Neurotrophin Levels Research Articles

Effects of cholecalciferol supplementation on depressive symptoms, C-peptide, serotonin, and neurotrophin-3 in type 2 diabetes mellitus: A double-blind, randomized, placebo-controlled trial

The coexistence of depression and type 2 diabetes mellitus (T2DM) can significantly worsen disease prognosis and lower quality of life. Emerging evidence suggests that vitamin D deficiency contributes to the progression of T2DM and is closely associated with the development of depression. The aim of this study was to investigate the effects of cholecalciferol on depression in patients with T2DM, exploring its mechanisms by analyzing its impact on C-peptide, serotonin, and neurotrophin-3 levels. A double-blind, randomized, placebo-controlled clinical trial was conducted at Cipto Mangunkusumo General Hospital, Jakarta, Indonesia, from April 2021 to September 2022. Patients with T2DM and depressive symptoms were randomly assigned to two groups: received 4000 IU of cholecalciferol daily and received a placebo for 12 weeks. Depression was assessed using the Beck Depression Inventory-II (BDI-II) before and 12 weeks after the intervention. The levels of C-peptide, serotonin, and neurotrophin-3 were measured at the end of the fourth week of intervention using the enzyme-linked immunosorbent assay (ELISA) method. Between-group comparisons were made using independent Student t-tests and Mann-Whitney U tests. Paired Student t-tests or Wilcoxon tests were applied for within-group comparisons between pre- and post-intervention. A total of 70 T2DM patients with depression were included in this study, comprising 38 patients in the cholecalciferol group and 32 in the placebo group. C-peptide levels increased significantly in the cholecalciferol group compared to the placebo group (p=0.006). No significant differences were observed in serotonin and NT-3 levels between the cholecalciferol group compared to the placebo group. The cholecalciferol group had a significantly greater reduction in BDI-II scores compared to the placebo group (p<0.001). This trial highlights that taking cholecalciferol might help ease mild to moderate depression symptoms in patients with T2DM by enhancing c-peptide levels, though its effects on serotonin and neurotrophin-3 are still unclear.

Hypoglycemic drugs, circulating inflammatory proteins, and gallbladder diseases: A mediation mendelian randomization study

BackgroundThe relationship of hypoglycemic drugs, inflammatory proteins and gallbladder diseases remain unknown. MethodsFour hypoglycemic drugs were selected as exposure: glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), and metformin. The outcome were two gallbladder diseases: cholecystitis and cholelithiasis. Mendelian Randomization (MR) was employed to determine the association between hypoglycemic drugs and gallbladder diseases. ResultsDPP-4i and SGLT-2i had no effect on cholecystitis and cholelithiasis. However, a causal relationship was found between inhibition of ETFDH gene, a target of metformin expressed in cultured fibroblasts, and cholelithiasis (OR: 0.84, 95 %CI: (0.72,0.97), p = 0.021), as well as between GLP1R expression in the brain caudate basal ganglia and cholecystitis (OR: 1.29, 95 %CI: (1.11,1.49), p = 0.001). The effect of ETFDH inhibition on cholelithiasis through Interleukin-10 receptor subunit beta (IL-10RB) levels and Neurotrophin-3 (NT-3) levels, with a mediated proportion of 8 % and 8 %, respectively. ConclusionMetformin plays a protective role in cholelithiasis, while GLP-1RA have a harmful effect on the risk of cholecystitis. Metformin may reduce the risk of cholelithiasis by modulating the levels of Neurotrophin-3 (NT-3) and Interleukin-10 receptor subunit beta (IL-10RB). Further clinical and mechanistic studies are required to confirm these findings.

New BDNF and NT-3 Cyclic Mimetics Concur with Copper to Activate Trophic Signaling Pathways as Potential Molecular Entities to Protect Old Brains from Neurodegeneration.

A low level of Neurotrophins (NTs), their Tyrosine Kinase Receptors (Trks), Vascular Endothelial Growth Factors (VEGFs) and their receptors, mainly VEGFR1 and VEGFR2, characterizes AD brains. The use of NTs and VEGFs as drugs presents different issues due to their low permeability of the blood-brain barrier, the poor pharmacokinetic profile, and the relevant side effects. To overcome these issues, different functional and structural NT mimics have been employed. Being aware that the N-terminus domain as the key domain of NTs for the binding selectivity and activation of Trks and the need to avoid or delay proteolysis, we herein report on the mimicking ability of two cyclic peptide encompassing the N-terminus of Brain Derived Growth Factor (BDNF), (c-[HSDPARRGELSV-]), cBDNF(1-12) and of Neurotrophin3 (NT3), (c-[YAEHKSHRGEYSV-]), cNT3(1-13). The two cyclic peptide features were characterized by a combined thermodynamic and spectroscopic approach (potentiometry, NMR, UV-vis and CD) that was extended to their copper(II) ion complexes. SH-SY5Y cell assays show that the Cu2+ present at the sub-micromolar level in the complete culture media affects the treatments with the two peptides. cBDNF(1-12) and cNT3(1-13) act as ionophores, induce neuronal differentiation and promote Trks and CREB phosphorylation in a copper dependent manner. Consistently, both peptide and Cu2+ stimulate BDNF and VEGF expression as well as VEGF release; cBDNF(1-12) and cNT3(1-13) induce the expression of Trks and VEGFRs.

Reversal of high-fat diet-induced cognitive impairment and oxidative stress in the brain through Zingiber officinale supplementation.

Obesity is a significant health concern that is correlated with various adverse health outcomes. Diet-induced obesity (DIO) is associated with impaired cognitive function. Pharmacological treatments for obesity are limited and may have serious adverse effects. Zingiber officinale (ZO) has anti-inflammatory and antioxidant effects, in addition to metabolic effects. This study aimed to assess the effects of Zingiber officinale supplementation on cognitive function, anxiety levels, neurotrophin levels, and the inflammatory and oxidative status in the cortex following DIO in mice. Two-month-old male Swiss mice were fed DIO or standard chow for 4 months and subsequently subdivided into the following groups (n = 10 mice/group): (i) control - vehicle (CNT + vehicle); (ii) CNT supplemented with ZO (CNT + ZO); (iii) obese mice (DIO + vehicle); and (iv) obese mice supplemented with ZO (DIO + ZO) (n = 10). Zingiber officinale extract (400mg/kg/day) was administered for 35 days via oral gavage. The DIO + vehicle group exhibited impaired recognition memory. The CNT + ZO group presented a greater number of crossings in the open field. No difference between the groups was observed in the plus maze test. DIO + vehicle increased the DCFH and carbonylation levels in the cortex. The DIO + vehicle group presented a reduction in catalase activity. The expression of inflammatory or neurotrophin markers in the cerebral cortex was not different. In conclusion, our findings indicate that supplementation with ZO reverses the cognitive impairment in DIO mice and enhances the antioxidant status of the cerebral cortex.

Biomolecular therapies for chronic discogenic low back pain: A narrative review.

Chronic low back pain caused by intervertebral disc (IVD) degeneration, also termed chronic discogenic low back pain (CD-LBP), is one of the most prevalent musculoskeletal diseases. Degenerative processes in the IVD, such as inflammation and extra-cellular matrix breakdown, result in neurotrophin release. Local elevated neurotrophin levels will stimulate sprouting and innervation of sensory neurons. Furthermore, sprouted sensory nerves that are directly connected to adjacent dorsal root ganglia have shown to increase microglia activation, contributing to the maintenance and chronification of pain. Current pain treatments have shown to be insufficient or inadequate for long-term usage. Furthermore, most therapeutic approaches aimed to target the underlying pathogenesis of disc degeneration focus on repair and regeneration and neglect chronic pain. How biomolecular therapies influence the degenerative IVD environment, pain signaling cascades, and innervation and excitability of the sensory neurons often remains unclear. This review addresses the relatively underexplored area of chronic pain treatment for CD-LBP and summarizes effects of therapies aimed for CD-LBP with special emphasis on chronic pain. Approaches based on blocking pro-inflammatory mediators or neurotrophin activity have been shown to hamper neuronal ingrowth into the disc. Furthermore, the tissue regenerative and neuro inhibitory properties of extracellular matrix components or transplanted mesenchymal stem cells are potentially interesting biomolecular approaches to not only block IVD degeneration but also impede pain sensitization. At present, most biomolecular therapies are based on acute IVD degeneration models and thus do not reflect the real clinical chronic pain situation in CD-LBP patients. Future studies should aim at investigating the effects of therapeutic interventions applied in chronic degenerated discs containing established sensory nerve ingrowth. The in-depth understanding of the ramifications from biomolecular therapies on pain (chronification) pathways and pain relief in CD-LBP could help narrow the gap between the pre-clinical bench and clinical bedside for novel CD-LBP therapeutics and optimize pain treatment.

Neurotrophic Factors in Cannabis-induced Psychosis: An Update.

Cannabis is the most widely used illicit substance. Numerous scientific evidence confirm the strong association between cannabis and psychosis. Exposure to cannabis can induce the development of psychosis and schizophrenia in vulnerable individuals. However, the neurobiological processes underlying this relationship are unknown. Neurotrophins are a class of proteins that serve as survival factors for central nervous system (CNS) neurons. In particular, Nerve Growth Factor (NGF) plays an important role in the survival and function of cholinergic neurons while Brain Derived Neurotrophic Factor (BDNF) is involved in synaptic plasticity and the maintenance of midbrain dopaminergic and cholinergic neurons. Glial Cell Derived Neurotrophic Factor (GDNF) promotes the survival of midbrain dopaminergic neurons and Neuregulin 1 (NrG- 1) contributes to glutamatergic signals regulating the N-methyl-D-aspartate (NMDA). They have a remarkable influence on the neurons involved in the Δ-9-THC (tethra-hydro-cannabinol) action, such as dopaminergic and glutamatergic neurons, and can play dual roles: first, in neuronal survival and death, and, second, in activity-dependent plasticity. In this brief update, reviewing in a narrative way the relevant literature, we will focus on the effects of cannabis on this class of proteins, which may be implicated, at least in part, in the mechanism of the psychostimulant-induced neurotoxicity and psychosis. Since altered levels of neurotrophins may participate in the pathogenesis of psychotic disorders which are common in drug users, one possible hypothesis is that repeated cannabis exposure can cause psychosis by interfering with neurotrophins synthesis and utilization by CNS neurons.

Gadd45A-mediated autophagy regulation and its impact on Alzheimer's disease pathogenesis: Deciphering the molecular Nexus

BackgroundThe growth arrest and DNA damage-inducible 45 (Gadd45) gene has been implicated in various central nervous system (CNS) functions, both normal and pathological, including aging, memory, and neurodegenerative diseases. In this study, we examined whether Gadd45A deletion triggers pathways associated with neurodegenerative diseases including Alzheimer's disease (AD). MethodsUtilizing transcriptome data from AD-associated hippocampus samples, we identified Gadd45A as a pivotal regulator of autophagy. Comprehensive analyses, including Gene Ontology enrichment and protein-protein interaction network assessments, highlighted Cdkn1A as a significant downstream target of Gadd45A. Experimental validation confirmed Gadd45A's role in modulating Cdkn1A expression and autophagy levels in hippocampal cells. We also examined the effects of autophagy on hippocampal functions and proinflammatory cytokine secretion. Additionally, a murine model was employed to validate the importance of Gadd45A in neuroinflammation and AD pathology. ResultsOur study identified 20 autophagy regulatory factors associated with AD, with Gadd45A emerging as a critical regulator. Experimental findings demonstrated that Gadd45A influences hippocampal cell fate by reducing Cdkn1A expression and suppressing autophagic activity. Comparisons between wild-type (WT) and Gadd45A knockout (Gadd45A−/−) mice revealed that Gadd45A−/− mice exhibited significant cognitive impairments, including deficits in working and spatial memory, increased Tau hyperphosphorylation, and elevated levels of kinases involved in Tau phosphorylation in the hippocampus. Additionally, Gadd45A−/− mice showed significant increases in pro-inflammatory cytokines and decreases autophagy markers in the brain. Neurotrophin levels and dendritic spine length were also reduced in Gadd45A−/− mice, likely contributing to the observed cognitive deficits. ConclusionsThese findings support the direct involvement of the Gadd45A gene in AD pathogenesis, and enhancing the expression of Gadd45A may represent a promising therapeutic strategy for the treatment of AD.

Beneficial effects of dietary omega 3 polyunsaturated fatty acids on offspring brain development in gestational diabetes mellitus

Various mechanisms through which maternal diet influences offspring brain development in gestational diabetes mellitus (GDM) remains unclear. We speculate that prenatal omega 3 fatty acids will improve the levels of brain neurotrophins and vascular endothelial growth factor (VEGF), an angiogenic factor leading to improved cognitive performance in the offspring. GDM was induced in Wistar rats using streptozotocin. They were assigned to either control, GDM or GDM+O (GDM + omega-3 fatty acid supplementation). The offspring were followed till 3 mo of age and cognitive assessment was undertaken. Data analysis was carried out using one-way ANOVA followed by LSD test. GDM induction increased (p < 0.01) dam glucose levels and lowered brain derived neurotrophic factor (BDNF) levels (p = 0.056) in the offspring at birth. At 3 months, GDM group showed significantly lower levels of neurotrophic tyrosine kinase receptor-2 (NTRK-2) and VEGF, lower mRNA levels of NTRK-2 and cAMP response element-binding protein (CREB) (P < 0.05 for all) as compared to control. The GDM offspring had a higher escape latency (p < 0.01), made lesser % correct choices and more errors (p < 0.05 for both). Prenatal supplementation with omega 3 polyunsaturated fatty acids was beneficial since it ameliorated some of the adverse effects of GDM.

Radiofrequency waves increase the brain levels of inflammatory biomarkers, neurotrophin and serotonin

The increase in mobile technology has raised concerns about the potential health effects of mobile phone radiation. The biological impact of exposure to radiofrequency (RF) waves emitted by electronic devices has been extensively studied and is a concern for the public, policymakers, and health researchers. The study aimed to examine the impact of 900 MHz radiofrequency waves on biomarkers such as interleukin (IL)-1α, IL-1β, tumour necrosis factor (TNF)-α, homocysteine, nerve growth factor, and serotonin in rats' serum and brain tissue. Thirty adult male Sprague Dawley rats (200 ± 20g) were randomly assigned to three groups (n=10): control (not exposed to RF), exposed I (2 hours per day), and exposed II (4 hours per day). The exposed groups were exposed to 900 MHz RFW for 30 consecutive days. The results showed that only the exposed group II significantly increased serum serotonin levels compared to the control group (P=0.0496). IL-1α, TNF-α, and nerve growth factor levels in brain tissue increased significantly in both exposed groups compared to the control group (P&lt;0.0001). The control group had significantly lower levels of IL-1β compared to exposed groups I (P=0.0289) and II (P=0.0004). Additionally, serotonin and homocysteine levels in the brains of exposed II were significantly higher compared to the other groups (P&lt;0.0001). The results showed disruptions in all biomarkers, indicating the potential impacts of daily exposure to 900 MHz radiofrequency waves from mobile phones on brain function. This suggests that mobile phone radiation may affect brain function.

Restoring Brain Pathways Involved in Diabetes-Associated Neurocognitive Disorders: The Potential of Dipeptidyl Peptidase 4 Inhibitors as a Therapeutic Strategy

Abstract: Diabetes, a widespread chronic metabolic disease, is projected to affect 783 million people globally by 2045. Recent studies emphasize the neuroprotective potential of dipeptidyl peptidase 4 (DPP4i) inhibitors, pointing toward a promising avenue for intervention in addressing cognitive challenges associated with diabetes. Due to limited data on the effect of DPP4i on brain pathways involved in diabetes-related neurocognitive disorders, the decision was made to conduct this study to fill existing knowledge gaps on this topic. The primary aim of our study was to evaluate the potential of DPP4 inhibitors (DPP4i) in preventing cognitive decline in mice with type 2 diabetes (T2D), placing special emphasis on gaining insight into the complex molecular mechanisms underlying this action. We examined drug efficacy in modulating neurotrophic factors, calcium levels, and the expression of key genes (HIF1α, APP, Arc) crucial for neural plasticity. Conducting cognitive assessments with the hole board and passive avoidance tests, we discerned a remarkable influence of short-term gliptin usage on the limiting progress of cognitive dysfunction in diabetic mice. The administration of DPP4 inhibitors led to heightened neurotrophin levels, increased HIF1α in the prefrontal cortex, and a significant elevation in Arc mRNA levels. Our findings reveal that DPP4 inhibitors effectively limit the progression of diabetes-related cognitive disorders. This breakthrough discovery not only opens new research avenues but also constitutes a potential starting point for creating innovative strategies for the treatment of central nervous system disorders focused on improving cognitive abilities.

Relationship Between Serum Brain-Derived Neurotrophic Factor and Neurotrophin-3 Levels and Hearing Thresholds in Patients With Age-Related Hearing Loss.

Age-related hearing loss (ARHL) is a general term used to describe the sensorineural type of hearing loss occurring in both ears in older adults. Neurotrophins are the most promising candidates for supporting the auditory nerve by increasing neuronal survival. This study aimed to help elucidate the pathophysiology of ARHL by determining whether any relationship exists between brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) levels in serum samples from patients diagnosed with ARHL. Seventy-seven individuals, a study group of 41 patients diagnosed with ARHL, and a control group of 36 participants without hearing loss were evaluated. Serum samples were collected and used to measure serum BDNF and NT-3 levels with the new Nepenthe enzyme-linked immunosorbent assay method. Median pure-tone average results in the 2000, 4000, and 6000 Hz ranges were 52.5 (44.3-67.3) dB HL in the ARHL group and 13.5 (11.1-17.1) dB HL in the control group. The difference was statistically significant (p = .001). Although NT-3 and BDNF levels were both lower in ARHL patients than in participants without hearing loss, only the BDNF levels were significantly (p = .002) lower. Mean left and right ear word recognition scores were also lower in ARHL patients than in control groups. The ARHL group was further divided into two subgroups based on word recognition scores to evaluate significant differences in BDNF and NT-3 levels. No statistically significant difference was observed in BDNF and NT-3 levels between these subgroups. However, there was a significant difference in word recognition scores. Low BDNF levels in the ARHL group suggest that BDNF may play a role in the pathogenesis of ARHL. Patients with low (ARHL1) and high (ARHL2) word recognition scores were compared for the first time in the literature in terms of BDNF and NT-3 levels. However, the results were not statistically significant. This article is a preliminary study and was written to provide guidance for our next comprehensive project.

Exploring causal correlations between inflammatory cytokines and Ménière's disease: a Mendelian randomization.

Previous studies have highlighted associations between certain inflammatory cytokines and Ménière's Disease (MD), such as interleukin (IL) -13 and IL-1β. This Mendelian randomization aims to comprehensively evaluate the causal relationships between 91 inflammatory cytokines and MD. A comprehensive two-sample Mendelian randomization (MR) analysis was conducted to determine the causal association between inflammatory cytokines and MD. Utilizing publicly accessible genetic datasets, we explored causal links between 91 inflammatory cytokines and MD risk. Comprehensive sensitivity analyses were employed to assess the robustness, heterogeneity, and presence of horizontal pleiotropy in our findings. Our findings indicate that MD causally influences the levels of two cytokine types: IL-10 (P=0.048, OR=0.945, 95%CI =0.894~1.000) and Neurotrophin-3 (P=0.045, OR=0954, 95%CI =0.910~0.999). Furthermore, three cytokines exhibited significant causal effects on MD: CD40L receptor (P=0.008, OR=0.865, 95%CI =0.777-0.963), Delta and Notch-like epidermal growth factor-related receptor (DNER) (P=0.010, OR=1.216, 95%CI =1.048-1.412), and STAM binding protein (P=0.044, OR=0.776, 95%CI =0.606-0.993). This study suggests that the CD40L receptor, DNER, and STAM binding protein could potentially serve as upstream determinants of MD. Furthermore, our results imply that when MD is regarded as the exposure variable in MR analysis, it may causally correlate with elevated levels of IL-10 and Neurotrophin-3. Using these cytokines for MD diagnosis or as potential therapeutic targets holds great clinical significance.

FNDC5/irisin mediates the protective effects of Innovative theta-shaking exercise on mouse memory

As a passive motion and non-invasive treatment, theta-shaking exercise is considered an alternative to traditional active exercise for slowing down brain ageing. Here, we studied the influence of theta-shaking exercise on fibronectin type III domain containing 5/irisin (FNDC5/irisin) in the anterior nucleus of the thalamus, hippocampus, and medial prefrontal cortex (ATN–HPC–MPFC). Further, we assessed memory in senescence-accelerated prone mice (SAMP-10 mice) using a behavioural test to confirm the protective effect of theta-shaking exercise against age-related memory decline. SAMP-10 mice were subjected to theta-shaking exercise for 9–30 weeks. Mice then performed the T-maze test and passive avoidance task. Immunohistochemical analysis and ELISA were used to assess FNDC5/irisin, nerve growth factor (NGF), and neurotrophin 4/5 (NT4/5) expression in the ATN–HPC–MPFC. In the shaking group, FNDC5 was locally upregulated within the hippocampus and MPFC area rather than exhibiting even distribution throughout brain tissue. Irisin levels were generally higher in the control group. Meanwhile, hippocampal NGF levels were significantly higher in the shaking group, with no differences noted in neurotrophin levels. Theta-shaking preserved normal neurons in certain sub-regions. However, no beneficial changes in neuronal density were noted in the ATN. Theta-shaking exercise positively affects memory function in SAMP-10 mice. FNDC5 upregulation and higher levels of NGF, along with the potential involvement of irisin, may have contributed to the preservation of normal neuronal density in the hippocampus and MPFC subregions.

Effects of Crocin on Brain Neurotrophins, Cognition, Balance and Pain in Toxic-Induced Demyelination Model

Objective: The purpose of this study was to investigate the effects of Crocin on brain neuroterophins, cognition, sensory and motor dysfunction and compare to fingolimod effects in toxic-induced demyelination with Ethidium Bromide (EB) in female Wistar rats. Methods: Animals were assigned in to 8 groups; Sham, Sham operated (ShOp), Experimental Autoimmune Encephalomyelitis (EAE), crocin treated (Cr5,10,20 mg/kg), Vehicle, Fingolompd (Fing) and fingolimod + crocin (Cr+Fing). Demyelination was induced by single dose injection of 10 μl of EB 0.1% into the fourth ventricle of the brain. Crocin and fingolimod were administered for 21 days, daily, oral gavage. BDNF, NGF1, tail flake latency, balance and behavioral variables were sampled and analyzed by paired t-test and ANOVA test with repeated post hoc measurements. Results: The results showed that crocin improves all studied factors, but remarkable improvements were observed in dosage of 10 mg/kg. Crocin (10mg/kg) and fingolimod (1mg/kg) significantly improved cognition variables in open field test, sensory and motor nerve conduction velocity, tail flick latency and clinical scores (p&lt;005). In addition, applying of crocin co-administered with fingolimod led to significant increases in all assessed factors, greater than crocin or fingolimod intervention alone (α≤0.001). Conclusion: Based on the current findings, crocin can improve the level of brain neurotrophins, exploratory behavior, balance and pain after toxin-demyelination as close as fingolimod results.

Paroxetine Effect on Nerve Growth Factor, Human Neurotrophin-4, Brain-Derived Neurotrophic Factor Levels in Post-stroke Depression.

The aim of this study is to explore paroxetine's effect on nerve growth factor (NGF), human neurotrophin-4 (NT-4), and brain-derived neurotrophic factor (BDNF) levels in post-stroke depression. Ninety-two post-stroke depression patients from April 2021 to April 2023 in our hospital were selected and numbered 1 to 92 after enrollment. Forty-six patients with odd number and 46 patients with even number were, respectively, included in the control and observation group. In addition to basic treatment, control group was treated with flupentixol melitracen tablets orally, and observation group received paroxetine hydrochloride orally. The levels of NGF, NT-4, BDNF, 5-hydroxytryptamine (5-HT), homocysteine (Hcy), noradrenaline (NE), Hamilton Depression Scale (HAMD) changes of National Institute of Health Stroke Scale (NIHSS). NGF, NT-4, and BDNF levels were compared between groups at T0, T1, and T2 levels were higher, and the levels at T2 were higher than those at T1, and observation group levels were higher (P < 0.05); NGF, NT-4, and BDNF levels were compared among groups, time, and interaction. 5-HT, Hcy, and NE levels at T0 were compared between groups; 5-HT and NE levels at T1 and T2 were higher than those at T0, the levels at T2 were higher than those at T1, and observation group levels were higher (P < 0.05); Hcy level at T1 and T2 was lower, its level at T2 was lower than those at T1, and observation group levels were lower (P < 0.05); 5-HT, Hcy, and NE levels were compared among groups, time, and interaction (P < 0.05). HAMD and NIHSS at T0 were compared; T1 and T2 were lower than T0, T2 was lower than T1, and observation group was lower (P < 0.05); HAMD and NIHSS were compared among groups, time, and interaction (P < 0.05). For post-stroke depression, paroxetine treatment can effectively improve NGF, NT-4, BDNF, 5-HT, Hcy, and NE levels and effectively reduce the degree of neurological damage and depression, which has high clinical application value.

Role of Allicin in Combination with Fluoxetine for the Treatment of Major Depressive Disorder in Rodents: Pharmacokinetic and Pharmacodynamic Study

Background: Depression is one of the most common neurological disorders for which only symptomatic treatment is available with synthetic drugs with serious side effects. Allicin [S-(2-propenyl)-2-propene-1-sulfinothioate] is a bioactive component derived from Allium sativum L. (Garlic). It has the property to penetrate the blood-brain barrier, which reveals its neuroprotective property. A synthetic drug named fluoxetine (selective serotonin re-uptake inhibitor) was introduced for the clinical treatment of depression. It is a selective serotonin re-uptake inhibitor that is well absorbed after oral administration. Aims and Objectives: This study aimed to evaluate the anti-depressant effect of fluoxetine alone and in combination with allicin. Methods: A pharmacokinetic study of allicin alone as well as in combination with fluoxetine was conducted to evaluate peak concentration, peak concentration time, and area under the curve in blood plasma. Furthermore, the biochemical analysis of neurotrophin levels of brain-derived neurotrophic factor (BDNF), serotonin, and dopamine was also performed to determine the anti-depressant activity with synergism effect of allicin and fluoxetine. Results: The results of a pharmacokinetic study for co-administration of fluoxetine with allicin and enhanced neurotrophins and monoamines levels confirmed their effectiveness against depression. They may also be effective in suicidal risk associated with anti-depressant drugs. Conclusion: A combination of synthetic drugs with herbal compounds may be an alternate and effective therapy to overcome harmful effects.

Peripheral neurotrophin levels during controlled crack/cocaine abstinence: a systematic review and meta-analysis

Cocaine/crack abstinence periods have higher risk of relapse. Abstinence as initial part of the recovery process is affected by learning and memory changes that could preserve the addictive cycle. To further understand how the interruption of cocaine/crack consumption affects neurotrophin level we performed the present systematic review and meta-analysis following the PRISMA statement (number CRD42019121643). The search formula was conducted in PubMed, Web of Science, Embase, ScienceDirect, and Google Scholar databases. The inclusion criterion was cocaine use disorder in 18 to 60-year-old people, measuring at least one neurotrophin in blood before and after a controlled abstinence period. Studies without pre-post design were excluded. Five investigations had nine different reports, four of them were subjected to a meta-analysis (n = 146). GRADE risk of bias method was followed. Individual studies reported increased peripheral brain derived neurotrophic factor (BDNF) after abstinence, evidence pooled by Hedge’s g showed no significant change in BDNF after abstinence. Relevant heterogeneity in the length of the abstinence period (12–32 days), last cocaine/crack consumption monitoring and blood processing were detected that could help to explain non-significant results. Further improved methods are suggested, and a potential BDNF augmentation hypothesis is proposed that, if true, would help to understand initial abstinence as a re-adaptation period influenced by neurotrophins such as the BDNF.

Enhanced peripheral levels of BDNF and proBDNF: elucidating neurotrophin dynamics in cocaine use disorder

Brain-derived neurotrophic factor (BDNF) and its precursor, proBDNF, are known to significantly contribute to brain homeostasis, neuroplasticity, and neuronal remodeling. Although these neurotrophins are thought to have opposing roles, both play a critical part in shaping long-lasting behavioral changes following substance use. In this context, our study sought to explore the implications of these neurotrophins in the pathophysiology of cocaine use disorder (CUD). We conducted a case-control study, which included 28 individuals seeking treatment for CUD and 38 matched healthy participants. We measured peripheral neurotrophin concentrations via an enzyme-linked immunosorbent assay. Additionally, all participants were screened for cocaine-associated pathways (e.g., cocaine intake, craving intensity), along with associated psychopathological data. Our findings highlighted an increased concentration of BDNF and proBDNF in CUD individuals when compared to healthy controls (BDNF: 18092.80 ± 6844.62 vs. 11334.42 ± 5061.85 pg/ml, p < 0.001; proBDNF: 87.03 ± 33.23 vs. 55.70 ± 23.26 ng/ml, p < 0.001). We further corroborated the relationship between neurotrophin levels and CUD using a linear regression model. Nevertheless, there was no significant difference in the proBDNF to BDNF ratio between the two groups. Interestingly, our study also demonstrated the influence of factors like usage of psychotropic medications, history of psychiatric hospitalizations, and psychiatric diagnoses on neurotrophin dynamics. In conclusion, our study underscores the significance of neurotrophin fluctuations in CUD. The observed increase in BDNF and proBDNF levels could play a pivotal role in driving craving and relapse risk. Thus, a nuanced understanding of these neurobiological underpinnings in CUD might contribute to the development of more targeted and effective therapeutic strategies.

Fraction of C. d. collilineatus venom containing crotapotin protects PC12 cells against MPP + toxicity by activating the NGF-signaling pathway.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. There is no effective treatment for neurodegenerative diseases. Snake venoms are a cocktail of proteins and peptides with great therapeutic potential and might be useful in the treatment of neurodegenerative diseases. Crotapotin is the acid chain of crotoxin, the major component of Crotalus durissus collilineatus venom. PD is characterized by low levels of neurotrophins, and synaptic and axonal degeneration; therefore, neurotrophic compounds might delay the progression of PD. The neurotrophic potential of crotapotin has not been studied yet. We evaluated the neurotrophic potential of crotapotin in untreated PC12 cells, by assessing the induction of neurite outgrowth. The activation of the NGF signaling pathway was investigated through pharmacological inhibition of its main modulators. Additionally, its neuroprotective and neurorestorative effects were evaluated by assessing neurite outgrowth and cell viability in PC12 cells treated with the dopaminergic neurotoxin MPP+ (1-methyl-4-phenylpyridinium), known to induce Parkinsonism in humans and animal models. Crotapotin induced neuritogenesis in PC12 cells through the NGF-signaling pathway, more specifically, by activating the NGF-selective receptor trkA, and the PI3K/Akt and the MAPK/ERK cascades, which are involved in neuronal survival and differentiation. In addition, crotapotin had no cytotoxic effect and protected PC12 cells against the inhibitory effects of MPP+ on cell viability and differentiation. These findings show, for the first time, that crotapotin has neurotrophic/neuroprotective/neurorestorative potential and might be beneficial in Parkinson's disease. Additional studies are necessary to evaluate the toxicity of crotapotin in other cell models.

Coconut oil ameliorates behavioral and biochemical alterations induced by D-GAL/AlCl3 in rats

Alzheimer's disease (AD) is a chronic, progressive neurodegenerative condition marked by cognitive impairment. Although coconut oil has been shown to be potentially beneficial in reducing AD-related cognitive deficits, information on its mechanism of action is limited. Thus, we investigated the effects of coconut oil on spatial cognitive ability and non-cognitive functions in a rat model of AD induced by G-galactose (D-GAL) and aluminum chloride (AlCl3), and examined the changes in synaptic transmission, cholinergic activity, neurotrophic factors and oxidative stress in this process. The AD model was established by administering D-GAL and AlCl3 for 90 days, while also supplementing with coconut oil during this time. Cognitive and non-cognitive abilities of the rats were evaluated at the end of the 90-day supplementation period. In addition, biochemical markers related to the pathogenesis of the AD were measures in the hippocampus tissue. Exposure to D-GAL/AlCl3 resulted in a reduction in locomotor activity, an elevation in anxiety-like behavior, and an impairment of spatial learning and memory (P < 0.05). The aforementioned behavioral disturbances were observed to coincide with increased oxidative stress and cholinergic impairment, as well as reduced synaptic transmission and levels of neurotrophins in the hippocampus (P < 0.05). Interestingly, treatment with coconut oil attenuated all the neuropathological changes mentioned above (P < 0.05). These findings suggest that coconut oil shows protective effects against cognitive and non-cognitive impairment, AD pathology markers, oxidative stress, synaptic transmission, and cholinergic function in a D-GAL/AlCl3-induced AD rat model.