Brain-derived Neurotrophic Factor Synthesis Research Articles

Brain Derived Neurotrophic Factor (BDNF) Immunolabeling in C4-C5 Spinal Cord of Adult Female Rats Following Acute Intermittent Hypoxia (AIH) Exposure Composed of 5,3-min Hypoxic Episodes (AIH5x3min) at 4-weeks After mid-thoracic SCI

Acute intermittent hypoxia (AIH) induces spinal neural plasticity in both respiratory and non-respiratory somatic motor systems. AIH-induced neural plasticity has been best studied in the respiratory neural control system, where exposure to moderate AIH (9-15% inspired O2), typically composed of 3,5-min hypoxic episodes (AIH3x5min), has been shown to consistently elicit a robust increase in phrenic motor activity due to a serotonin-dependent mechanism that promotes de novo synthesis of BDNF and activation of high affnity BDNF-TrkB receptors to initiate ERK MAP kinase signaling in phrenic motoneurons. Whether other protocols that use a total duration of 15 min of hypoxic exposure, but with an increased number of shorter duration hypoxic episodes ( e.g, AIH5x3min) similarly elicit serotonin-dependent BDNF pathway-mediated neural plasticity mechanisms in this region remains to be determined. To begin to assess this possibility, we evaluated BDNF expression in C4-C5 spinal cord segments containing the phrenic motor nucleus following single exposure to AIH5x3min (12% O2) in urethane-anesthetized spontaneously breathing adult female rats at 4-weeks after mid-thoracic SCI. Experiments using AIH3x5min (12% O2) exposure and intermittent normoxia (Nx, 21% O2) exposure served as controls. At ~60-90 min after the AIH or Nx exposure protocol, the rats were transcardially perfused with saline followed by 4% PFA, and various regions of the CNS, including the C3-C5 spinal cord were removed, post-fixed, and cryoprotected. 20 μm thick transverse sections were then cut to obtain sets of slides for single- or double-label fluorescence IHC staining to localize BDNF protein expression in the C4-C5 spinal cord, including the region containing the phrenic motor nucleus. Preliminary analyses show that both AIH5x3min and AIH3x5min exposures elicit increased BDNF expression when compared to Nx exposure, with both diffuse cytosolic and punctate immunofluorescence labeling in and around neurons within the phrenic motor nucleus region, including labeling of presumptive phrenic motoneurons. No labeling was seen in adjacent tissue sections that were incubated without the primary antibody. Immunofluorescence labeling was also seen in the more medial regions of lamina VIII in the ventral horn, the medial regions of laminae VI and VII, and throughout lamina X; these regions have been reported to contain the V0-V3 classes of spinal interneurons (SpINs) albeit we did not verify BDNF labeling of specific classes of presumptive SpINs. These preliminary observations suggest that AIH5x3min exposure likely recruits a serotonin-dependent BDNF pathway-mediated mechanism for neural plasticity in a manner similar to that seen for AIH3x5min exposure. APS Summer Undergraduate Research Fellowship; DOD CDMRP W81XWH-17-1-0260; NYS DOH SCIRB C37711GG. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Acute physical exercise prevents memory amnesia caused by protein synthesis inhibition in rats' hippocampus

The benefits of physical exercise (PE) on memory consolidation have been well-documented in both healthy and memory-impaired animals. However, the underlying mechanisms through which PE exerts these effects are still unclear. In this study, we aimed to investigate the role of hippocampal protein synthesis in memory modulation by acute PE in rats. After novel object recognition (NOR) training, rats were subjected to a 30-min moderate-intensity acute PE on the treadmill, while control animals did not undergo any procedures. Using anisomycin (ANI) and rapamycin (RAPA), compounds that inhibit protein synthesis through different mechanisms, we manipulated protein synthesis in the CA1 region of the hippocampus to examine its contribution to memory consolidation. Memory was assessed on days 1, 7, and 14 post-training. Our results showed that inhibiting protein synthesis by ANI or RAPA impaired NOR memory consolidation in control animals. However, acute PE prevented this impairment without affecting memory persistence. We also evaluated brain-derived neurotrophic factor (BDNF) levels after acute PE at 0.5h, 2h, and 12h afterward and found no differences in levels compared to animals that did not engage in acute PE or were only habituated to the treadmill. Therefore, our findings suggest that acute PE could serve as a non-pharmacological intervention to enhance memory consolidation and prevent memory loss in conditions associated with hippocampal protein synthesis inhibition. This mechanism appears not to depend on BDNF synthesis in the early hours after exercise.

TrkB-BDNF Signalling and Arc/Arg3.1 Immediate Early Genes in the Anterior Cingulate Cortex and Hippocampus: Insights into Novel Memory Milestones Through Behavioural Tagging.

In recent years, there has been a surge in interest in investigating the mechanisms underlying memory consolidation. However, our understanding of the behavioural tagging (BT) model and its establishment in diverse brain regions remains limited. This study elucidates the contributions of the anterior cingulate cortex (ACC) and hippocampus in the formation of long-term memory (LTM) employing behaviour tagging as a model for studying the underlying mechanism of LTM formation in rats. Existing knowledge highlights a protein synthesis-dependent phase as imperative for LTM. Brain-derived neurotrophic factor (BDNF) stands as a pivotal plasticity-related protein (PRP) in mediating molecular alterations crucial for long-term synaptic plasticity and memory consolidation. Our study offers evidence suggesting that tropomyosin receptor kinase B (TrkB), the receptor of BDNF, may act as a combined "behavioural tag/PRP". Interfering with the expression of these molecules resulted in impaired LTM after 24h. Furthermore, augmenting BDNF expression led to an elevation in Arc protein levels in both the ACC and hippocampus regions. Introducing novelty around weak inhibitory avoidance (IA) training resulted in heightened step-down latencies and expression of these molecules, respectively. We also demonstrate that the increase in Arc expression relies on BDNF synthesis, which is vital for the memory consolidation process. Additionally, inhibiting BDNF using an anti-BDNF function-blocking antibody impacted Arc expression in both the ACC and hippocampus regions, disrupting the transformations from labile to robust memory. These findings mark the initial identification of a "behavioural tag/PRP" combination and underscore the involvement of the TrkB-BDNF-Arc cascade in the behavioural tagging model of learning and memory.

Effect of Administration of Mackerel Oil During Pregnancy on the Expression of Brain Derived Neurotrophic Factor (BDNF) in the Cerebrum of Newborn Mice

Omega 3 contained in mackerel oil extract is an important constituent of neuron cell walls and the raw material for building fetal brain cells. DHA and EPA in omega 3 regulate BDNF synthesis through a p38-MAPK dependent mechanism. BDNF has a role in regulating cell survival and programming cell death (apoptosis) in the brain. This study aims to determine the effect of giving mackerel oil during pregnancy on BDNF expression in the cerebrum of newborn rats. Posttest research design only control group with true experimental type. A sample of 30 rats with 10 each per group. The first group was the control group (K), the second group was mackerel oil (P1), and the third group was omega 3 supplements (P2). BDNF expression examination methods with immunohistochemistry. The data were analyzed analytically with ANOVA and continued with post hoc LSD. There was a significant difference in the expression of BDNF cerebral newborn rats between groups with a value of p = 0.000 (2.780 ± 0.52 in the control group, 3.670 ± 0.36 in the mackerel oil group, and 3.670 ± 0.45 in the omega 3 supplement group ) . The conclusion of this study was that the group given mackerel oil extract had a higher BDNF cerebral expression than the other groups.

β-glucan, a specific immuno-stimulant, produces rapid antidepressant effects by stimulating ERK1/2-dependent synthesis of BDNF in the hippocampus

A decline in microglia in the dentate gyrus of the hippocampus has recently been described as an important mechanism for the progression of depression. Reversal of this decline by innate immune system stimulants may represent a novel strategy to ameliorate the depressive phenotype in chronically stressed animals. β-glucan is a polysaccharide from Saccharomyces cerevisiae. It can efficiently stimulate microglia without inducing the production of pro-inflammatory cytokines. Therefore, β-glucan could be an ideal drug to ameliorate depressive phenotypes. In the present study, we found that a single injection of β-glucan reversed depression-like behaviors in mice induced by chronic unpredictable stress (CUS) in a dose-dependent manner, which was accompanied by a reversal of the CUS-induced decrease in brain-derived neurotrophic factor (BDNF) protein levels in the dentate gyrus. The crucial role of BDNF signaling in the antidepressant effect of β-glucan was demonstrated by experiments showing that infusion of an anti-BDNF antibody into dentate gyrus, construction of BDNF-Val68Met allele knock-in mice, or treatment with the BDNF receptor antagonist K252a abolished the antidepressant effect of β-glucan. The increased BDNF signaling induced by β-glucan was mediated by extracellular signal-regulated kinase1/2 (ERK1/2)-mediated BDNF synthesis, and inhibition of ERK1/2 by SL327 was able to abolish the antidepressant effect of β-glucan. Moreover, inhibition or depletion of microglia by minocycline or PLX3397 abolished the reversal effect of β-glucan on CUS-induced depression-like behaviors and CUS-induced impairment of ERK1/2-BDNF signaling. These results suggest that β-glucan exhibits antidepressant effects by stimulating microglia-mediated activation of ERK1/2 and synthesis of BDNF in the hippocampus.

Microglial stimulation triggered by intranasal lipopolysaccharide administration produces antidepressant-like effect through ERK1/2-mediated BDNF synthesis in the hippocampus

We recently reported that reversing the chronic stress-induced decline of microglia in the dentate gyrus (DG) of the hippocampus by intraperitoneal injection of a low dose of lipopolysaccharide (LPS) ameliorated depression-like behavior in chronically stressed mice. In this study, we found that a single intranasal administration of LPS dose-dependently improved depression-like behavior in mice treated with chronic unpredictable stress (CUS), as evidenced by the reduction of immobility time in the tail suspension test (TST) and forced swimming test (FST) and by the increase of sucrose uptake in the sucrose preference test (SPT). The antidepressant effects of intranasal administration of LPS could be abolished by inhibition of brain-derived neurotrophic factor (BDNF) signaling by infusion of an anti-BDNF antibody, by knock-in of the mutant BDNF Val68Met allele, or by the BDNF receptor antagonist K252a. In addition, intranasal administration of LPS was found to exert antidepressant effects in a BDNF-dependent manner via promotion of BDNF synthesis mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling but not protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling in DG. Inhibition of microglia by minocycline or depletion of microglia by PLX3397 was able to abolish the reversal effect of intranasal LPS administration on CUS-induced depression-like behaviors as well as the CUS-induced decrease in phospho-ERK1/2 and BDNF protein levels in DG. These results demonstrate that stimulation of hippocampal microglia by intranasal LPS administration can induce antidepressant effects via ERK1/2-dependent synthesis of BDNF protein, providing hope for the development of new strategies for the treatment of depression.

An 840 kb distant upstream enhancer is a crucial regulator of catecholamine-dependent expression of the Bdnf gene in astrocytes.

Brain-derived neurotrophic factor (BDNF) plays a fundamental role in the developing and adult nervous system, contributing to neuronal survival, differentiation, and synaptic plasticity. Dysregulation of BDNF synthesis, secretion or signaling has been associated with many neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Although the transcriptional regulation of the Bdnf gene has been extensively studied in neurons, less is known about the regulation and function of BDNF in non-neuronal cells. The most abundant type of non-neuronal cells in the brain, astrocytes, express BDNF in response to catecholamines. However, genetic elements responsible for this regulation have not been identified. Here,we investigated four potential Bdnf enhancer regions and based on reporter gene assays, CRISPR/Cas9 engineering and CAPTURE-3C-sequencing we conclude that a region 840 kb upstream of the Bdnf gene regulates catecholamine-dependent expression of Bdnf in rodent astrocytes. We also provide evidence that this regulation is mediated by CREB and AP1 family transcription factors. This is the first report of an enhancer coordinating the transcription of Bdnf gene in non-neuronal cells.

High throughput assay for compounds that boost BDNF expression in neurons.

Deficiencies in brain-derived neurotrophic factor (BDNF) have been linked to several brain disorders, making compounds that can boost neuronal BDNF synthesis attractive as potential therapeutics. However, a sensitive and quantitative BDNF assay for high-throughput screening (HTS) is still missing. Here we report the generation of a new mouse Bdnf allele, BdnfNLuc, in which the sequence encoding nano luciferase (NLuc) is inserted into the Bdnf locus immediately before the stop codon so that the allele will produce a BDNF-NLuc fusion protein. BDNF-NLuc protein appears to function like BDNF as BdnfNLuc/NLuc homozygous mice grew and behaved almost normally. We were able to establish and optimize cultures of cortical and hippocampal BdnfNLuc/+ neurons isolated from mouse embryos in 384-well plates. We used the cultures as a phenotypic assay to detect the ability of 10 mM KCl to stimulate BDNF synthesis and achieved a reproducible Z' factor > 0.50 for the assay, a measure considered suitable for HTS. We successfully scaled up the assay to screen the 1280-compound LOPAC library (Library of Pharmacologically Active Compounds). The screen identified several BDNF-boosting compounds, one of which is Bay K8644, a L-type voltage-gated calcium channel (L-VGCC) agonist, which was previously shown to stimulate BDNF synthesis. These results indicate that our phenotypic neuronal assay is ready for HTS to identify novel BDNF-boosting compounds.

Brain-derived neurotrophic factor - a key player in the gastrointestinal system.

Brain-derived neurotrophic factor (BDNF) is highly expressed throughout the gastrointestinal (GI) tract and plays a critical role in the regulation of intestinal motility, secretion, sensation, immunity, and mucosal integrity. Dysregulation of BDNF signalling has been implicated in the pathophysiology of various GI disorders including inflammatory bowel disease, irritable bowel syndrome, functional dyspepsia, and diabetic gastroenteropathy. This review provides a comprehensive overview of BDNF localization, synthesis, receptors, and signalling mechanisms in the gut. In addition, current evidence on the diverse physiologic and pathophysiologic roles of BDNF in the control of intestinal peristalsis, mucosal transport processes, visceral sensation, neuroimmune interactions, gastrointestinal mucosal healing, and enteric nervous system homeostasis are discussed. Finally, the therapeutic potential of targeting BDNF for the treatment of functional GI diseases is explored. Advancing knowledge of BDNF biology and mechanisms of action may lead to new therapies based on harnessing the gut trophic effects of this neurotrophin.

Nitric Oxide Linked to mGluR5 Upregulates BDNF Synthesis by Activating MMP2 in the Caudate and Putamen after Challenge Exposure to Nicotine in Rats.

Nitric oxide (NO) linked to glutamate receptors in the caudate and putamen (CPu) regulates neuroadaptation after drug exposure. Matrix-metalloproteinase (MMP), a Ca2+-dependent zinc-containing endopeptidase, increases mature brain-derived neurotrophic factor (BDNF) synthesis after drug exposure in the brain. The present study determined that NO synthesis linked to metabotropic glutamate receptor subtype 5 (mGluR5) stimulation after challenge exposure to nicotine activates MMP, which upregulates BDNF synthesis in the CPu. Subcutaneous injection of challenge nicotine (1.0 mg/kg) after repeated injections of nicotine (1.0 mg/kg/day) for 14 days and 7 days of nicotine withdrawal increased MMP2 activity and BDNF expression in the CPu of rats. These increases were prevented by the bilateral intra-CPu infusion of the mGluR5 antagonist, MPEP (0.1 nmol/side), the IP3 receptor antagonist, xestospongin C (0.004 nmol/side) or the neuronal nitric oxide synthase (nNOS) and NO inhibitor, Nω-propyl (0.1 nmol/side) prior to the challenge nicotine. Furthermore, bilateral intra-CPu infusion of the MMP2 inhibitor, OA-Hy (1 nmol/side) prevented the challenge nicotine-induced increase in the expression of BDNF. These findings suggest that elevation of NO synthesis linked to mGluR5 potentiates BDNF synthesis via activation of MMP2 after challenge exposure to nicotine in the CPu of rats.

The effects of curcumin in learning and memory impairment associated with hypothyroidism in juvenile rats: the role of nitric oxide, oxidative stress, and brain-derived neurotrophic factor.

The effect of curcumin (Cur) on cognitive impairment and the possible role of brain tissue oxidative stress, nitric oxide (NO) levels, and brain-derived neurotrophic factor (BDNF) were investigated in juvenile hypothyroid rats. The juvenile rats (21 days old) were allocated into the following groups: (1) control; (2) hypothyroid (0.05% propylthiouracil (PTU) in drinking water); (3-5) hypothyroid-Cur 50, 100, and 150, which in these groups 50, 100, or 150 mg/kg, Cur was orally administered by gavage during 6 weeks. In the hypothyroid rats, the time elapsed and the traveled distance to locate the hidden platform in the learning trials of Morris water maze (MWM) increased, and on the probe day, the amount of time spent in the target quadrant and the distance traveled in there was decreased. Hypothyroidism also decreased the latency and increased the time spent in the darkroom of the passive avoidance (PA) test. Compared with the hypothyroid group, Cur enhanced the performance of the rats in both MWM and PA tests. In addition, Cur reduced malondialdehyde concentration and NO metabolites; however, it increased thiol content as well as the activity of catalase (CAT) and superoxide dismutase enzymes in both the cortex and hippocampus. Cur also increased hippocampal synthesis of BDNF in hypothyroid rats. The beneficial effects of Cur cognitive function in juvenile hypothyroid rats might be attributed to its protective effect against oxidative stress and potentiation of BDNF production.

ERK1/2-dependent BDNF synthesis and signaling is required for the antidepressant effect of microglia stimulation

Depressed mice have lower numbers of microglia in the dentate gyrus (DG). Reversal of this decline by a single low dose of lipopolysaccharide (LPS) may have antidepressant effects, but there is little information on the molecular mechanisms underlying this effect. It is known that impairment of brain-derived neurotrophic factor (BDNF) signaling is involved in the development of depression. Here, we used a combination of neutralizing antibodies, mutant mice, and pharmacological approaches to test the role of BDNF-tyrosine kinase receptor B (TrkB) signaling in the DG in the effect of microglial stimulation. Our results suggest that inhibition of BDNF signaling by infusion of an anti-BDNF antibody, the BDNF receptor antagonist K252a, or knock-in of the mutant BDNF Val68Met allele abolished the antidepressant effect of LPS in chronically stressed mice. Increased BDNF synthesis in DG, mediated by extracellular signal-regulated kinase1/2 (ERK1/2) signaling but not protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling, was essential for the antidepressant effect of microglial stimulation. These results suggest that increased BDNF synthesis through activation of ERK1/2 caused by a single LPS injection and subsequent TrkB signaling are required for the antidepressant effect of hippocampal microglial stimulation.

Is Brain-Derived Neurotrophic Factor a Metabolic Hormone in Peripheral Tissues?

Simple SummaryThe activity of brain-derived neurotrophic factor (BDF) in the central nervous system has been well-studied, but its physiological role in other organs has not been clearly defined. This review summarizes the current findings on the functionality of BDNF in various peripheral tissues and discusses several unresolved questions in the field.Brain-derived neurotrophic factor (BDNF) is an important growth factor in the central nervous system. In addition to its well-known activities in promoting neuronal survival, neuron differentiation, and synaptic plasticity, neuronal BDNF also regulates energy homeostasis by modulating the hypothalamus’s hormonal signals. In the past decades, several peripheral tissues, including liver, skeletal muscle, and white adipose tissue, were demonstrated as the active sources of BDNF synthesis in response to different metabolic challenges. Nevertheless, the functions of BDNF in these tissues remain obscure. With the use of tissue-specific Bdnf knockout animals and the availability of non-peptidyl BDNF mimetic, increasing evidence has reported that peripheral tissues-derived BDNF might play a significant role in maintaining systemic metabolism, possibly through the regulation of mitochondrial dynamics in the various tissues. This article reviews the autocrine/paracrine/endocrine functions of BDNF in non-neuronal tissues and discusses the unresolved questions about BDNF’s function.

The Molecular Effects of BDNF Synthesis on Skeletal Muscle: A Mini-Review.

The brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family which is generated mainly by the brain. Its main role involve synaptic modulation, neurogenesis, neuron survival, immune regulation, myocardial contraction, and angiogenesis in the brain. Together with the encephalon, some peripheral tissues synthesize BDNF like skeletal muscle. On this tissue, this neurotrophin participates on cellular mechanisms related to muscle function maintenance and plasticity as reported on recent scientific works. Moreover, during exercise stimuli the BDNF contributes directly to strengthening neuromuscular junctions, muscle regeneration, insulin-regulated glucose uptake and β-oxidation processes in muscle tissue. Given its vital relevance on many physiological mechanisms, the current mini-review focuses on discussing up-to-date knowledge about BDNF production in skeletal muscle and how this neurotrophin impacts skeletal muscle biology.

Correlation between antenatal magnesium sulfate (MgSO4) total dose and delivery time interval with umbilical cord blood brain-derived neurotrophic factor (BDNF) levels as a neuroprotection strategy in preterm birth

Background: Administration of antenatal magnesium sulfate (MgSO4) to pregnant women is thought to increase the synthesis of Brain-Derived Neurotrophic Factor (BDNF), which functions as a nerve-growth factor for the process of neurogenesis and also strengthen neuronal resilience in the hypoxic condition that occurs during preterm delivery. Protocols for administering antenatal MgSO4 differ between countries and institutions. One of the concerns is whether the dose is given and the time interval to delivery has a big contribution towards a better fetal outcome. These relationships have not been studied before. This study aimed to analyze the correlation of the total dose of MgSO4 and time interval to delivery with BDNF levels in cord blood. Methods: This study enrolled 72 pregnant women who will deliver the baby prematurely, with gestational age 28-34 weeks. Subjects were divided into three protocols groups: (1) 4 g iv. only, (2) 4 g iv. initial continued with 1 g/hours until maximum 24 hours, and (3) 6 g iv. initial continued with 2 g/hours until a maximum of 24 hours. At the time of delivery, cord blood of preterm babies was collected. The antenatal MgSO4 total dose and time interval to delivery were collected, and BDNF serum levels were then measured with enzyme-linked immunosorbent assay (ELISA). The correlation between antenatal MgSO4 total dose and time interval to delivery with BDNF levels was analyzed using Spearman’s correlation test. Result: There was a weak significant correlation of antenatal MgSO4 total dose and BDNF cord blood levels (p<0.001; r=0.381). There was no significant correlation between delivery time interval and BDNF cord blood levels (p=0.44; r=0.092). Conclusion: Regarding the weak correlation of total dose and time interval to delivery with BDNF, we suggest that all protocols provide comparable outcomes if seen only from the BDNF increase perspective.

Antillatoxin-Stimulated Neurite Outgrowth Involves the Brain-Derived Neurotrophic Factor (BDNF) - Tropomyosin Related Kinase B (TrkB) Signaling Pathway.

Voltage-gated sodium channel (VGSC) activators promote neurite outgrowth by augmenting intracellular Na+ concentration ([Na+]i) and upregulating N-methyl-d-aspartate receptor (NMDAR) function. NMDAR activation stimulates calcium (Ca2+) influx and increases brain-derived neurotrophic factor (BDNF) release and activation of tropomyosin receptor kinase B (TrkB) signaling. The BDNF-TrkB pathway has been implicated in activity-dependent neuronal development. We have previously shown that antillatoxin (ATX), a novel lipopeptide isolated from the cyanobacterium Moorea producens, is a VGSC activator that produces an elevation of [Na+]i. Here we address the effect of ATX on the synthesis and release of BDNF and determine the signaling mechanisms by which ATX enhances neurite outgrowth in immature cerebrocortical neurons. ATX treatment produced a concentration-dependent release of BDNF. Acute treatment with ATX also resulted in increased synthesis of BDNF. ATX stimulation of neurite outgrowth was prevented by pretreatment with a TrkB inhibitor or transfection with a dominant-negative Trk-B. The ATX activation of TrkB and Akt was blocked by both a NMDAR antagonist (MK-801) and a VGSC blocker (tetrodotoxin). These results suggest that VGSC activators such as the structurally novel ATX may represent a new pharmacological strategy to promote neuronal plasticity through a NMDAR-BDNF-TrkB-dependent mechanism.

Neuroplasticity Mechanisms and Prospects for Personalized Rehabilitation Strategies in Patients with Motor and Cognitive Impairments

Aim. To highlight the most important areas of research on the problems of rehabilitation after stroke and the prospects for the development of new rehabilitation strategies, taking into account individual characteristics. Neuroplastic outcomes of anemic infarctions are presented by multi-pattern positive processes of synaptogenesis, sprouting, synthesis of neuroprotective proteins, and destructive effects of stress plasticity inducing dystonic disturbances, deterioration of stabilometric parameters and locomotor gait mechanisms with support deterioration [1]. Thus, specialists in neurorehabilitation should know the basics of fundamental neurophysiological processes in the central nervous system, interhemispheric networks of the brain, and optimize rehabilitation programs, taking into account individualized recovery profiles [2]. One of the factors influencing recovery after a stroke is nervous reorganization, which is proportional to the amount of damage [3]. The processes of neuroplasticity are studied from the standpoint of returning to the pre-stroke recovery model (with minor injuries) – forming “optimal” plasticity and compensatory strategies of “destructive” plasticity (with extensive hemispheric injuries). Micro-RNA (miRNA) are understudied in the neuroprotective reaction to cerebral ischemia. Another important modulator of stroke outcomes is the brain-derived neurotrophic factor (BDNF). Processing of the defective BDNF synthesis when the amino acid valine is replaced by methionine (val-met) that occurs during allelic disorders is of outstanding interest. Conclusion. Promising research areas for strategic approaches to rehabilitation after a stroke are the study of hemispheric introduction, miRNA and neuroprotection cascades; BDNF as an inducer of neuronal differentiation. Allelic BDNF polymorphisms induce lower recovery potential after stroke. Under certain environmental conditions motor learning can overcome the neuroplasticity deficit in the BDNF gene polymorphism. The studies have shown general patterns of positive effects of aerobic stimuli with enhanced BDNF secretion in the recovery of patients with cognitive and motor impairments; nevertheless, the onset period, intensity, duration and exercises rhythmicity have not been established in cerebral stroke. Future studies are likely to optimize rehabilitation profiles based on genetic characteristics.

Role of brain-derived neurotrophic factor in shaping the behavioural response to environmental stressors.

Brain-derived neurotrophic factor (BDNF) is an important neurotrophin involved in an integration of the brain activity in physiological and pathological conditions, with formation of a short- and long-term functional and structural neuroplasticity. This process proceeds, with a changeable dynamics, in the subsequent stages of ontogenesis. In addition to many other functions in the central nervous system, BDNF is also involved in shaping a response to stress stimuli in the form of precisely adjusted behavioural reactions involving the limbic system, and the endocrine system with stimulation of the hypothalamic-pituitary-adrenal axis (HPA). Although almost every stressor increases the activity of the HPA, the neuronal response to it can vary substantially. This may be due to involvement of different neurotransmitter pathways, neuromodulators and neurohormones, as well as changes in gene expression. It is widely accepted that BDNF synthesis and secretion are modulated by stress. Furthermore, age is an important factor influencing the BDNF expression in response to different stressors. In this work, we focused on the analysis of the role of mild stressful stimuli, which commonly occur in the natural environment, on changes in BDNF expression at various stages of ontogenetic development. Although, the presented data comes from animal studies, probably similar mechanisms of stress regulation are also present in humans. This comprehensive review shows that the influence of stressors on the BDNF expression depends on many factors, including a type and duration of a stressor, time of neurotrophin detection, animal's resistance to stress, brain area, and genotypic characteristics of an individual. A more detailed understanding of the mechanisms shaping stress reactions, including the role of BDNF, may be of both theoretical and practical importance, allowing designing more effective strategies for preventing and treating stress itself and the stress-related disorders.

Antidepressant Actions of Ketamine: Potential Role of L-Type Calcium Channels.

Recently, the United States Food and Drug Administration approved esketamine, the S-enantiomer of ketamine, as a fast-acting therapeutic drug for treatment-resistant depression. Although ketamine is known as an N-methyl-d-aspartate (NMDA) receptor antagonist, the underlying mechanisms of how it elicits an antidepressant effect, specifically at subanesthetic doses, are not clear and remain an advancing field of research interest. On the other hand, high-dose (more than the anesthetic dose) ketamine-induced neurotoxicity in animal models has been reported. There has been progress in understanding the potential pathways involved in ketamine-induced antidepressant effects, some of which include NMDA-receptor antagonism, modulation of voltage-gated calcium channels, and brain-derived neurotrophic factor (BDNF) signaling. Often these pathways have been shown to be linked. Voltage-gated L-type calcium channels have been shown to mediate the rapid-acting antidepressant effects of ketamine, especially involving induction of BDNF synthesis downstream, while BDNF deficiency decreases the expression of L-type calcium channels. This review focuses on the reported studies linking ketamine's rapid-acting antidepressant actions to L-type calcium channels with an objective to present a perspective on the importance of the modulation of intracellular calcium in mediating the effects of subanesthetic (antidepressant) versus high-dose ketamine (anesthetic and potential neurotoxicant), the latter having the ability to reduce intracellular calcium by blocking the calcium-permeable NMDA receptors, which is implicated in potential neurotoxicity.

Metabolomic Profiling and Neuroprotective Effects of Purslane Seeds Extract Against Acrylamide Toxicity in Rat's Brain.

Acrylamide (ACR) is an environmental pollutant with well-demonstrated neurotoxic and neurodegenerative effects in both humans and experimental animals. The present study aimed to investigate the neuroprotective effect of Portulaca oleracea seeds extract (PSE) against ACR-induced neurotoxicity in rats and its possible underlying mechanisms. PSE was subjected to phytochemical investigation using ultra-high-performance liquid chromatography (UPLC) coupled with quantitative time of flight mass spectrometry (qTOF-MS). Multivariate, clustering and correlation data analyses were performed to assess the overall effects of PSE on ACR-challenged rats. Rats were divided into six groups including negative control, ACR-intoxicated group (10mg/kg/day), PSE treated groups (200 and 400mg/kg/day), and ACR + PSE treated groups (200 and 400mg/kg/day, respectively). All treatments were given intragastrically for 60days. PSE markedly ameliorated brain damage as evidenced by the decreased lactate dehydrogenase (LDL), increased acetylcholinesterase (AchE) activities, as well as the increased brain-derived neurotrophic factor (BDNF) that were altered by the toxic dose of ACR. In addition, PSE markedly attenuated ACR-induced histopathological alterations in the cerebrum, cerebellum, hippocampus and sciatic nerve and downregulated the ACR-inclined GFAP expression. PSE restored the oxidative status in the brain as indicated by glutathione (GSH), lipid peroxidation and increased total antioxidant capacity (TAC). PSE upregulated the mRNA expression of protein kinase B (AKT), which resulted in an upsurge in its downstream cAMP response element-binding protein (CREB)/BDNF mRNA expression in the brain tissue of ACR-intoxicated rats. All exerted PSE beneficial effects were dose-dependent, with the ACR-challenged group received PSE 400mg/kg dose showed a close clustering to the negative control in both unsupervised principal component analysis (PCA) and supervised orthogonal partial least square discriminant analysis (OPLS-Da) alongside with the hierarchical clustering analysis (HCA). The current investigation confirmed the neuroprotective capacity of PSE against ACR-induced brain injury, and our findings indicate that AKT/CREB pathways and BDNF synthesis may play an important role in the PSE-mediated protective effects against ACR-triggered neurotoxicity.