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Route to fast antidepressants? Antidepressants such as selective serotonin re-uptake inhibitors can take months to take effect, but small doses of ketamine, a glutamatergic N-methyl-D-aspartate receptor (NMDAR) agonist, can have antidepressant effects within hours. The antidepressant mechanism of ketamine is not well understood. Work in mice shows that antidepressant-like effects of ketamine depend on rapid synthesis of brain-derived neurotrophic factor (BDNF). Ketamine-mediated NMDAR blockade deactivates eukaryotic elongation factor 2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation and de-suppression of BDNF translation. These findings raise the possibility of this pathway as a therapeutic target for fast-acting antidepressants. Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR ( N -methyl- D -aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear 1 , 2 , 3 . Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks 1 , 2 , 3 , unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients 3 . The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.

Key Points Brain-derived neurotrophic factor (BDNF) is widely produced in the cortex throughout life, where it influences neuronal function. Levels of BDNF become deficient in the cerebral cortex in Alzheimer's disease. In animal models of Alzheimer's disease, BDNF exhibits potent therapeutic effects that include prevention of cell death, stimulation of neuronal function, improvement in synaptic markers and improvements in learning and memory. Accordingly, BDNF represents a potentially promising therapeutic avenue in Alzheimer's disease. Other neurological and psychiatric disorders — for example, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and depression — could also respond to BDNF treatment. Therapeutic BDNF delivery to the brain is a major challenge. BDNF does not readily cross the blood–brain barrier, and widespread central administration causes intolerable adverse effects. Localized and sustained delivery of the growth factor will be required to treat many neurological disorders. Gene therapy may be a useful method of delivering BDNF to specific brain regions in neurological disorders. For example, clinical trials involving BDNF gene delivery to the entorhinal and/or the hippocampal circuitry regions in Alzheimer's disease are planned. Other methods for increasing BDNF levels in the brain include the use of small peptide mimetics, drug-induced increases in BDNF and even exercise. It remains to be established, however, whether these methods can induce sufficient increases in BDNF levels to effectively treat neurological diseases. Brain-derived neurotrophic factor (BDNF), which acts through its receptor tropomyosin-related kinase receptor type B, has diverse effects on neuronal function and survival in the adult brain. Nagahara and Tuszynski review the potential therapeutic use of BDNF in the treatment of various disorders of the central nervous system, such as Alzheimer's disease, and discuss the challenges to effective delivery of BDNF and possible strategies to overcome them. The growth factor brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase receptor type B (TRKB) are actively produced and trafficked in multiple regions in the adult brain, where they influence neuronal activity, function and survival throughout life. The diverse presence and activity of BDNF suggests a potential role for this molecule in the pathogenesis and treatment of both neurological and psychiatric disorders. This article reviews the current understanding and future directions in BDNF-related research in the central nervous system, with an emphasis on the possible therapeutic application of BDNF in modifying fundamental processes underlying neural disease.

Brain-derived neurotrophic factor precursor (proBDNF) plays a critical role in the pathogenesis and progression of various human diseases. Through its interaction with p75NTR and sortilin receptors, proBDNF promotes apoptosis, impairs synaptic plasticity, and contributes to the regulation of immune system function, inflammatory responses and cellular metabolic processes. proBDNF is widely distributed throughout the body, and as such, extensive research has demonstrated that proBDNF is significantly associated with the pathophysiological mechanisms underlying several diseases. In the present review, the mechanisms by which proBDNF contributes to different diseases are summarized to highlight its potential therapeutic and diagnostic implications. Specifically, the role of proBDNF in cognitive disorders, focusing on its effects on synaptic function and neural network dynamics, while analyzing the cascade reactions involving proBDNF and downstream effector molecules in inflammatory diseases, to elucidate its bidirectional regulatory effects in tumor initiation and progression. Furthermore, the function of proBDNF in neurogenesis, the mechanism by which it regulates the memory of fear, and enhances individual behavioral flexibility is discussed. Finally, the potential of proBDNF as a biomarker for disease diagnosis and the therapeutic prospects of targeting it using monoclonal antibodies are highlighted while also proposing future research directions. The present review can serve as a reference for translational medical research on proBDNF and its receptors.

An emerging body of data suggests that the early onset of Alzheimer's disease (AD) is associated with decreased brain-derived neurotrophic factor (BDNF). Because BDNF plays a critical role in the regulation of high-frequency synaptic transmission and long-term potentiation in the hippocampus, the up-regulation of BDNF may rescue cognitive impairments and learning deficits in AD. In the present study, we investigated the effects of hippocampal BDNF in a rat model of AD produced by a ventricle injection of amyloid-β1-42 (Aβ1-42). We found that a ventricle injection of Aβ1-42 caused learning deficits in rats subjected to the Morris water maze and decreased BDNF expression in the hippocampus. Chronic intra-hippocampal BDNF administration rescued learning deficits in the water maze, whereas infusions of NGF and NT-3 did not influence the behavioral performance of rats injected with Aβ1-42. Furthermore, the BDNF-related improvement in learning was ERK-dependent because the inhibition of ERK, but not JNK or p38, blocked the effects of BDNF on cognitive improvement in rats injected with Aβ1-42. Together, our data suggest that the up-regulation of BDNF in the hippocampus via activation of the ERK signaling pathway can ameliorate Aβ1-42-induced learning deficits, thus identifying a novel pathway through which BDNF protects against AD-related cognitive impairments. The results of this research may shed light on a feasible therapeutic approach to control the progression of AD.

The purpose of this study was to test if different intensities of aerobic exercise could influence abdominal fat, isoforms of BDNF and executive function. Twenty obese men (30.0 ± 5.4 years old; 34.4 ± 3.5 kg/m 2 ) were randomized to moderate-intensity continuous training (MICT, n = 10) and high-intensity intermittent training (HIIT, n = 10) three times a week for 6 weeks, with isoenergetic energetic expenditure for each exercise session (~ 300 kcal) between conditions. Abdominal fat was assessed pre- and post-intervention; executive function (Coding subtest from BETA-III non-verbal intelligence test and Stroop Color and Word Test), concentrations of mBDNF and proBDNF were assessed in response to acute exercise pre- and post-intervention. Abdominal fat did not change in either group. There was a significant increase in mBDNF immediately after acute exercise in both groups before and after intervention. proBDNF did not present changes acutely nor after 6 weeks. Executive function presented a main effect of time at pre- and post-intervention time-points Stroop Word and Stroop Color and Coding subtest presented improved performance from pre- to post-acute exercise session, in both groups. In conclusion, executive function improvements and acute exercise session-induced increases in mBDNF concentration were found from pre- to post-exercise intervention similarly between MICT and HIIT in obese men.

Recent clinical studies demonstrate that serum levels of brain-derived neurotrophic factor (BDNF) are significantly decreased in patients with major depressive disorder (MDD) and that antidepressant treatments reverse this effect, indicating that serum BDNF is a biomarker of MDD. These findings raise the possibility that serum BDNF may also have effects on neuronal activity and behavior, but the functional significance of altered serum BDNF is unknown. To address this issue, we determined the influence of peripheral BDNF administration on depression- and anxiety-like behavior, including the forced swim test (FST), chronic unpredictable stress (CUS)/anhedonia, novelty-induced hypophagia (NIH) test, and elevated-plus maze (EPM). Furthermore, we examined adult hippocampal neurogenesis as well as hippocampal and striatal expression of BDNF, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), in order to determine whether peripherally administered BDNF produces antidepressant-like cellular responses in the brain. Peripheral BDNF administration increased mobility in the FST, attenuated the effects of CUS on sucrose consumption, decreased latency in the NIH test, and increased time spent in the open arms of an EPM. Moreover, adult hippocampal neurogenesis was increased after chronic, peripheral BDNF administration. We also found that BDNF levels as well as expression of pCREB and pERK were elevated in the hippocampus of adult mice receiving peripheral BDNF. Taken together, these results indicate that peripheral/serum BDNF may not only represent a biomarker of MDD, but also have functional consequences on molecular signaling substrates, neurogenesis, and behavior.

GABA is a pain Neuropathic pain, one of the most debilitating of all pain states, often arises from injury to a peripheral nerve that depends on activation of a specific cell type known as microglia. This prompts the question, how do the microglia signal to spinal pain neurons? Coull et al . have now identified the biophysical mechanism by which microglia, activated by ATP, cause hyperexcitability of spinal neurons. The microglia release brain-derived neurotrophic factor, which alters chloride ion distribution across the plasma membrane of neurons in lamina I of the spinal cord. This results in the neurotransmitter, GABA, activating (rather than inhibiting) these cells that form part of a major pathway that signals pain. A collection of recent reprints on neuropathic pain, taken from Nature Publishing Group journals is, now available online via tinyurl.com/dzw86. Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord 1 , 2 , 3 . Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury 4 . Signalling between microglia and neurons is therefore an essential link in neuropathic pain transmission, but how this signalling occurs is unknown. Here we show that ATP-stimulated microglia cause a depolarizing shift in the anion reversal potential ( E anion ) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (γ-amino butyric acid), as has been shown to occur after peripheral nerve injury 5 . Applying brain-derived neurotrophic factor (BDNF) mimics the alteration in E anion . Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the E anion shift that follows both nerve injury and administration of ATP-stimulated microglia. ATP stimulation evokes the release of BDNF from microglia. Preventing BDNF release from microglia by pretreating them with interfering RNA directed against BDNF before ATP stimulation also inhibits the effects of these cells on the withdrawal threshold and E anion . Our results show that ATP-stimulated microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signalling molecule between microglia and neurons. Blocking this microglia–neuron signalling pathway may represent a therapeutic strategy for treating neuropathic pain.

As a means of environmental enrichment, music environment has positive and beneficial effects on biological neural development. Kunming white mice (61 days old) were randomly divided into the control group (group C), the group of D-tone (group D), the group of A-tone (group A) and the group of G-tone (group G). They were given different tonal music stimulation (group A) for 14 consecutive days (2 h/day) to study the effects of tonal music on the neural development of the hippocampus and prefrontal cortex of mice in early life and its molecular mechanisms. The results showed that the number of neurons in the hippocampus and prefrontal cortex of mice increased, with the cell morphology relatively intact. In addition, the number of dendritic spines and the number of dendritic spines per unit length were significantly higher than those in group C, and the expressions of synaptic plasticity proteins (SYP and PSD95) were also significantly elevated over those in group C. Compared with group C, the expression levels of BDNF, TRKB, CREB, PI3K, AKT, GS3Kβ, PLCγ1, PKC, DAG, ERK and MAPK genes and proteins in the hippocampus and prefrontal cortex of mice in the music groups were up-regulated, suggesting that different tones of music could regulate neural development through BDNF and its downstream pathways. The enrichment environment of D-tone music is the most suitable tone for promoting the development of brain nerves in early-life mice. Our study provides a basis for screening the optimal tone of neuroplasticity in early-life mice and for the treatment of neurobiology and neurodegenerative diseases.

Neurotrophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) exhibit pro-survival and homeostatic properties, but their clinical translation is limited by protein instability and rapid clearance. We evaluated a PEGylated human serum albumin (HSA) nanoparticle system for BDNF/NT3 co-delivery, focusing on physicochemical stability, ocular biodistribution in the rabbit eye, intracellular protein delivery, and protection against oxidative stress-associated cellular damage in human cells. PEGylated HSA-BDNF-NT3 nanoparticles with nominal neurotrophin concentrations of 5 µg/mL (NeO5) or 10 µg/mL (NeO10) were generated by spontaneous self-assembly and characterized using multiangle dynamic light scattering, electrophoretic light scattering, and atomic force microscopy. In vivo performance was assessed after intravitreal injection in rabbits by enzyme-linked immunosorbent assay (ELISA)-based protein quantification and exploratory reverse transcription quantitative polymerase chain reaction (RT-qPCR) profiling of survival-, proliferation-, and apoptosis-related genes. Functional delivery was examined in sodium iodate-stressed ARPE-19 and 6-hydroxydopamine-stressed retinoic acid-differentiated SH-SY5Y cells using ELISA assays, JC-1 analysis, Annexin V/ propidium iodide flow cytometry, high-performance liquid chromatography for malondialdehyde quantification, and RT-qPCR. Both formulations formed stable, spherical nanoparticles (5.9-54.2 nm) with low polydispersity index (≈ 0.18) and preserved colloidal integrity over 28 days. In vivo, BDNF was detectable in ocular tissues up to 72 h and RT qPCR did not reveal a coordinated pro-apoptotic response under the tested conditions. In vitro, nanoparticle treatment significantly increased intracellular BDNF and NT3 levels, improved viability, reduced apoptotic cell fractions, and markedly decreased lipid peroxidation, particularly for NeO10. Increased tropomyosin receptor kinase B and cAMP response element-binding protein expression provided supportive molecular evidence consistent with neurotrophin-related cellular responses. PEGylated HSA nanoparticles enable stable neurotrophin loading, efficient intracellular delivery, and attenuation of oxidative stress-induced cytotoxicity. These findings support further development of albumin-based nanocarriers for translational nanomedicine applications.

INTRODUCTION Postoperative delirium (POD) is common in older surgical patients and is clinically associated with an increased risk of long‐term cognitive decline and dementia; disrupted BDNF signaling and circadian dysregulation are implicated, but their coordinated mechanisms remain unclear. METHODS Aged male C57BL/6J mice were exposed to anesthesia, surgery, and intensive care unit‐like stress (ASI). Hippocampal neuroplasticity, dendritic morphology, epigenetic regulation, and circadian signaling were assessed using molecular assays, imaging, and protein–protein interaction (PPI) network analysis. RESULTS ASI reduced brain‐derived neurotrophic factor (BDNF)–activity‐regulated cytoskeleton‐associated protein signaling, dendritic structural complexity, and attention, with accompanying histone hypoacetylation, an increased 5‐methylcytosine/5‐hydroxymethylcytosine ratio, and disruption of network hubs centered on BDNF and circadian regulators. Suberoylanilide hydroxamic acid mitigated these effects and improved short‐term cognitive performance. DISCUSSION Perioperative stress is associated with an epigenetically repressed, synaptically impaired hippocampal state linked to delirium‐like behavior and cognitive vulnerability. Targeting chromatin accessibility and BDNF–circadian coupling with histone deacetylase inhibition may mitigate acute cognitive consequences following surgery. Highlights ASI suppresses hippocampal BDNF–TrkB–CREB–ARC signaling and promotes dendritic structural alterations in aged mice. Perioperative stress is associated with epigenetic dysregulation characterized by histone hypoacetylation and increased DNA methylation‐linked transcriptional repression. Network analysis identifies BDNF and core CLOCK genes as convergent hubs linking synaptic and circadian disruption. HDAC inhibition mitigates epigenetic dysregulation, restores synaptic structure, and attenuates delirium‐like cognitive deficits. Perioperative epigenetic and synaptic alterations may intersect with biological pathways of cognitive vulnerability and potential risk for long‐term cognitive decline and dementia.