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Neuroinflammation is associated with several neurological disorders including temporal lobe epilepsy. Seizures themselves can induce neuroinflammation. In an in vivo model of epilepsy, the supplementation of brain-derived neurotropic factor (BDNF) and fibroblast growth factor-2 (FGF-2) using a Herpes-based vector reduced epileptogenesis-associated neuroinflammation. The aim of this study was to test whether the attenuation of the neuroinflammation obtained in vivo with BDNF and FGF-2 was direct or secondary to other effects, for example, the reduction in the severity and frequency of spontaneous recurrent seizures. An in vitro model of neuroinflammation induced by lipopolysaccharide (LPS, 100 ng/mL) in a mouse primary mixed glial culture was used. The releases of cytokines and NO were analyzed via ELISA and Griess assay, respectively. The effects of LPS and neurotrophic factors on cell viability were determined by performing an MTT assay. BDNF and FGF-2 were tested alone and co-administered. LPS induced a significant increase in pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and NO. BDNF, FGF-2, and their co-administration did not counteract these LPS effects. Our study suggests that the anti-inflammatory effect of BDNF and FGF-2 in vivo in the epilepsy model was indirect and likely due to a reduction in seizure frequency and severity.

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Indoleamine 2,3-dioxygenase 2 (IDO2) is an enzyme of the tryptophan-kynurenine pathway that is constitutively expressed in the brain. To provide insight into the physiological role of IDO2 in the brain, behavioral and neurochemical analyses in IDO2 knockout (KO) mice were performed. IDO2 KO mice showed stereotyped behavior, restricted interest and social deficits, traits that are associated with behavioral endophenotypes of autism spectrum disorder (ASD). IDO2 was colocalized immunohistochemically with tyrosine-hydroxylase-positive cells in dopaminergic neurons. In the striatum and amygdala of IDO2 KO mice, decreased dopamine turnover was associated with increased α-synuclein level. Correspondingly, levels of downstream dopamine D1 receptor signaling molecules such as brain-derived neurotrophic factor and c-Fos positive proteins were decreased. Furthermore, decreased abundance of ramified-type microglia resulted in increased dendritic spine density in the striatum of IDO2 KO mice. Both chemogenetic activation of dopaminergic neurons and treatment with methylphenidate, a dopamine reuptake inhibitor, ameliorated the ASD-like behavior of IDO2 KO mice. Sequencing analysis of exon regions in IDO2 from 309 ASD samples identified a rare canonical splice site variant in one ASD case. These results suggest that the IDO2 gene is, at least in part, a factor closely related to the development of psychiatric disorders.

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Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin gene family gene that encodes proteins vital for the growth, maintenance, and survival of neurons in the nervous system. The study aimed to screen natural compounds against BDNF variant (V66M), which affects memory, cognition, and mood regulation. BDNF variant (V66M) as a target structure was selected, and Vitamin D, Curcumin, Vitamin C, and Quercetin as ligands structures were taken from PubChem database. Multiple tools like AUTODOCK VINA, BIOVIA discovery studio, PyMOL, CB-dock, IMOD server, Swiss ADEMT, and Swiss predict ligands target were used to analyze binding energy, interaction, stability, toxicity, and visualize BDNF-ligand complexes. Compounds Vitamin D3, Curcumin, Vitamin C, and Quercetin with binding energies values of - 5.5, - 6.1, - 4.5, and - 6.7 kj/mol, respectively, were selected. The ligands bind to the active sites of the BDNF variant (V66M) via hydrophobic bonds, hydrogen bonds, and electrostatic interactions. Furthermore, ADMET analysis of the ligands revealed they exhibited sound pharmacokinetic and toxicity profiles. In addition, an MD simulation study showed that the most active ligand bound favorably and dynamically to the target protein, and protein-ligand complex stability was determined. The finding of this research could provide an excellent platform for discovering and rationalizing novel drugs against stress related to BDNF (V66M). Docking, preclinical drug testing and MD simulation results suggest Quercetin as a more potent BDNF variant (V66M) inhibitor and forming a more structurally stable complex.

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Neuropsychiatric disorders including Alzheimer's disease (AD) may cause gut inflammation and dysbiosis. Gut inflammation-suppressing probiotics alleviate neuropsychiatric disorders. Herein, to understand whether anti-inflammatory probiotics Lactobacillus mucosae NK41 and Bifidobacterium longum NK46, which suppressed tumor necrosis factor (TNF)-α expression in lipopolysaccharide (LPS)-stimulated macrophages, could alleviate cognitive impairment, we first examined their effects on cognitive function, gut inflammation, and gut microbiota composition in 5xFAD-transgenic mice. Oral administration of NK41 or NK46 decreased cognitive impairment-like behaviors, hippocampal amyloid-ß (Aß), TNF-α and interleukin (IL)-1ß expression, hippocampal NF-κB+Iba1+ cell population, and Aß accumulation, while hippocampal brain-derived neurotropic factor (BDNF) and IL-10 expression and BDNF+NeuN+ cell population increased. They also decreased TNF-α and IL-1ß expression and NF-κB+CD11c+ cell population in the colon. They also reduced fecal and blood LPS levels and gut Proteobacteria and Verrucomicrobia populations (including Akkkermansiaceae), which are positively associated with hippocampal TNF-α and fecal LPS levels and negatively correlated with hippocampal BDNF level. However, they increased Odoribactericeae, which positively correlated with BDNF expression level and TNF-α to IL-10 expression ratio. The combination of NK41 and NK46 (4:1, NKc), which potently inhibited TNF-α expression in LPS-stimulated macrophages, additively alleviated cognitive impairment-like behaviors in 5xFAD-transgenic or aged mice. NKc increased hippocampal BDNF+NeuN+ cell population and BDNF expression in 5xFAD-transgenic or aged mice, while hippocampal TNF-α and IL-1ß expression decreased. NKc also decreased TNF-α and IL-1ß expression in the colon and LPS levels in the blood and feces. These findings suggest that gut bacteria and its product LPS may be closely connected with occurrence of cognitive impairment and neuroinflammation and the combination of NK41 and NK46 can additively alleviate cognitive impairment and neuroinflammation by inducing NF-κB-suppressed BDNF expression and suppressing LPS-producing gut bacteria.

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Brain-derived neurotropic factor (BDNF) has been shown to be expressed in many nonneuronal tissues including skeletal muscle. Skeletal muscle BDNF has been studied regarding its function in metabolism and exercise; however, less is known about its role in skeletal muscle injury. The precursor to BDNF, proBDNF, has an unknown role in skeletal muscle. The levels of proBDNF, mature BDNF, and their receptors were compared in the skeletal muscle and brain tissues of C57BL/6J mice. Tourniquet-induced hind limb ischemia-reperfusion injury was used to assess the function of skeletal muscle-derived proBDNF in skeletal muscle injury. Skeletal muscle-specific knockout of BDNF and pharmacological inhibition of p75NTR, the proBDNF receptor, were used to determine the role of proBDNF-p75NTR signaling. We show for the first time that proBDNF is the predominantly expressed form of BDNF in skeletal muscle and that proBDNF is significantly upregulated in skeletal muscle following hind limb ischemia-reperfusion injury. Skeletal muscle-specific knockout of BDNF blunted the inflammatory response in the injured tissue and appears to be mediated by the proBDNF-p75NTR pathway, as shown by the pharmacological inhibition of p75NTR. These findings suggest that skeletal muscle proBDNF plays a critical role in driving the inflammatory response following skeletal muscle injury.

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Traumatic brain injury (TBI) causes transitory or permanent neurological and cognitive impairments, which can intensify over time due to secondary neuronal death. However, no therapy currently exists that can effectively treat brain injury following TBI. Here, we evaluate the therapeutic potential of irradiated engineered human mesenchymal stem cells over-expressing brain-derived neurotrophic factor (BDNF), which we denote by BDNF-eMSCs, in protecting the brain against neuronal death, neurological deficits, and cognitive impairment in TBI rats. BDNF-eMSCs were administered directly into the left lateral ventricle of the brain in rats that received TBI damage. A single administration of BDNF-eMSCs reduced TBI-induced neuronal death and glial activation in the hippocampus, while repeated administration of BDNF-eMSCs reduced not only glial activation and delayed neuronal loss but also enhanced hippocampal neurogenesis in TBI rats. In addition, BDNF-eMSCs reduced the lesion area in the damaged brain of the rats. Behaviorally, BDNF-eMSC treatment improved the neurological and cognitive functions of the TBI rats. The results presented in this study demonstrate that BDNF-eMSCs can attenuate TBI-induced brain damage through the suppression of neuronal death and increased neurogenesis, thus enhancing functional recovery after TBI, indicating the significant therapeutic potential of BDNF-eMSCs in the treatment of TBI.

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Background: Red ginseng (RG) alleviates psychiatric disorders. Fermented red ginseng (fRG) alleviates stress-induced gut inflammation. Gut dysbiosis causes psychiatric disorders with gut inflammation. To understand the gut microbiota-mediated action mechanism of RG and fRG against anxiety/depression (AD), we investigated the effects of RG, fRG, ginsenoside Rd, and 20(S)-ß-D-glucopyranosyl protopanaxadiol (CK) on gut microbiota dysbiosis-induced AD and colitis in mice. Methods: Mice with AD and colitis were prepared by exposing to immobilization stress (IS) or transplanting the feces of patients with ulcerative colitis and depression (UCDF). AD-like behaviors were measured in the elevated plus maze, light/dark transition, forced swimming, and tail suspension tests. Results: Oral gavage of UCDF increased AD-like behaviors and induced neuroinflammation, gastrointestinal inflammation, and gut microbiota fluctuation in mice. Oral administration of fRG or RG treatment reduced UCDF-induced AD-like behaviors, hippocampal and hypothalamic IL-6 expression, and blood corticosterone level, whereas UCDF-suppressed hippocampal BDNF+NeuN+ cell population and dopamine and hypothalamic serotonin levels increased. Furthermore, their treatments suppressed UCDF-induced colonic inflammation and partially restored UCDF-induced gut microbiota fluctuation. Oral administration of fRG, RG, Rd, or CK also decreased IS-induced AD-like behaviors, blood IL-6 and corticosterone and colonic IL-6 and TNF-α levels, and gut dysbiosis, while IS-suppressed hypothalamic dopamine and serotonin levels increased. Conclusion: Oral gavage of UCDF caused AD, neuroinflammation, and gastrointestinal inflammation in mice. fRG mitigated AD and colitis in UCDF-exposed mice by the regulation of the microbiota-gut-brain axis and IS-exposed mice by the regulation of the hypothalamic-pituitary-adrenal axis.

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INTRODUCTION: Use of high-dose androgens causes drastic changes in hormonal milieu and is associated with adverse medical, psychological, and cognitive effects. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors plays a critical role in neuroplasticity, with implications for cognitive function and mental health. The impact of long-term, high-dose androgen use on BDNF in a natural setting has not been investigated. This study examined the association between long-term androgen exposure and BDNF levels, and the links between BDNF, heavy resistance exercise, hormones, androgens, and mental health. METHODS: We measured serum levels of BDNF and sex steroid hormones in male weightlifters (N = 141) with a history of current (n = 59), past (n = 29), or no (n = 52) androgen use. All participants completed questionnaires assessing maximum strength and measures of anxiety and depression. Group differences in BDNF were tested using general linear models adjusting for age and associations between BDNF and strength, anxiety, and depression using Pearson's or Kendall's correlations. RESULTS: Both current (mean: 44.1 ng/mL [SD: 12.7]) and past (39.5 ng/mL [SD: 13.9]) androgen users showed lower serum BDNF levels compared to nonusing controls (51.5 [SD: 15.3], p < 0.001, ηp2 = 0.10). BDNF levels were negatively related to maximal strength, and with hormonal status in past androgen users, but no significant associations were found with measures of depression and anxiety. CONCLUSION: Lower circulating BDNF concentrations in current and past androgen users suggest that high-dose androgen exposure triggers persistent changes in BDNF expression. Further studies are needed to verify the relationship and its potential clinical implications.

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African American/Black individuals have been excluded from several lines of prominent neuroscience research, despite exhibiting disproportionately higher risk factors associated with the onset and magnitude of neurodegeneration. Therefore, the objective of the current investigation was to examine potential relationships among brain derived neurotropic factor (BDNF), peripheral vascular function, and body composition with cognition in a sample of midlife, African American/Black individuals. Midlife adults (men: n = 3, 60 ± 4 years; women: n = 9, 58 ± 5 years) were invited to complete two baseline visits separated by 4 weeks. Peripheral vascular function was determined by venous occlusion plethysmography, a dual-energy X-ray absorptiometry was used to determine body composition, and plasma was collected to quantify BDNF levels. The CNS Vital Signs computer-based test was used to provide scores on numerous cognitive domains. The principal results included that complex attention (r = 0.629) and processing speed (r = 0.734) were significantly (p < 0.05) related to the plasma BDNF values. However, there was no significant (p > 0.05) relationship between any vascular measure and any cognitive domain or BDNF value. Secondary findings included the relationship between lean mass and peak hyperemia (r = 0.758) as well as total hyperemia (r = 0.855). The major conclusion derived from these results was that there is rationale for future clinical trials to use interventions targeting increasing BDNF to potentially improve cognition. Additionally, these results strongly suggest that clinicians aiming to improve cognitive health via improvements in the known risk factor of vascular function should consider interventions capable of promoting the size and function of skeletal muscle, especially in the African American/Black population.

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Background: Soy peptide, when consumed as a functional food, has been reported to improve cognitive function. This study aimed to verify the combined effect of soy peptide supplementation and exercise on cognitive function among community-dwelling older adults in Japan. Methods: In this population-based, non-blinded randomized controlled trial, 72 community-dwelling older adults who were independent in activities of daily living were randomly assigned to an "exercise plus nutrition" program (Ex + Nt group, n = 36) or an exercise program (Ex group, n = 36). For 3 months, both groups participated in an exercise and cognitive training regimen once per week, with the Ex + Nt group receiving soy supplementation once per week. Pre- and post-intervention measurements included grip strength, gait speed, skeletal muscle mass index, and scores on Addenbrooke's Cognitive Examination-Revised, trail-making test A, and the Geriatric Depression Scale. Participant enrollment for this study started in January 2019 and ended in April 2019. Results: Exercise training increased the skeletal muscle mass index by 2.0% and 3.0% in the Ex + Nt and Ex groups, respectively. The Ex + Nt group exhibited a significant 0.3-point increase in the memory score. Conclusion: A 3-month exercise program combined with soy peptide supplementation may be effective in improving both motor and memory function in community-dwelling older adults.

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Diabetes Mellitus (DM) currently ranks as the most common endocrine disorder worldwide. Current opinion views DM as a group of heterogeneous metabolic diseases characterized by hyperglycemia triggered by defects in the ability of the body to produce or use insulin in type 1 and 2 DM, respectively. Brain-derived neurotrophic factor (BDNF), one of the neurotrophin family of growth factors, has been linked to the pathogenesis of DM and insulin resistance. Moreover, vitamin D has been associated with insulin resistance and DM. Recently, the interactions between vitamin D and BDNF have been investigated in diabetic rats. However, this correlation has never been investigated in humans. Thus, the aim of the present study was to assess the alterations in serum BDNF and vitamin D levels in T2DM patients in Jordan, prior to and following vitamin D supplementation. A combination of non-experimental case-control and experimental designed studies were utilized to assess the relationship between serum BDNF and vitamin D levels in T2DM patients. The levels of BDNF and vitamin D were measured using commercially available ELISA kits, and fasting blood glucose (FBG) and HbA1c levels were measured in medical labs. The results showed that diabetic patients had lower levels of serum vitamin D and higher levels of BDNF compared with the healthy controls. Moreover, linear regression analysis indicated that BDNF levels were inversely correlated with serum vitamin D levels. Furthermore, vitamin D supplementation significantly increased vitamin D serum levels and decreased BDNF serum levels in diabetic patients. Intriguingly, FBG and HbA1c levels were significantly improved post vitamin D supplementation. These data demonstrate a positive effect of vitamin D supplementation in diabetic patients suggesting the implementation of vitamin D as part of future T2DM treatment plans. However, additional studies are needed to investigate the direct link between vitamin D, BDNF, and T2DM.

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Posttraumatic stress disorder (PTSD) is an anxiety disorder that occurs following exposure to somatic or psychotic trauma. Physical activity is known to improve symptoms of certain neuropsychiatric disorders. However, the role of exercise on acquired PTSD-like phenotype was not examined. The present study investigated the effects of prior moderate treadmill exercise on anxiety-like behaviors, serum corticosterone and BDNF levels, hippocampal BDNF and mRNA expression of apoptotic - related proteins in the single prolonged stress (SPS) as an animal model of PTSD in rats. Male and female rats underwent a regular treadmill exercise regimen (4 weeks, 5 days per week). Following the exercise, rats were exposed to SPS (restraint for 2 h, forced swimming for 20 min and ether anesthesia), and then they were kept undisturbed for 14 days. After testing anxiety-like behaviours in the elevated plus maze, the levels of corticosterone and BDNF in serum and BDNF and apoptosis markers (Bax, Bcl-2, and Caspase) in hippocampus were measured. Sedentary male and female SPS rats significantly (Ps ranging <0.05 to <0.0001) exhibited increased anxiety levels in the elevated plus maze, enhanced serum corticosterone, reduced serum and hippocampal BDNF and enhanced hippocampal apoptosis than the corresponding control group. Prior exercise significantly (Ps ranging <0.05 to <0.001) alleviated all SPS-induced behavioral and biochemical alterations as compared with the sedentary SPS rats. There were no significant differences in serum and hippocampal BDNF and serum corticosterone levels and hippocampal apoptotic markers between male and female rats in all of groups. Our findings strongly support that short term prior exercise training can prevent the harmful effects of traumatic events, and the resulting trauma-related disorders in both sexes.

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BACKGROUND: There is evidence that brain-derived neurotropic factor (BDNF) plays a protective role in the brain. Peripheral levels of BDNF correlate with its concentration in the brain. Previous studies have revealed lower serum BDNF levels in patients with mental illnesses. In most studies serum BDNF correlates negatively with psychiatric disorders and disease severity. Most studies in this field are on psychiatric diagnosis and personality traits. The aim of our study is to explore associations between general psychiatric symptoms, independent of diagnostic groups, and serum BDNF as well as the inflammatory biomarker high-sensitive CRP (hs-CRP). Comparison between the group regularly using psychotropic medication and those not using psychotropic medication is conducted. METHODS: The study is a cross sectional study with 132 participants from a general open inpatient psychiatric ward at the Nordland Hospital Trust, Bodoe, Norway. Participants were assessed on serum levels of BDNF and hs-CRP. Psychiatric symptoms were assessed by a self-rating scale (Symptom check list, SCL-90- R). Multiple linear regression model was used for statistical analyses of associations between levels of BDNF, hs-CRP and symptoms. RESULTS: We found a positive association (p < 0.05), for most SCL-90 symptom clusters with BDNF in the psychotropic medication-free group. No associations were found in the group of patients using psychotropic medication, except one, the paranoid ideation cluster (p 0.022). No associations were found between hs-CRP and symptom clusters. CONCLUSION: We found no relation between symptom clusters and the inflammatory biomarker hs-CRP. Serum BDNF levels were positively associated with intensity of psychiatric symptoms in the group of patients not using psychotropic medication. Our findings are in conflict with several previous studies reporting increased hs-CRP as well as decreased rather than increased BDNF in mental suffering. Patients on psychotropic medication may not require the same upregulation because the medication is modulating the underlying biological pathology.

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We investigated whether irradiated brain-derived neurotropic factor (BDNF)-overexpressing engineered human mesenchymal stem cells (BDNF-eMSCs) improve paracrine efficiency and, thus, the beneficial potency of naïve MSCs against severe hypoxic ischemic (HI) brain injury in newborn rats. Irradiated BDNF-eMSCs hyper-secreted BDNF > 10 fold and were >5 fold more effective than naïve MSCs in attenuating the oxygen-glucose deprivation-induced increase in cytotoxicity, oxidative stress, and cell death in vitro. Only the irradiated BDNF-eMSCs, but not naïve MSCs, showed significant attenuating effects on severe neonatal HI-induced short-term brain injury scores, long-term progress of brain infarct, increased apoptotic cell death, astrogliosis and inflammatory responses, and impaired negative geotaxis and rotarod tests in vivo. Our data, showing better paracrine potency and the resultant better therapeutic efficacy of the irradiated BDNF-eMSCs, compared to naïve MSCs, suggest that MSCs transfected with the BDNF gene might represent a better, new therapeutic strategy against severe neonatal HI brain injury.

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Objective: To evaluate whether a common polymorphism (Val66Met) in the gene for brain-derived neurotrophic factor (BDNF)-a gene thought to influence plasticity-contributes to inter-individual variability in responses to continuous theta-burst stimulation (cTBS), and explore whether variability in stimulation-induced plasticity among Val66Met carriers relates to differences in stimulation intensity (SI) used to probe plasticity. Methods: Motor evoked potentials (MEPs) were collected from 33 healthy individuals (11 Val66Met) prior to cTBS (baseline) and in 10 min intervals immediately following cTBS for a total of 30 min post-cTBS (0 min post-cTBS, 10 min post-cTBS, 20 min post cTBS, and 30 min post-cTBS) of the left primary motor cortex. Analyses assessed changes in cortical excitability as a function of BDNF (Val66Val vs. Val66Met) and SI. Results: For both BDNF groups, MEP-suppression from baseline to post-cTBS time points decreased as a function of increasing SI. However, the effect of SI on MEPs was more pronounced for Val66Met vs. Val66Val carriers, whereby individuals probed with higher vs. lower SIs resulted in paradoxical cTBS aftereffects (MEP-facilitation), which persisted at least 30 min post-cTBS administration. Conclusions: cTBS aftereffects among BDNF Met allele carriers are more variable depending on the SI used to probe cortical excitability when compared to homozygous Val allele carriers, which could, to some extent, account for the inconsistency of previously reported cTBS effects. Significance: These data provide insight into the sources of cTBS response variability, which can inform how best to stratify and optimize its use in investigational and clinical contexts.

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An adverse maternal environment (AME) predisposes adult offspring toward cognitive impairment in humans and mice. However, the underlying mechanisms remain poorly understood. Epigenetic changes in response to environmental exposure may be critical drivers of this change. Epigenetic regulators, including microRNAs, have been shown to affect cognitive function by altering hippocampal neurogenesis which is regulated in part by brain-derived neurotropic factor (BDNF). We sought to investigate the effects of AME on miR profile and their epigenetic characteristics, as well as neurogenesis and BDNF expression in mouse hippocampus. Using our mouse model of AME which is composed of maternal Western diet and prenatal environmental stress, we found that AME significantly increased hippocampal miR-10b-5p levels. We also found that AME significantly decreased DNA methylation and increased accumulations of active histone marks H3 lysine (K) 4me3, H3K14ac, and -H3K36me3 at miR-10b promoter. Furthermore, AME significantly decreased hippocampal neurogenesis by decreasing cell numbers of Ki67+ (proliferation marker), NeuroD1+ (neuronal differentiation marker), and NeuN+ (mature neuronal marker) in the dentate gyrus (DG) region concurrently with decreased hippocampal BDNF protein levels. We speculate that the changes in epigenetic profile at miR-10b promoter may contribute to upregulation of miR-10b-5p and subsequently lead to decreased BDNF levels in a model of impaired offspring hippocampal neurogenesis and cognition in mice.

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Maternal diabetes during pregnancy affects the development of hippocampus in the offspring. Brain-derived neurotrophic factor (BDNF) has received increasing attention for its role in regulating the survival and differentiation of neuronal cells in developing and adult brain. In the current study, we evaluated the effects of maternal diabetes and insulin treatment on expression and distribution pattern of BDNF in the hippocampus of neonatal rats at the first two postnatal weeks. We found no differences in hippocampal expression of BDNF between diabetics with normal control or insulin treated neonatal rats at postnatal day (P0) (P > 0.05 each). Nevertheless, there was a marked BDNF downregulation in both sides' hippocampi of male/female diabetic group in two-week-old offspring (P ≤ 0.05 each). Furthermore, the numerical density of BDNF+ cells was significantly reduced in the right/left dentate gyrus (DG) of male and female newborns born to diabetic animals at all studied postnatal days (P ≤ 0.05 each). In addition, a lower number of reactive cells have shown in the all hippocampal subareas in the diabetic pups at P14 (P ≤ 0.05 each). Our results have demonstrated that the insulin-treatment improves some of the negative impacts of diabetes on the expression of hippocampal BDNF in the newborns. We conclude that diabetes in pregnancy bilaterally disrupts the expression of BDNF in the hippocampus of the both male and female newborns at early postnatal days. In addition, good glycemic control by insulin in the most cases is sufficient to prevent the alterations in expression of BDNF protein in developing hippocampus.

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BACKGROUND: Brain-derived neurotropic factor (BDNF) plays a vital role in neuronal survival and plasticity and facilitates long-term potentiation, essential for memory. Alterations in BDNF signaling have been associated with cognitive impairment, dementia, and Alzheimer's disease. Although peripheral BDNF levels are reduced in dementia patients, it is unclear whether changes in BDNF levels precede or follow dementia onset. OBJECTIVE: In the present study, we examined the association between BDNF plasma levels and dementia risk over a follow-up period of up to 16 years. METHODS: Plasma BDNF levels were assessed in 758 participants of the Rotterdam Study. Dementia was assessed from baseline (1997-1999) to follow-up until January 2016. Associations of plasma BDNF and incident dementia were assessed with Cox proportional hazards models, adjusted for age and sex. Associations between plasma BDNF and lifestyle and metabolic factors are investigated using linear regression. RESULTS: During a follow up of 3,286 person-years, 131 participants developed dementia, of whom 104 had Alzheimer's disease. We did not find an association between plasma BDNF and risk of dementia (adjusted hazard ratio 0.99; 95%CI 0.84-1.16). BDNF levels were positively associated with age (B = 0.003, SD = 0.001, p = 0.002), smoking (B = 0.08, SE = 0.01, p = < 0.001), and female sex (B = 0.03, SE = 0.01, p = 0.03), but not with physical activity level (B = -0.01, SE = 0.01, p = 0.06). CONCLUSION: The findings suggest that peripheral BDNF levels are not associated with an increased risk of dementia.

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