will focus on inflammation and the neurotrophic factor, brain-derived neurotrophic factor (BDNF). Finally, given supplementation of diets with omega-3 and curcumin has been shown to have positive effects on cognitive function in healthy ageing humans and in disease states, we will discuss how these nutritional interventions may attenuate diet-induced cognitive decline. We hope this approach will provide important insights into the causes of diet-induced cognitive deficits, and inform the development of novel therapeutics to prevent or ameliorate such memory impairments.     

刺五加脑灵液联合扎来普隆治疗失眠症的临床研究

目的探讨刺五加脑灵液联合扎来普隆片治疗失眠症的临床疗效。方法选择2018年2月-2019年2月在成都市第四人民医院诊治的失眠症患者86例,根据用药的差别分为对照组(43例)和治疗组(43例)。对照组睡前口服扎来普隆片,5 mg/次,1次/d;治疗组在对照组的基础上口服刺五加脑灵液,10 mL/次,2次/d。两组患者均经10 d治疗。观察两组患者临床疗效,同时比较治疗前后两组患者PSQI、AIS、PHQ-9、WEMWBS和QLQ-C30评分,睡眠质量以及血清血清5-羟色胺(5-HT)、脑源性神经营养因子(BDNF)、白细胞介素-1β(IL-1β)、食欲素A(Orexin-A)、肿瘤坏死因子-α(TNF-α)和IL-2水平。结果治疗后,对照组临床有效率为81.40%,显著低于治疗组的97.67%,两组比较差异有统计学意义(P<0.05)。经治疗,两组患者PSQI评分、AIS评分和PHQ-9评分均显著降低(P<0.05),但WEMWBS评分和QLQ-C30评分均显著升高(P<0.05),且治疗组这些评分项目改善更明显(P<0.05)。经治疗,两组患者总睡眠时间、REM睡眠时间、睡眠效率均提高(P<0.05),而睡眠潜伏期、觉醒时间均显著缩短(P<0.05),且以治疗组改善最为明显(P<0.05)。经治疗,两组患者血清5-HT、BDNF水平均明显升高(P<0.05),但IL-1β、Orexin-A、TNF-α、IL-2水平均明显降低(P<0.05),且以治疗组改善最为明显(P<0.05)。结论刺五加脑灵液联合扎来普隆片治疗失眠症可显著改善睡眠情况,提高生活质量,有利于焦虑抑郁状态和心理健康状态改善。     

BDNF promoter methylation and suicidal behavior in depressive patients

Introduction

Suicide is a major health problem, and depression is a major psychiatric cause of suicide. Suicide is influenced by the multifactorial interaction of many risk factors. Therefore, epigenetic research may lead to understandings that are applicable to suicide. This study investigated whether epigenetic changes are associated with suicidal behavior and evaluated the treatment outcome of suicidal ideation in depressive patients.

Methods

In 108 patients with major depression, the promoter methylation of the gene encoding brain-derived neurotrophic factor (BDNF) was measured. Sociodemographic and clinical characteristics including a history of previous depressive episodes, age at onset, duration of illnesses, family history of depression, and number of stressful life events as well as subjective perception of stress and assessment scales for depression (HAMD), anxiety (HAMA), function (SOFAS), disability (WHODAS-12), and quality of life (WHOQOL-BREF) were evaluated at baseline. Suicidal behavior was ascertained using a semistructured clinical interview with questions about severity and intent. Beck Scale for Suicide Ideation (BSS) was administered during 12 weeks of treatment with antidepressants.

Results

A higher BDNF promoter methylation status was significantly associated with a previous suicidal attempt history, suicidal ideation during treatment, and suicidal ideation at last evaluation as well as with higher BSS scores and poor treatment outcomes for suicidal ideation.

Limitations

Methylation status was investigated with limited area of the BDNF gene and sample size was relatively small.

Conclusions

BDNF methylation status could be a proxy marker for previous suicidal attempts and a clinical biomarker for poor treatment outcomes of suicidal ideation in depression.     

Roles of BDNF in spinal neuroplasticity in cats subjected to partial dorsal ganglionectomy

This study investigated the role of brain-derived neurotrophic factor (BDNF) in neuroplasticity in cats subjected to the removal of dorsal root ganglia (DRG). Following partial ganglionectomy, the number of BDNF-positive varicosities from spared L6 DRG decreased significantly. This reduction was observed at 3 days post operation (dpo) in spinal lamina II of L3 and L5. Whereas the percentages of positive neurons for BDNF and its mRNA in spared L6 DRG at 10 dpo were significantly increased, and accumulated BDNF was seen on the DRG side of the ligated axons. Importantly, BDNF antibody neutralization in vivo results in a significant reduction in the number of varicosities in spinal lamina II, evidenced by BDNF and calcitonin gene-related peptide immunohistochemical staining. These findings suggested that peripheral-derived BDNF could play a critical role in spinal neuroplasticity in cats subjected to partial ganglionectomy. This may underlie the basis of molecular therapy depending on gene drug-like BDNF release.     

Presenilin mediates neuroprotective functions of ephrinB and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors

Activation of EphB receptors by ephrinB (efnB) ligands on neuronal cell surface regulates important functions, including neurite outgrowth, axonal guidance, and synaptic plasticity. Here, we show that efnB rescues primary cortical neuronal cultures from necrotic cell death induced by glutamate excitotoxicity and that this function depends on EphB receptors. Importantly, the neuroprotective function of the efnB/EphB system depends on presenilin 1 (PS1), a protein that plays crucial roles in Alzheimer's disease (AD) neurodegeneration. Furthermore, absence of one PS1 allele results in significantly decreased neuroprotection, indicating that both PS1 alleles are necessary for full expression of the neuroprotective activity of the efnB/EphB system. We also show that the ability of brain-derived neurotrophic factor (BDNF) to protect neuronal cultures from glutamate-induced cell death depends on PS1. Neuroprotective functions of both efnB and BDNF, however, were independent of γ-secretase activity. Absence of PS1 decreases cell surface expression of neuronal TrkB and EphB2 without affecting total cellular levels of the receptors. Furthermore, PS1-knockout neurons show defective ligand-dependent internalization and decreased ligand-induced degradation of TrkB and Eph receptors. Our data show that PS1 mediates the neuroprotective activities of efnB and BDNF against excitotoxicity and regulates surface expression and ligand-induced metabolism of their cognate receptors. Together, our observations indicate that PS1 promotes neuronal survival by regulating neuroprotective functions of ligand-receptor systems.