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1.
Perisynaptic astrocytes as a potential target for novel antidepressant drugs.
Frizzo, ME, Ohno, Y
Journal of pharmacological sciences. 2021;(1):60-68
Abstract
Emerging evidence suggests that dysfunctions in glutamatergic signaling are associated with the pathophysiology of depression. Several molecules that act on glutamate binding sites, so-called glutamatergic modulators, are rapid-acting antidepressants that stimulate synaptogenesis. Their antidepressant response involves the elevation of both extracellular glutamate and brain-derived neurotrophic factor (BDNF) levels, as well as the postsynaptic activation of the mammalian target of rapamycin complex 1. The mechanisms involved in the antidepressant outcomes of glutamatergic modulators, including ketamine, suggest that astrocytes must be considered a cellular target for developing rapid-acting antidepressants. It is well known that extracellular glutamate levels and glutamate intrasynaptic time-coursing are maintained by perisynaptic astrocytes, where inwardly rectifying potassium channels 4.1 (Kir4.1 channels) regulate both potassium and glutamate uptake. In addition, ketamine reduces membrane expression of Kir4.1 channels, which raises extracellular potassium and glutamate levels, increasing postsynaptic neural activities. Furthermore, inhibition of Kir4.1 channels stimulates BDNF expression in astrocytes, which may enhance synaptic connectivity. In this review, we discuss glutamatergic modulators' actions in regulating extracellular glutamate and BDNF levels, and reinforce the importance of perisynaptic astrocytes for the development of novel antidepressant drugs.
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A reconciling hypothesis centred on brain-derived neurotrophic factor to explain neuropsychiatric manifestations in rheumatoid arthritis.
Pedard, M, Quirié, A, Tessier, A, Garnier, P, Totoson, P, Demougeot, C, Marie, C
Rheumatology (Oxford, England). 2021;(4):1608-1619
Abstract
Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease characterized by synovitis leading to joint destruction, pain and disability. Despite efficient antirheumatic drugs, neuropsychiatric troubles including depression and cognitive dysfunction are common in RA but the underlying mechanisms are unclear. However, converging evidence strongly suggests that deficit in brain-derived neurotrophic factor (BDNF) signalling contributes to impaired cognition and depression. Therefore, this review summarizes the current knowledge on BDNF in RA, proposes possible mechanisms linking RA and brain BDNF deficiency including neuroinflammation, cerebral endothelial dysfunction and sedentary behaviour, and discusses neuromuscular electrical stimulation as an attractive therapeutic option.
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3.
Brain-Derived Neurotrophic Factor in Neonatal Seizures.
Sullivan, BJ, Kadam, SD
Pediatric neurology. 2021;:35-39
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Abstract
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has an extensively studied classical role in neuronal growth, differentiation, survival, and plasticity. Neurotrophic, from the Greek neuro and trophos, roughly translates as "vital nutrition for the brain." During development, BDNF and its associated receptor tyrosine receptor kinase B are tightly regulated as they influence the formation and maturation of neuronal synapses. Preclinical research investigating the role of BDNF in neurological disorders has focused on the effects of decreased BDNF expression on the development and maintenance of neuronal synapses. In contrast, heightened BDNF-tyrosine receptor kinase B activity has received less scrutiny for its role in neurological disorders. Recent studies suggest that excessive BDNF-tyrosine receptor kinase B signaling in the developing brain may promote the hyperexcitability that underlies refractory neonatal seizures. This review will critically examine BDNF-tyrosine receptor kinase B signaling in the immature brain, its role in the emergence of refractory neonatal seizures, and the potential of targeting BDNF-TrkB signaling as a novel antiseizure strategy.
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4.
Molecular Basis of the Beneficial Actions of Resveratrol.
Repossi, G, Das, UN, Eynard, AR
Archives of medical research. 2020;(2):105-114
Abstract
Resveratrol modulates the transcription factor NF-κB, cytochrome P450 isoenzyme CYP1A1, expression and activity of cyclooxygenase (COX) enzymes, Fas/Fas ligand mediated apoptosis, p53, mTOR and cyclins and various phospho-diesterases resulting in an increase in cytosolic cAMP levels. Cyclic AMP, in turn, activates Epac1/CaMKKβ/AMPK/SIRT1/PGC-1α pathway that facilitates increased oxidation of fatty acids, mitochondrial respiration and their biogenesis and gluconeogenesis. Resveratrol triggers apoptosis of activated T cells and suppresses tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17) and other pro-inflammatory molecules and inhibits expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) that may explain its anti-inflammatory actions. Polyunsaturated fatty acids (PUFAs) and their anti-inflammatory metabolites lipoxin A4, resolvins, protectins and maresins have a significant role in obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome and cancer. We observed that PUFAs (especially arachidonic acid, AA) and BDNF (brain-derived neurotrophic factor) protect against the cytotoxic actions of alloxan, streptozotocin, benzo(a)pyrene (BP) and doxorubicin. Thus, there is an overlap in the beneficial actions of resveratrol, PUFAs and BDNF suggesting that these molecules may interact and augment synthesis and action of each other. This is supported by the observation that resveratrol and PUFAs modulate gut microbiota and influence stem cell proliferation and differentiation. Since resveratrol is not easily absorbed from the gut it is likely that it may act on endocannabinoid and light, odor, and taste receptors located in the gut, which, in turn, convey their messages to the various organs via vagus nerve.
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Peripheral Blood Brain-Derived Neurotrophic Factor as a Biomarker of Alzheimer's Disease: Are There Methodological Biases?
Balietti, M, Giuli, C, Conti, F
Molecular neurobiology. 2018;(8):6661-6672
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Abstract
Mounting evidence that alterations in brain-derived neurotrophic factor (BDNF) levels and signaling may be involved in the etiopathogenesis of Alzheimer's disease (AD) has suggested that its blood levels could be used as a biomarker of the disease. However, higher, lower, or unchanged circulating BDNF levels have all been described in AD patients compared to healthy controls. Although the reasons for such different findings are unclear, methodological issues are likely to be involved. The heterogeneity of participant recruitment criteria and the lack of control of variables that influence circulating BDNF levels regardless of dementia (depressive symptoms, medications, lifestyle, lack of overlap between serum and plasma, and experimental aspects) are likely to bias result and prevent study comparability. The present work reviews a broad panel of factors, whose close control could help reduce the inconsistency of study findings, and offers practical advice on their management. Research directed at elucidating the weight of each of these variables and at standardizing analytical methodologies is urgently needed.
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6.
Association of Brain-derived neurotrophic factor gene polymorphisms with body mass index: A systematic review and meta-analysis.
Akbarian, SA, Salehi-Abargouei, A, Pourmasoumi, M, Kelishadi, R, Nikpour, P, Heidari-Beni, M
Advances in medical sciences. 2018;(1):43-56
Abstract
BACKGROUND Many studies with inconsistent results have assessed the association of Brain-derived neurotrophic factor (BDNF) gene polymorphisms with prevalence of obesity and overweight. This review aims to provide a summary of the literature evaluating the relation between BDNF genotype and body mass index (BMI). METHODS A systematic search through PubMed, Scopus, Science direct, Ovid and Cochrane was performed. We included observational studies with cross-sectional and case-control design, which investigated relationship between all kinds of BDNF polymorphisms with BMI, as a representative index of obesity and overweight. Newcastle-Ottawa Scale was used to assess the quality of included articles. RESULTS Thirty five studies were included in quantitative synthesis. Analyses were performed separately using OR, β coefficient and mean. Significant association were documented between rs925946 and BMI (OR=1.12, 95% CI=1.08-1.17, P heterogeneity=0.317), rs10501087 and BMI (OR=1.14, 95% CI=1.04-1.24, P heterogeneity=0.861), rs6265 and BMI (OR=1.13, 95% CI=1.07-1.19, P heterogeneity=0.406), rs988712 and BMI (OR=1.29, 95% CI=1.18-1.40, P heterogeneity=0.602). According to pooled β coefficient analysis, significant result was only observed in the rs925946 polymorphism subgroup. Pooled mean analysis showed that overall effects for the association between BDNF polymorphisms and BMI were not statistically significant. CONCLUSION This meta-analysis suggests that some polymorphisms in BDNF gene including rs925946, rs10501087, rs6265 and rs988712 can be considered as genetic determinants of obesity.
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Developmental origins of adult health and disease: The metabolic role of BDNF from early life to adulthood.
Briana, DD, Malamitsi-Puchner, A
Metabolism: clinical and experimental. 2018;:45-51
Abstract
Accumulating evidence suggests that the origins of adult disease may occur during fetal life. Thus, the concept of "developmental programming" has been introduced and supported by epidemiological and experimental data. This concept supports the idea that the nutritional and hormonal status during pregnancy could interfere in metabolism control. The mechanisms responsible for this "developmental programming" remain poorly documented. Current research indicates that neurotrophins and particularly brain-derived neurotrophic factor (BDNF) may play a crucial role in this process. Although mainly expressed in the nervous system, BDNF and its receptor, tropomyosin-related kinase B (TrkB), are immunolocalized in several regions of the human placenta and have important functions during pregnancy. BDNF serves widespread roles in regulating energy homeostasis in both fetuses and adults, by controlling patterns of fetal growth, adult feeding and physical activity, and by regulating glucose metabolism in peripheral tissues. Impaired BDNF signaling may be implicated in the etiopathogenesis of the metabolic syndrome. Novel BDNF-focused interventions are being developed for obesity, diabetes and neurological disorders. The aim of this article is to provide a brief comprehensive literary review regarding the potential implications of BDNF in "developmental programming", through regulation of metabolism and energy balance from early life to adulthood.
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The role of brain-derived neurotrophic factor and its single nucleotide polymorphisms in stroke patients.
Kotlęga, D, Peda, B, Zembroń-Łacny, A, Gołąb-Janowska, M, Nowacki, P
Neurologia i neurochirurgia polska. 2017;(3):240-246
Abstract
Stroke is the main cause of motoric and neuropsychological disability in adults. Recent advances in research into the role of the brain-derived neurotrophic factor in neuroplasticity, neuroprotection and neurogenesis might provide important information for the development of new poststroke-rehabilitation strategies. It plays a role as a mediator in motor learning and rehabilitation after stroke. Concentrations of BDNF are lower in acute ischemic-stroke patients compared to controls. Lower levels of BDNF are correlated with an increased risk of stroke, worse functional outcomes and higher mortality. BDNF signalling is dependent on the genetic variation which could affect an individual's response to recovery after stroke. Several single nucleotide polymorphisms of the BDNF gene have been studied with regard to stroke patients, but most papers analyse the rs6265 which results in a change from valine to methionine in the precursor protein. Subsequently a reduction in BDNF activity is observed. There are studies indicating the role of this polymorphism in brain plasticity, functional and morphological changes in the brain. It may affect the risk of ischemic stroke, post-stroke outcomes and the efficacy of the rehabilitation process within physical exercise and transcranial magnetic stimulation. There is a consistent trend of Met alleles' being connected with worse outcomes and prognoses after stroke. However, there is no satisfactory data confirming the importance of Met allele in stroke epidemiology and the post-stroke rehabilitation process. We present the current data on the role of BDNF and polymorphisms of the BDNF gene in stroke patients, concentrating on human studies.
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The Efficacy of Non-Pharmacological Interventions on Brain-Derived Neurotrophic Factor in Schizophrenia: A Systematic Review and Meta-Analysis.
Sanada, K, Zorrilla, I, Iwata, Y, Bermúdez-Ampudia, C, Graff-Guerrero, A, Martínez-Cengotitabengoa, M, González-Pinto, A
International journal of molecular sciences. 2016;(10)
Abstract
Several studies have investigated the relationship between non-pharmacological interventions (NPIs) and peripheral brain-derived neurotrophic factor (BDNF) in schizophrenia patients. We conducted a systematic review and meta-analysis to review the efficacy of NPIs on peripheral serum and plasma BDNF in subjects with schizophrenia (including schizoaffective disorder). Meta-analyses were conducted to examine the effects of NPIs on blood BDNF levels by using the standardized mean differences (SMDs) between the intervention groups and controls. In total, six randomized controlled trials with 289 participants were included. Of them, five studies used exercise, physical training or diet products. One study used cognitive training. Overall, the BDNF levels in the NPI group increased significantly compared with the control groups (SMD = 0.95, 95% confidence interval (CI) = 0.07 to 1.83, p = 0.03). Subgroup analyses indicated beneficial effects of a non-exercise intervention on peripheral BDNF levels (SMD = 0.41, 95% CI = 0.08 to 0.74, p = 0.01). Meta-regression analyses showed that the completion rate influenced the variation in SMD (p = 0.01). Despite insufficient evidence to draw a conclusion, our results suggest that use of NPIs as adjunctive treatments, specifically non-exercise interventions, may affect positively serum or plasma BDNF in patients with schizophrenia.
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10.
[Neurotrophic effects of lithium stimulate the reduction of ischemic and neurodegenerative brain damage].
Pronin, AV, Gogoleva, IV, Torshin, IY, Gromovа, OA
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2016;(2):99-108
Abstract
For over 60 years, high doses of lithium (hundreds of milligrams of elemental lithium) have being used to treat bipolar disorder. However, only during the past 20 years the relevant basic and clinical studies have shown that neuroprotective and neurotrophic effects of lithium are possible in much smaller doses ( hundreds of micrograms of elemental lithium). These data indicate a significant potential for the clinical applications of lithium-based drugs in modern neurology for the purposes of prevention and treatment of neurodegenerative and ischemic pathologies. Pharmacological and molecular biology studies indicated that the inhibition of glycogen synthase kinase-syntentase-3 (GSK-3) and induction of brain-derived neurotrophic factors are the main mechanisms of neurotropic actions of lithium. Also, by inhibiting the NMDA receptors, lithium regulates the calcium homeostasis and inhibits the activation of calcium-dependent apotosis. These and other molecular mechanisms of lithium action protect neurons from ischemia and neurodegeneration thus contributing to a significant reduction of neurological deficit in various models of stroke and neurodegenerative diseases.