BDNF Levels Research Articles

Spinal cord stimulation induces Neurotrophin-3 to improve diabetic foot disease.

Low-extremity ischemic disease is a common complication in diabetic patients, leading to reduced quality of life and potential amputation. This study investigated the therapeutic effect of spinal cord stimulation (SCS) on patients with diabetic foot disease and a rat model of diabetic foot injury. SCS was applied to patients with diabetic foot disease, with clinical assessments performed before and after therapy. Blood levels of NGF, BDNF, and NT-3 were determined by ELISA. A rat model of diabetic foot injury was established to validate NT-3's role in SCS therapy. SCS therapy improved the condition of patients with diabetic ischemic foot disease and promoted wound healing in the rat model. NT-3 levels significantly increased after SCS therapy in both patients and rats. Recombinant NT-3 administration improved wound healing and re-vascularization in the rat model, while NT-3 neutralization abrogated SCS's therapeutic effect. SCS improves the condition of patients with diabetic ischemic foot disease by inducing NT-3 production. Both SCS and NT-3 supplementation show therapeutic potential for ameliorating diabetic foot disease.

Lactobacillus Helveticus Improves Controlled Cortical Impact Injury-Generated Neurological Aberrations by Remodeling of Gut-Brain Axis Mediators.

Considerable studies augured the potential of gut microbiota-based interventions in brain injury-associated complications. Based on our earlier study results, we envisaged the sex-specific neuroprotective effect of Lactobacillus helveticus by remodeling of gut-brain axis. In this study, we investigated the effect of L. helveticus on neurological complications in a mouse model of controlled cortical impact (CCI). Adult, male and female, C57BL/6 mice underwent CCI surgery and received L. helveticus treatment for six weeks. Sensorimotor function was evaluated via neurological severity score and rotarod test. Long-term effects on anxiety-like behavior and cognition were assessed using the elevated-zero maze (EZM) and novel object recognition test (NORT). Brain perilesional area, blood, colon, and fecal samples were collected post-CCI for molecular biology analysis. CCI-operated mice displayed significant neurological impairments at 1-, 3-, 5-, and 7-days post-injury (dpi) and exhibited altered behavior in EZM and NORT compared to sham-operated mice. However, these behavioral changes were ameliorated in mice receiving L. helveticus. GFAP, Iba-1, TNF-α, and IL-1β expressions and corticotrophin-releasing hormone (CRH) levels were elevated in the perilesional cortex of CCI-operated male/female mice. These elevated biomarkers and decreased BDNF levels in both male/female mice were modified by L. helveticus treatment. Additionally, L. helveticus treatment restored altered short-chain fatty acids (SCFAs) levels in fecal samples and improved intestinal integrity but did not affect decreased plasma levels of progesterone and testosterone in CCI mice. These results indicate that L. helveticus exerts beneficial effects in the CCI mouse model by mitigating inflammation and remodeling of gut microbiota-brain mediators.

Features оf Changes in the Level of Neurotransmitters and Markers of Neurodegeneration in the Brain of Rats with Experimental Parkinson’s Disease Against the Background of Course Therapy with Steroid Glycoalkaloids

Parkinson’s disease is a chronic neurodegenerative disease, one of the pathobiochemical manifestations of which is an imbalance of neurotransmitters in the brain. The aim of this work is to study the effect of glycoalkaloids on changes in the level of neurotransmitters and markers of brain neurodegeneration in rats with experimental Parkinson’s disease. Parkinson’s disease was modeled in animals by intracerebral administration of rotenone. The studied glycoalkaloids were administered orally at a dose of 0.06 mg / kg, a course of 28 days after pathology modeling. The study found that the use of the analyzed glycoalkaloids did not affect the concentration of dopamine and serotonin, and also significantly (p 0.05) reduced the level of ACh by 35.9% and increased the level of GABA by 55.1%, reduced the concentration of S100β protein by 68.6% and increased the level of BDNF by 52.4%.

Darbepoetin alpha has an anxiolytic and anti-neuroinflammatory effect in male rats

AimsWe aimed to investigate the anxiolytic effect of darbepoetin alpha (DEPO), an erythropoietin derivative, in a neuroinflammation model regarding different behaviors and biological pathways.MethodsForty adult male Wistar albino rats were divided into four groups (control, LPS, DEPO, and DEPO + LPS). The rats were treated with 5 µg /kg DEPO once a week for four weeks, after which neuroinflammation was induced with 2 mg/kg lipopolysaccharide (LPS). The elevated plus maze, open-field, and light‒dark box tests were conducted to assess anxiety levels. Harderian gland secretions were scored via observation. Tumor necrosis factor alpha (TNF-α), Interleukin-1-beta (IL-1β), brain-derived growth factor (BDNF), serotonin, cortisol, total antioxidant/oxidant (TAS/TOS), and total/free thiol levels were measured in the prefrontal cortex, striatum, and serum.ResultsDEPO had a potent anxiolytic effect on both DEPO and DEPO + LPS groups. Compared to the control group, DEPO administration caused an increase in serotonin and BDNF levels and decreased basal cortisol and TNF-α levels in naive rats. IL-1β did not alter after DEPO administration in naive rats. Prophylactic DEPO treatment remarkably downregulated cortisol, IL-1β, and TNF-α in the DEPO + LPS group. In addition, prophylactic DEPO administration significantly attenuated the decrease in serotonin and BDNF levels in the DEPO + LPS group. Furthermore, DEPO ameliorated excessive harderian gland secretion in the DEPO + LPS group. Compared with those in the control group, the free thiol content in the serum increased after DEPO administration. No similar effect was seen in the DEPO + LPS group receiving prophylactic DEPO. TAS showed no difference among all experimental groups. DEPO administration increased TOS and OSI in the serum and prefrontal cortex but not in the striatum. This effect was not seen in the DEPO + LPS group.ConclusionDarbepoetin alpha had an anxiolytic effect on many physiological mechanisms in a neuroinflammation model and naive rats.

FAAH Inhibition Counteracts Neuroinflammation via Autophagy Recovery in AD Models

Endocannabinoids have attracted great interest for their ability to counteract the neuroinflammation underlying Alzheimer’s disease (AD). Our study aimed at evaluating whether this activity was also due to a rebalance of autophagic mechanisms in cellular and animal models of AD. We supplied URB597, an inhibitor of Fatty-Acid Amide Hydrolase (FAAH), the degradation enzyme of anandamide, to microglial cultures treated with Aβ25-35, and to Tg2576 transgenic mice, thus increasing the endocannabinoid tone. The addition of URB597 did not alter cell viability and induced microglia polarization toward an anti-inflammatory phenotype, as shown by the modulation of pro- and anti-inflammatory cytokines, as well as M1 and M2 markers; moreover microglia, after URB597 treatment released higher levels of Bdnf and Nrf2, confirming the protective role underlying endocannabinoids increase, as shown by RT-PCR and immunofluorescence experiments. We assessed the number and area of amyloid plaques in animals administered with URB597 compared to untreated animals and the expression of autophagy key markers in the hippocampus and prefrontal cortex from both groups of mice, via immunohistochemistry and ELISA. After URB597 supply, we detected a reduction in the number and areas of amyloid plaques, as detected by Congo Red staining and a reshaping of microglia activation as shown by M1 and M2 markers’ modulation. URB597 administration restored autophagy in Tg2576 mice via an increase in BECN1 (Beclin1), ATG7 (Autophagy Related 7), LC3 (light chain 3) and SQSTM1/p62 (sequestrome 1) as well as via the activation of the ULK1 (Unc-51 Like Autophagy Activating Kinase 1) signaling pathway, suggesting that it targets mTOR/ULK1-dependent autophagy pathway. The potential of endocannabinoids to rebalance autophagy machinery may be considered as a new perspective for therapeutic intervention in AD.

Methylation Patterns of Diabetes and Obesity Susceptibility Genes in Gestational Diabetes Mellitus: A Cross-Sectional Analysis from Karachi, Pakistan.

Background: Women with gestational diabetes mellitus (GDM) and their offspring have an increased risk of adverse perinatal and long-term health outcomes, which may be attributable to epigenetic modification of diabetes and obesity susceptibility genes. We aimed to investigate the methylation patterns of eight genes in GDM and normoglycemic (NG) mothers, and their respective offspring. Methods: This cross-sectional study, conducted at Aga Khan University from August 2019 to December 2022, recruited pregnant women in the first trimester of gestation from the outpatient obstetrics clinic. Participants were classified as NG or GDM based on the Society of Obstetricians and Gynecologists Pakistan. Venous blood samples were collected from mothers and cord blood from neonates. Peripheral blood mononuclear cells were used for DNA extraction and methylation analysis using methylation-specific PCR. Maternal and neonatal clinical data were recorded. Statistical analysis was performed using R, including binary logistic regression to assess the association between various gene methylation levels and GDM. Results: The study found that GDM mothers had significantly higher fasting blood glucose, 2-hr OGTT, and serum carboxymethyl lysine (CML) levels compared to NG mothers, but no significant differences in neonatal birth weight or serum CML levels. Chemerin methylation was significantly lower in GDM mothers and their babies, while NAMPT, MTNR1B, FNDC5, FAT4, and FTO methylation levels were higher in GDM offspring compared to NG offspring. GDM mothers also had higher methylation levels of brain-derived neurotrophic factor gene (BDNF). Multivariable binary logistic regression identified methylation levels of maternal BDNF and neonatal MTNR1B to be independently associated with GDM. Conclusions: Our study shows a trend of epigenetic modifications in both GDM mothers and their offspring in various genes related to metabolism and inflammation, suggesting an intergenerational transmission of increased risk of developing metabolic disorders. These findings emphasize the need for high throughput studies, early screening, tight glucose control during pregnancy, and postnatal follow-up to mitigate long-term health risks.

Study on the Mechanism of Dictyophora duplicata Polysaccharide in Reducing Depression-like Behavior in Mice.

Depression is a prevalent worldwide mental health disorder that inflicts significant harm to individuals and society. Dictyophora duplicata is an edible fungus that contains a variety of nutrients, including polysaccharides. This study aims to investigate the monosaccharide composition and molecular weight of the Dictyophora duplicata polysaccharide (DDP-B1), followed by an exploration of its antidepressant effects in chronic unpredictable mild stress (CUMS) mice. Dictyophora duplicata was purified using a DEAE-52 column and an S-400 column to obtain DDP-B1. The monosaccharide composition and molecular weight of DDP-B1 were investigated via high-performance gel permeation chromatograph. Six-week-old C57BL/6 male mice were utilized for the CUMS modeling to evaluate the antidepressant efficacy of DDP-B1. Fluoxetine served as the positive control group. The depressive-like behaviors and brain pathology of mice were evaluated. Immunofluorescence (IF) staining, metabolomics analysis, and western blot were employed to further investigate the underlying mechanisms. DDP-B1 significantly alleviated the depression-like behavior of CUMS mice and increased the expression of SYN and PSD-95 in the mice's brains, which was further validated by western blot. Metabolomics analysis indicated a reduction in serum glutamate in CUMS mice following DDP-B1 treatment. Moreover, DDP-B1 treatment led to an increase in levels of GABAAR, BDNF, p-TrkB and p-p70S6K. DDP-B1 regulated abnormalities in the glutamatergic system, subsequently activated the BDNF-TrkB-mTOR pathway and mitigated the pathological manifestations of CUMS mice. This study validated the potential of DDP-B1 as an antidepressant medication and established a theoretical foundation for the development of fungi with similar properties.

Vanillic acid ameliorates diethyl phthalate and bisphenol S-induced oxidative stress and neuroinflammation in the hippocampus of experimental rats.

Long-term adverse effects on human health are caused by exogenous compounds that alter the functions of biological systems, especially neuroendocrine disruptors like diethyl phthalate (DEP) and bisphenol S (BPS). Although vanillic acid (VA) has pertinent neuropharmacological characteristics, its effect against DEP + BPS-induced neurotoxicity has not been explored. This study proposed that VA may offer protection against the neurotoxicity caused by DEP + BPS. Thirty male Wistar rats were randomly distributed across five groups: a control group receiving DMSO, a group exposed to a mixture of BPS and DEP, two BPS + DEP-exposed groups treated with VA at doses of 25 mg/kg or 50 mg/kg, and a nonexposed group treated with 50 mg VA/kg. After 21 days, the hippocampal tissues were processed for biochemical analyses. Our results indicate that exposure to DEP + BPS upregulated neurosignaling mediators (NTPDase, ADA, MAO-A, and Ca2+), inhibited others (AChE and Ca2+/Mg2+-ATPase), decreased hippocampus antioxidants (GSH, GPx, CAT, and SOD), and elevated markers of oxidative stress/damage (NO, H2O2, MDA, and AOPP). AR, BAX, TNF-α, BAK1, and IL-1β expressions were upregulated, while IL-10 and BDNF expressions were downregulated. NF-κB and caspase-3/9 pathways were also upregulated. Co-treatment with vanillic acid remarkably precluded these neurotoxic outcomes by improving neurosignaling, augmenting antioxidant status, abrogating oxidative damage, inflammation (TNF-α, IL-1β), and apoptosis (BAX, BAK1, caspase-3/9). Vanillic acid also restored IL-10 and BDNF levels, thereby exhibiting neuroprotective effects, corroborated by histological examinations. We posit vanillic acid as a safe and effective therapeutic agent against neurotoxicity occasioned by exposure to neuroendocrine disruptors.

Ascorbic acid Mitigates behavioural disturbances associated with letrozole-induced PCOS via switching-off JAK2/STAT5 and JAK2/ERK1/2 pathways in rat hippocampus

PurposePolycystic ovary syndrome (PCOS) is an endocrine disorder with the highest prevalence among other disorders in sexually-active women. It is associated with broad-spectrum hormonal and metabolic disturbances with behavioural difficulties. Experimentally, letrozole administration causes similar findings. Ascorbic acid is powerful anti-oxidant; and its cellular levels decrease with “hyperglycemic and poor anti-oxidative” status, which is, a main hallmark of PCOS. Thus, ascorbic acid administration may prevent the induction of PCOS and its consequences.Basic procedures: Forty female rats were divided into four groups (n = 10 in each): normal control (CTRL), ascorbic acid (ASC), letrozole (LTZ), and ascorbic acid + letrozole (ASC + LTZ) group. Behavioural tests (Y-maze spontaneous alteration, tail suspension test, forced swimming test) were performed. In serum, hormones (testosterone, estradiol, progesterone), glycemia (blood glucose, insulin and HOMA-IR) and oxidative stress (SOD activity, GSH) markers were measured. In hippocampus, inflammation and apoptosis indicators (p-JAK2, p-STAT5, p-ERK1/2, NF-κB, BAX, Bcl2, BAX/Bcl2 ratio) and neurotransmitters (DA, 5-HT, NE, BDNF) were determined. Lastly, ovary histopathological investigation was conducted to confirm PCOS induction.Principal results: Letrozole induced PCOS with subsequent disturbances. Testosterone levels were augmented while estradiol and progesterone were declined. Fasting blood glucose, insulin, HOMA-IR and oxidative stress markers were elevated. The expression of p-JAK2, p-STAT5, p-ERK1/2, BAX and the levels of NF-κB were increased, but Bcl2 expression, monoamines and BDNF levels were lowered. Importantly, ASC abated the last mentioned parameters markedly. Major conclusions: Ascorbic acid mitigated the behavioural difficulties of PCOS possibly by switching-off JAK2/STAT5 and JAK2/ERK1/2 pathways in hippocampus along with its neurotransmission-improving, hormonal-normalizing, anti-hyperglycemic and anti-oxidative effects.

Sex differences in contextual fear conditioning and extinction after acute and chronic nicotine treatment

BackgroundChronic cigarette smokers report withdrawal symptomology, including affective dysfunction and cognitive deficits. While there are studies demonstrating sex specific withdrawal symptomology in nicotine-dependent individuals, literature examining the underlying biological mediators of this is scant and not in complete agreement. Therefore, in this study, we evaluated the sex specific effects of nicotine and withdrawal on contextual fear memory, a hippocampally dependent aspect of cognition that is disrupted in nicotine withdrawal.MethodsMale and female B6/129F1 mice (8–13 weeks old) were used in all experiments. For the acute nicotine experiment, mice received intraperitoneal saline or nicotine (0.5 mg/kg) prior to contextual fear conditioning and test. For the chronic nicotine experiment, mice received nicotine (18 mg/kg/day) or saline for 11 days, then underwent contextual fear conditioning and test. Following the test, mice underwent minipump removal to elicit withdrawal or sham surgery, followed by the fear extinction assay. Bulk cortical tissue was used to determine nicotinic acetylcholine receptor levels via single point [3H]Epibatidine binding assay. Gene expression levels in the dorsal and ventral hippocampus were quantified via RT-PCR.ResultsWe found that female mice had a stronger expression of contextual fear memory than their male counterparts. Further, following acute nicotine treatment, male, but not female, subjects demonstrated augmented contextual fear memory expression. In contrast, no significant effects of chronic nicotine treatment on fear conditioning were observed in either sex. When examining extinction of fear learning, we observed that female mice withdrawn from nicotine displayed impaired extinction learning, but no effect was observed in males. Nicotine withdrawal caused similar suppression of fosb, cfos, and bdnf, our proxy for neuronal activation and plasticity changes, in the dorsal and ventral hippocampus of both sexes. Additionally, we found that ventral hippocampus erbb4 expression, a gene implicated in smoking cessation outcomes, was elevated in both sexes following nicotine withdrawal.ConclusionsDespite the similar impacts of nicotine withdrawal on gene expression levels, fosb, cfos, bdnf and erbb4 levels in the ventral hippocampus were predictive of delays in female extinction learning alone. This suggests sex specific dysfunction in hippocampal circuitry may contribute to female specific nicotine withdrawal induced deficits in extinction learning.

Neonatal hypoxia-ischemia alters the events governing the hippocampal critical period of postnatal synaptic plasticity leading to deficits in working memory in mice

The postnatal critical period of synaptic plasticity (CPsp) is characterized by profound neural network refinement, which is shaped by synaptic activity and sculpted by maturation of the GABAergic network. Even after therapeutic hypothermia (TH), neonatal hypoxia-ischemia (HI) impairs two triggers for the initiation of the CPsp in the hippocampus: i) PSA-NCAM developmental decline and ii) parvalbumin (PV) + interneuron (IN) maturation. Thus, we investigated whether neonatal HI despite TH disturbs other events governing the onset, consolidation and closure of the postnatal CPsp in the hippocampus. We induced cerebral HI in P10 C57BL6 mice with right carotid ligation and 45 m of hypoxia (FiO2 = 0.08), followed by normothermia (36 °C, NT) or TH (31 °C) for 4 h with anesthesia-exposed shams as controls. ELISA, immunoblotting and immunohistochemistry were performed at 24 h (P11), 5 days (P15), 8 days (P18) and 30 days (P40) after HI injury. We specifically assessed: i) BDNF levels and TrkB activation, controlling the CPsp, ii) Otx2 and NPTX2 immunoreactivity (IR), engaging CPsp onset and iii) NogoR1, Lynx1 IR, PNN formation and myelination (MBP) mediating CPsp closure. Pups aged to P40 also received a battery of tests assessing working memory. Here, we documented deficits in hippocampal BDNF levels and TrkB activation at P18 in response to neonatal HI even with TH. Neonatal HI impaired in the CA1 the developmental increase in PV, Otx2, and NPTX2 between P11 and P18, the colocalization of Otx2 and PV at P18 and P40, the accumulation of NPTX2 in PV+ dendrites at P18 and P40, and the expression of NogoR and Lynx1 at P40. Furthermore, neonatal HI decreased BDNF and impaired PNN development and myelination (MBP) at P40. Most of these abnormalities were insensitive to TH and correlated with memory deficits. Neonatal HI appears to disrupt many of the molecular and structural events initiating and consolidating the postnatal hippocampal CPsp, perhaps due to the early and delayed deficits in TrkB activation leading to memory deficits.

Maternal separation alters peripheral immune responses associated with IFN-γ and OT in mice

The co-evolution of social behavior and the immune system plays a critical role in individuals' adaptation to their environment. However, also need for further research on the key molecules that co-regulate social behavior and immunity. This study focused on neonatal mice that were separated from their mothers for 4 hours per day between the 6th and 16th day after birth. The results showed that these mice had lower plasma levels of IFN-γ and oxytocin, but higher levels of plasma glucocorticoids (GC), then impacting their social abilities. Additionally, maternal separation led to decreased levels of BDNF, IGF2, and CREB mRNAs in the hippocampus, while levels in the prefrontal cortex (PFC) remained unaffected. Maternal separation also resulted in increased levels of oxytocin and CRH mRNA in the hypothalamus, as well as an increase in CD45+ lymphocyte subsets in the meninges and choroid plexus (CP), with CD8+ lymphocytes in meninges and CD4+ lymphocytes in CP showing an increase. In IFN-γ-/- mice, a decrease in social preference was observed alongside lower plasma oxytocin levels. Moreover, IFN-γ-/- mice exhibited reduced numbers of oxytocin neurons in the paraventricular nucleus of the paraventricular nucleus of hypothalamus (PVN), decreased BDNF levels in the PFC and hippocampus, and alterations in CD45+ lymphocytes in CP and meninges, with an increase in CD8+ lymphocytes in meninges and CD4+ lymphocytes in CP. These findings highlight the immunological impact of social stress on IFN-γ regulation, suggesting that the immunomodulatory molecule IFN-γ may influence social behavior by affecting synaptic efficiency in brain regions such as the hippocampus and PFC, which are linked to oxytocin in the PVN.

Evaluation of Hesperidin-Zinc Complex as a Novel Therapeutic Agent for Depression Treatment in Rats

Introduction: The complex contains hesperidin and zinc. The zinc is essential micronutrient that is important for human metabolism and catalyzes over 100 enzymes. It can be used to treat Wilson disease, decreased immunity, acute and chronic diarrhea. The hesperidin is a bioflavonoid found in many citrus plants. It has numerous activities like antioxidant, antibacterial, antimicrobial, anti-inflammatory, used to treat inflammation, Hypotension, varicose veins, venous ulcer, oxidative stress. There is no scientific evidence to support the claim that the complex of hesperidin and zinc have antidepressant properties even though zinc and hesperidin both separately have been linked to antidepressant activity in the literature. Objectives: The aim of this research is to find out whether complex of hesperidin and zinc can prevent reserpine induced depression. Methods: Wistar rats were used in this study after acclimatization. The induction group will be induced with reserpine to produce the depression in rats. The experiment included various treatment group of high and low dose of the test drug. Rats were used for the assessments, based on behavioral parameter like tail suspension test (TST), forced swimming test (FST), and elevated plus maze test then histopathology of hippocampus, cortical and substantia nigra region has been analysed, and along with measuring the BDNF levels. Results: On reserpine induced depression, complex of Hesperidin and zinc at low dose (100 mg/kg) shows negligible improvement in depressed behavior, when compare with standard fluoxetine (10 mg/kg). On the other hand, high dose (200 mg/kg) of the complex shows greater improvement also showed normal morphology in all 3 regions of the brain and showed increased level of BDNF in brain compared to low dose (100 mg/kg). Conclusions: Hesperidin-zinc complex was discovered to be a successful antidepressant drug, according to the study's findings. According to the findings, however a high dose of complex is more effective at treating reserpine induced depression than a low dose of complex.

Differential effects of chronic and intermittent administration of taurine on alcohol binge drinking in male rats

Episodic consumption of high doses of alcohol in a short period (binge drinking - BD) among adolescents is known to be harmful to their brain development. Chronic use of taurine increases voluntary alcohol consumption and shows an anxiolytic-like effect in rats. In this study, we evaluated the differential effects of chronic and intermittent taurine administration on alcohol consumption and behavioral changes in adolescent and young adult rats subjected to the BD model. Male Wistar rats (35 days old) were divided into 4 groups for daily intraperitoneal administration of saline (SAL); taurine, 100 mg/kg (TAU); taurine on BD days and saline on intervals (TAU/SAL); and saline on BD days and taurine on intervals (SAL/TAU). They were exposed to 4 cycles of BD, with free access to alcoholic solution (20 % w/v), for 2 h, 3 days per week. At the end of the 3rd cycle, anxiety-like behaviors were assessed using the light-dark task. After euthanasia, plasma and prefrontal cortex samples were collected to measure corticosterone and BDNF levels, respectively. Chronic taurine treatment did not alter alcohol consumption in rats, whereas intermittent administration increased alcohol intake after 4 BD exposures (TAU/SAL: +19.4 % and SAL/TAU: +21.6 %). No anxiolytic-like effects were found by taurine administration, nor were there changes in serum corticosterone or BDNF levels in the frontal cortex of young adult rats. Intermittent taurine, but not chronic treatment, increased alcohol intake among rats after the second week of exposure. The translation of these results to humans is concerning since the combination of alcohol and drinks containing taurine is common among adolescent and young adult individuals.

Neuroinflammation in Severe COVID-19: The Dynamics of Inflammatory and Brain Injury Markers During Hospitalization.

Patients with COVID-19 can develop excessive inflammation in the brain and consequent neurological complications. The aim of this study was to evaluate the inflammatory, endothelial and brain injury markers in hospitalized COVID-19 patients and compare those with or without neurological symptoms. A total of 30 intensive care unit (ICU) COVID-19 patients were allocated into COVID-19 (without neurological symptoms) or neuro-COVID-19 (with neurological symptoms) groups. Patients with respiratory infection symptoms but negative for COVID-19 were included as a control group. Peripheral blood samples were collected at hospital admission (T1) (controls and ICU patients) and during hospitalization (T2: last 72h before hospital discharge or in-hospital death) (ICU COVID-19 patients) to analyze inflammatory markers. Higher ICAM-1, CCL26 and VEGF at T1 were identified in both COVID-19 groups compared with control. Neuro-COVID-19 patients presented lower systemic BDNF levels compared with the control group and increased S100B compared with the control and COVID-19 groups. BDNF levels in survivors were lower in the neuro-COVID-19 group compared to the COVID-19 group, while S100B were higher, regardless of the outcome. In addition, all COVID-19 patients presented increased ICAM-1 and CCL26 levels over the hospitalization period (T2 > T1). Furthermore, S100B, ICAM-1, CCL26 and VEGF levels increased in relation to T1 in neuro-COVID-19 patients, with S100B and CCL26 being significantly higher in relation to the COVID-19 group. In conclusion, high levels of brain injury biomarkers were found in patients with neuro-COVID-19, indicating neuroinflammatory and consequent brain injury in the last 72h of hospitalization.

Factors influencing brain recovery from stroke via possible epigenetic changes.

Aim: To examine epigenetic changes leading to functional repair after damage to the central motor system.Data sources: A literature search was conducted using medical and health science electronic databases (PubMed, MEDLINE, Scopus) up to July 2023.Study selection: Data were summarized for type of intervention, study design, findings including human and animal studies.Data extraction: Data were extracted and double-checked independently for methodological quality. By means of the influence of environmental (calorie restriction or physical exercise) and other factors, epigenetic instructions were found to increase levels of BDNF and enhance synaptic neurotransmission, possibly leading to larger scale changes in structural and functional assets, which may end up to cognitive and motor repair after stroke.

Isomalto-Oligosaccharide Potentiates Alleviating Effects of Intermittent Fasting on Obesity-Related Cognitive Impairment during Weight Loss and the Rebound Weight Gain.

Obesity-related cognitive dysfunction poses a significant threat to public health. The present study demonstrated mitigating effects of intermittent fasting (IF) and its combination with isomalto-oligosaccharides and IF (IF + IMO) on cognitive impairments induced by a high-fat-high-fructose (HFHF) diet in mice, with IF + IMO exhibiting superior effects. Transcriptomic analysis of the hippocampus revealed that the protective effects on cognition might be attributed to the suppression of toll-like receptor 4 (TLR4)/NFκB signaling, oxidative phosphorylation, and neuroinflammation. Moreover, both IF and IF + IMO modulated the gut microbiome and promoted the production of short-chain fatty acids, with IF + IMO displaying more pronounced effects. IF + IMO-modulated gut microbiota, metabolites, and molecular targets associated with cognitive impairments were further corroborated using human data from public databases Gmrepo and gutMgene. Furthermore, the fecal microbiome transplantation confirmed the direct impacts of IF + IMO-derived microbiota on improving cognition functions by suppressing TLR4/NFκB signaling and increasing BDNF levels. Notably, prior exposure to IF + IMO prevented weight-regain-induced cognitive decline, suppressed TLR4/NFκB signaling and inflammatory cytokines in the hippocampus, and mitigated weight regain-caused gut dysbacteriosis without altering body weight. Our study underscores that IMO-augmented alleviating effects of IF on obesity-related cognitive impairment particularly during weight-loss and weight-regain periods, presenting a novel nutritional strategy to tackle obesity-related neurodegenerative disorders.

Npbwr1 signaling mediates fast antidepressant action.

Chronic stress is a major risk factor for depression, a leading cause of disability and suicide. Because current antidepressants work slowly, have common side effects, and are only effective in a minority of patients, there is an unmet need to identify the underlying molecular mechanisms. Here, we identify the receptor for neuropeptides B and W, Npbwr1, as a key regulator of depressive-like symptoms. Npbwr1 is increased in the nucleus accumbens of chronically stressed mice and postmortem in patients diagnosed with depression. Using viral-mediated gene transfer, we demonstrate a causal link between Npbwr1, dendritic spine morphology, the biomarker Bdnf, and depressive-like behaviors. Importantly, microinjection of the synthetic antagonist of Npbwr1, CYM50769, rapidly ameliorates depressive-like behavioral symptoms and alters Bdnf levels. CYM50769 is selective, well tolerated, and shows effects up to 7 days after administration of a single dose. In summary, these findings advance our understanding of mood and chronic stress and warrant further investigation of CYM50769 as a potential fast-acting antidepressant.

Functional associations of the gut microbiome with dopamine, serotonin, and BDNF in schizophrenia: a pilot study

BackgroundSchizophrenia is a complex neuropsychiatric disorder with various etiologic factors. Aberrant levels of neurotransmitters or growth factors such as dopamine, serotonin, and BDNF have been shown to cause cognitive impairment in schizophrenia. Recently, the gut microbiome has also been suggested as a factor in the development of the disorder. To explore this potential link, we conducted a pilot study to examine the relationship between the gut microbiome and plasma levels of neurotransmitters and growth factors in schizophrenia. Shotgun metagenome sequencing of total RNA from fecal samples were used to profile the gut microbiome of schizophrenia patients (SCZ) and healthy controls (HC). The MetaPhlAn2 and HUMaN2 pipelines were used for bioinformatic analyses. ELISA was used to measure the plasma levels of dopamine, serotonin, and BDNF. Spearman’s rank correlation coefficient was used for correlation analysis.ResultsWe found that butyrate-producing bacteria were enriched in HC, whereas succinate-producing bacteria, namely Phascolarctobacterium succinatutens and Paraprevotella clara, were enriched in SCZ. The gut microbiota of SCZ was enriched in lipid biosynthesis pathways related to bile-resistant bacteria, whereas phospholipid pathways linked with butyrate-producing bacteria were enriched in HC. Alistipes indistinctus, Dorea longicatena, and Roseburia inulinivorans were negatively correlated with dopamine levels. Roseburia intestinalis and Parabacteroides goldsteini were negatively correlated with serotonin and BDNF levels, respectively. We found a significant correlation between dopamine and serotonin levels, and the super-pathway of purine deoxyribonucleoside degradation.ConclusionsThis study provides further support that gut microbiota could modulate neurotransmitter levels. The results suggest that gut microbiome-targeted therapies may help to rebalance neurotransmitter levels, offering new hope for the treatment of schizophrenia.

Anticholinesterase, Antioxidative and Neuroprotective Effects of Hydroethanolic Extracts of Guiera Senegalensis J. F. Gmel. Leaves on Scopolamine Induced Alzheimer’s Disease in Wistar Rat Models

Background: Medicinal plants like Guiera senegalensis J. F. Gmel. (GS) have gained attention for their potential neuroprotective effects due to their rich composition of bioactive compounds, including flavonoids and polyphenolic acids. While previous studies have highlighted the antioxidant, anti-inflammatory, and neuroplasticity-enhancing properties of GS extract, its efficacy in mitigating dementia-related pathology remains to be fully understood. Objectives: This study aimed to investigate the neuroprotective effects of hydroethanolic GS extract against scopolamine (Sco)-induced dementia in Wistar rats, focusing on its impact on cholinergic function, oxidative stress, neuroinflammation, neurodegeneration, and memory impairment. Methods: Fresh leaves were processed for extraction using standard methods. Antioxidant activity was evaluated using FRAP and DPPH assays. Adult male Wistar rats were used for behavioral tests (Y-maze, NOR, MWM) and biochemical analyses, including ELISA for cholinergic activity, oxidative stress markers (Aβ1-42, phosphorylated Tau), pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IFN-γ), GFAP, BDNF, and IL-10. Brain tissues underwent histopathological examination. Data were analyzed using GraphPad Prism software. Results: The study assessed the antioxidant potential of GS extract and found that it significantly scavenged DPPH radicals (70.29%) and reduced Fe3+ (49.69%). Behavioral tests showed that GS extract (100 - 400 mg/kg) improved spatial memory and learning in Sco-treated rats. Y-maze results indicated increased spontaneous alternation with GS extract (P < 0.01). NOR and MWM tests showed improved memory and learning, with GS extract-treated rats spending more time in the target quadrant. Biochemical analysis revealed that GS extract increased acetylcholine (ACh), Superoxide Dismutase (SOD), Catalase (CAT), Glutathione (GSH), IL-10, and BDNF levels, while decreasing acetylcholinesterase (AChE), malondialdehyde (MDA), nitrite, Aβ1-42, phosphorylated Tau, IL-1β, TNF-α, IL-6, IFN-γ, and GFAP levels in the hippocampus. Histological analysis confirmed restored hippocampal tissue architecture in AD rats treated with GS extract. Conclusions: Our findings suggest that GS modulates cholinergic, antioxidant, anti-inflammatory, and neuroplasticity pathways, exerting beneficial effects on cognitive functions and biochemical markers associated with Alzheimer's disease (AD) pathology. These results indicate the potential of GS as a neuroprotective agent for the treatment of AD.