BDNF Expression Research Articles

Lateral hypothalamic area high-frequency deep brain stimulation rescues memory decline in aged rat: behavioral, molecular, and electrophysiological study.

To examine the effect of DBS of the lateral hypothalamic area (LHA) on age-related memory changes, neuronal firing from CA1, oxidative stress, and the expression of Hsp70, BDNF, and synaptophysin. 72 male rats were randomly allocated into 6 equal groups: a) normal young group (8 W), b) sham young group, c) DBS young group, d) normal old group (24months), e) sham old group and f) DBS old group. Memory tests (passive avoidance and Y maze), oxidative stress markers (MDA, catalase, and GSH) and expression of Nrf2, HO-1, Hsp70, BDNF, and synaptophysin were measured by the end of the experiment. Also, in vivo recording of the neuronal firing of the CA1 region in the hippocampus was done. Old rats show significant decline in memories, antioxidant genes (Nrf2 and HO-1), antioxidants (GSH and catalase), Hsp70, BDNF, and synaptophysin with significant increase in MDA in hippocampus (p < 0.05) and DBS for LHA caused a significant improvement in memories in old rats, with significant rise in fast gamma and theta waves in CA1 region in old rats (p < 0.05). This was associated with a significant increase in antioxidants (GSH and CAT), antioxidant genes (Nrf2, HO-1), Hsp70, BDNF, and synaptophysin with significant reduction in MDA in hippocampus (p < 0.05). DBS for LHA ameliorates the age-induced memory decline. This might be due to increase in fast gamma in CA1, attenuation of oxidative stress, upregulation of Nrf2, HO-1, Hsp70, BDNF, and synaptophysin in the hippocampus.

Impact of Exercise on Tramadol-Conditioned Place Preference.

Tramadol (TRA) is an opioid that is used to manage moderate to severe pain. Long-term use of TRA can lead to the development of opioid use disorder. This study investigates the role of forced exercise in reducing TRA-seeking behavior. Adult male rats (240-260 g) were divided into five groups; the control group received vehicle injections, the TRA group received TRA (75 mg/kg, i.p) every other day for 8 days, and three TRA-exercise groups were forced to run on a treadmill (60 min/day, 5 days/week) for 2, 4, or 6 weeks prior to conditioning with TRA. A tramadol-conditioned place preference (CPP) procedure assessed TRA reinforcement, after which all rats were euthanized, tissue extracted, and mRNA expression for brain-derived neurotrophic factor (Bdnf) and interleukin 1 beta (Il-1β) determined in hippocampus (Hipp), prefrontal cortex (PFC), and nucleus accumbens (NAc). TRA-seeking behavior was seen in the TRA group and the 6 weeks forced exercise group. By contrast, forced exercise for 2 or 4 weeks attenuated TRA-seeking behavior. This attenuation was associated with a significant increase in Bdnf mRNA expression in the Hipp and NAc, but not the PFC. Additionally, the TRA-induced elevations in Il-1β mRNA expression were reversed by all durations of exercise in Hipp. However, only 2 and 4 weeks, but not 6 weeks, of exercise reduced elevations in PFC and NAc Il-1β expression. Forced exercise for 2 and 4 weeks attenuates TRA-seeking behavior partially through the regulation of Bdnf and Il-1β mRNA expression.

The Role of SIRT1-BDNF Signaling Pathway in Fluoride-Induced Toxicity for Glial BV-2 Cells.

Chronic fluorosis is often accompanied by neurological symptoms, leading to attention, memory and learning ability decline and causing tension, anxiety, depression, and other mental symptoms. In the present study, we analyzed the molecular mechanisms of SIRT1-BDNF regulation of PI3K-AKT, MAPK, and FOXO1A in F-treated BV2 cells. The cytotoxic effect of sodium fluoride (NaF) on BV2 cells was assessed using Cell Counting Kit-8 (CCK-8), crystal violet, and 5-ethynyl-2'-deoxyuridine (EdU) staining. Cell cycle progression and apoptosis were evaluated through flow cytometry and western blotting. Reactive oxygen species (ROS) levels, oxidative stress, and inflammatory markers were measured by ROS staining, microplate reader assays, and western blotting. The role of SIRT1 in fluoride-induced toxicity for glial cells was determined using the SIRT1 activator SRT1720. The experiments demonstrated that NaF was toxic to BV2 cells, inhibited their proliferative ability, halted their cell cycle progression, triggered cellular apoptosis, promoted cellular oxidative stress (detected by ROS, SOD, MDA, GSH-Px, T-AOC) and associated protein NQO-1 and HO-1, and elevated inflammatory mediator associated protein IL-1and IL-6 expression). The fluoride-exposed groups had reduced SIRT1, BDNF, TrkB, PI3K, AKT, and MAPK protein expression levels, and increased FOXO1A protein expression. SRT1720 mitigated the harmful effects of NaF, stimulated cell proliferation and cell cycle progression, decreased apoptosis, reduced oxidative stress and inflammatory factors, elevated SIRT1, BDNF, TrkB, PI3K, AKT, and MAPK protein levels, and suppressed FOXO1A protein expression. The results indicate that NaF potentially harms glial cells by suppressing SIRT1 activation, and SIRT1 significantly mitigated the damage. Furthermore, the SIRT1 signaling pathway might regulate the nerve damage caused by fluoride poisoning and may be a protective factor in treating fluoride-induced brain injury.

Circadian rhythm disruptions exacerbate inner ear damage in a murine endolymphatic hydrops model.

Meniere's disease (MD) is an inner ear disease characterized by endolymphatic hydrops (EH). Maintaining a regular daily routine is crucial for MD patients. However, the relationship between circadian rhythms and MD remains unclear. Therefore, we investigated the effect of circadian rhythm on endolymphatic hydrops and its underlying mechanisms. Mice with endolymphatic hydrops were subjected to chronic jet lag (CJL) conditions to simulate the MD patients under circadian rhythm disruptions. We assessed whether this disruption would exacerbate inner ear damage with endolymphatic hydrops. RNA-seq of the inner ear and bioinformatic analysis were performed. Then, the expression of PER2, AQP2, AQP4, AQP5, and BDNF were assessed, and the morphological changes were evaluated in the inner ear. Our findings showed circadian rhythm disruption affected the cochlear internal clock genes in the inner ear, particularly in mice with EH. EH mice under CJL conditions exhibited exacerbated hearing impairment and an increased severity of EH. GO enrichment analysis revealed that the regulation of fluid homeostasis and neurotransmitter release at synapses were significantly enriched. Disruption of circadian rhythms disturbed the expression pattern of PER2, reduced BDNF levels, and affected the expression of aquaporins in the cochlea. Moreover, the disruption of circadian rhythm compromised inner hair cell synapses and auditory nerve fibers. This study indicated that disruption of circadian rhythms may exacerbate inner ear damage in endolymphatic hydrops mice by affecting the aquaporins and compromising synapses and auditory nerves in the inner ear. BDNF and PER2 may play a central role in these pathophysiological processes.

Cichorium intybus L. Oligo-Polysaccharides (CIO) Exerts Antianxiety and Antidepressant Effects on Mice Experiencing Behavioral Despair and Chronic Unpredicted Mild Stress.

Cichorium intybus L. oligo-polysaccharides (CIOs), obtained from Cichorium intybus L., is a mixture of oligosaccharides and polysaccharides. This study explores the antianxiety and antidepressant effects and mechanisms of CIOs by using acute behavioral despair and chronic unpredictable mild stress mice models and measuring the levels of 5-HT and the expression of proteins related to the BDNF/ERK and PI3K/Akt/mTOR pathways. Moreover, 56 male C57BL/6N mice were used to test behavioral despair. They were randomized into seven groups (Control, Citalopram, CIO 12.5 mg/kg, CIO 25 mg/kg, CIO 100 mg/kg, and CIO 200 mg/kg) based on body weight; they were administered with the corresponding medication daily for 7 days; and behavioral tests were conducted on them (forced swimming test (FST) and tail suspension test (TST)) after 7 days. Seventy male C57BL/6N mice were adopted in the next part of the experiment and randomly divided into seven groups (Control, CUMS, Fluoxetine, MOO, CIO 25 mg/kg, and CIO 100 mg/kg) based on the sucrose preference index. Except for the control group, the other groups were subjected to 6 weeks of CUMS. From the fifth week of stress, the corresponding drugs were administered by gavage until the end of the behavioral tests. In the behavioral despair tests, the immobility time was significantly reduced in the FST and TST after the CIO (25 and 100 mg/kg) treatment of 7 days. After 6 weeks of chronic unpredicted mild stress (CUMS) treatment, CIO (25, 50, and 100 mg/kg) administration significantly reduced the number of buried beads in the marble burying test (MBT), decreased the latency in the novelty-suppressed feeding test (NSFT), and shortened the immobility time in the FST and TST. CIO administration significantly increased the sucrose preference index in the sucrose preference test (SPT). Additionally, CIO treatment increased hippocampal 5-HT levels while upregulating the expression of BDNF, P-PI3K/PI3K, P-ERK/ERK, P-Akt/Akt, and P-mTOR/mTOR. In summary, CIO exerted promising antidepressant effects in behavioral despair and antianxiety and antidepressant effects in CUMS-induced depressive mice. Moreover, CIO therapy was facilitated by increasing the 5-HT content, alleviating the damage of hippocampal neurons, and upregulating the BDNF/ERK and PI3K/AKT/mTOR cascade. Thus, CIO is a substance with the potential to treat anxiety and depression.

Selenium ameliorates cognitive impairment through activating BDNF/TrkB pathway.

Alzheimer's disease (AD) is a neurodegenerative disorder that primarily affects older adults. Selenium, an essential micronutrient for humans, plays a crucial role in the body's normal physiological and metabolic processes. A long-term deficiency in selenium intake can lead to various diseases and even contribute to the ageing process. This study aims to explore the ameliorative effect of selenium on cognitive impairment in 3 × Tg-AD mice and to determine if its effects are related to the BDNF/TrkB pathway. We employed the APP/PS1/tau 3 × Tg-AD mouse model for dietary selenium intervention. Behavioural experiments were conducted to assess learning and memory. Additionally, we measured selenium and GSH-Px levels in whole blood and brain tissue. Neuronal apoptosis in the hippocampus was observed using transmission electron microscopy. The expressions of Aβ, P-tau, BDNF, TrkB, and CREB were measured via RT-qPCR, while the expressions of Aβ, P-tau, BDNF, TrkB, p-CREB, and CREB were quantified using Western blot analysis. Our findings indicate that selenium supplementation can improve spatial learning and memory deficiencies in 3 × Tg-AD mice. Selenium supplementation increased selenium and GSH-Px levels in the brain tissue of 3 × Tg-AD mice and significantly enhanced neuronal conditions. Furthermore, the expression levels of proteins related to the BDNF/TrkB pathway significantly increased following selenium supplementation. Our study demonstrates that selenium can ameliorate memory impairment in 3 × Tg-AD mice by activating the BDNF/TrkB pathway.

Dihuang Yinzi improves scopolamine-induced learning and memory impairment by regulating plasma exosome-derived BDNF.

Dihuang Drink (DHD), formulated by Liu Hejian during the Yuan Dynasty, is listed as one of the first ancient classical prescriptions by the National Medical Products Administration of China. It is commonly used for the prevention and treatment of Alzheimer's disease (AD). This study further investigates the therapeutic effects and potential mechanisms of DHD in AD. This study aimed to evaluate the cognitive improvement effects of DHD on scopolamine (SCOP)-induced memory impairment in mice and to explore its anti-AD mechanisms mediated by exosomes. A cognitive impairment model was established in C57BL/6J mice via intraperitoneal injection of SCOP (1mg/kg) for 21 consecutive days, followed by DHD intervention to assess its effects on learning, memory, hippocampal synaptic density, and the cholinergic system. SD rats were gavaged with DHD (22.00g/kg) for 7 days, and plasma exosomes were extracted. These exosomes were injected into SCOP-treated mice (2mg/kg, every other day for 14 days, 7 injections) to verify the role of exosomes in improving cognitive function. Behavioral performance and brain ChAT and BDNF levels were measured. DHD improved learning and memory in SCOP model mice, attenuated neuronal loss and decreases in dendritic spines induced by scopolamine, and modulated the expression of BDNF, SYN-1, PSD95, and M1 mAChR. DHD-derived plasma exosomes further enhanced learning and memory function and significantly increased brain ChAT activity and BDNF levels. DHD may alleviate cognitive impairment in SCOP model mice, potentially through exosome-mediated neuroprotection.

Neuroprotective Efficacy and Complementary Treatment with Medicinal Herbs: A Comprehensive Review of Recent Therapeutic Approaches in Epilepsy Management.

Central Nervous System (CNS) disorders affect millions of people worldwide, with a significant proportion experiencing drug-resistant forms where conventional medications fail to provide adequate seizure control. This abstract delves into recent advancements and innovative therapies aimed at addressing the complex challenge of CNS-related drug-resistant epilepsy (DRE) management. The idea of precision medicine has opened up new avenues for epilepsy treatment. Herbs such as curcumin, ginkgo biloba, panax ginseng, bacopa monnieri, ashwagandha, and rhodiola rosea influence the BDNF pathway through various mechanisms. These include the activation of CREB, inhibition of NF-κB, modulation of neurotransmitters, reduction of oxidative stress, and anti- inflammatory effects. By promoting BDNF expression and activity, these herbs support neuroplasticity, cognitive function, and overall neuronal health. Novel antiepileptic drugs (AEDs) with distinct mechanisms of action demonstrate efficacy in refractory cases where traditional medications falter. Additionally, repurposing existing drugs for antiepileptic purposes presents a cost-effective strategy to broaden therapeutic choices. Cannabidiol (CBD), derived from cannabis herbs, has garnered attention for its anticonvulsant properties, offering a potential adjunctive therapy for refractory seizures. In conclusion, recent advances and innovative therapies represent a multifaceted approach to managing drug-resistant epilepsy. Leveraging precision medicine, neurostimulation technologies, novel pharmaceuticals, and complementary therapies, clinicians can optimize treatment outcomes and improve the life expectancy of patients living with refractory seizures. Genetic testing and biomarker identification now allow for personalized therapeutic approaches tailored to individual patient profiles. Utilizing next-generation sequencing techniques, researchers have elucidated genetic mutations.

Research development of Salacca zalacca skin against metabolic syndrome: A Review

Metabolic syndrome (MetS) is a group of metabolic disorders involving obesity, insulin resistance, dyslipidaemia and hypertension. The pathogenesis of MetS includes contributing factors such as genetics and epigenetics, physical inactivity, pollutant exposure, and high fat-high sugar intake that develop into a variety of interrelated pathomechanisms. There are various approaches to managing the MetS, including development of herbal medicine which is currently trending. One of the potential herbal products is Salacca zalacca (SZ) skin. Salak is a native Indonesian fruit that is also grown in the Asia Pacific region, such as Malaysia, Thailand, the Philippines, and others. However, the management of SZ skin is still limited. Thus, we reviewed studies on SZ skin related to MetS. In this review, we found that SZ skin of various cultivars contain saponins, flavonoids, triterpenoids, steroids, and phenols, which are sources of antioxidants. Moreover, an in vitro study found that SZ skin extract inhibits the activity of α-glucosidase enzyme, a key glucose breakdown enzyme that plays a role in the development of hyperglycaemia. In vivo studies also observed that SZ skin extract at a dose of 0.4 mg/mL can increase the expression of SIRT-1, BDNF, and SOD in zebrafish exposed to 3% glucose. In alloxan-induced diabetic rat model showed that the administration of SZ skin extract can reduce blood glucose levels. However, studies on SZ skin as anti-hypertensive and anti-hypercholesterol are very limited. Further studies are needed to consider SZ skin as a potential herbal medicine candidate, especially in managing MetS.

Neuronal nitric oxide synthase activation by tadalafil protects neurological impairments in a zebrafish larva model of hyperammonemia.

Hyperammonaemia (HA) is a metabolic disorder characterized by increased ammonia levels in the blood and is associated with severe neurological impairments. Some previous findings have shown the involvement of the nitric oxide pathway in HA-induced neurological impairments. The current study explored the impact of tadalafil on neurological impairments induced by HA in a zebrafish larval model due to its reported indirect interactions with the nitric oxide pathway. HA was induced in zebrafish larvae by ammonium acetate exposure from 2 to 9 days post fertilization (dpf). Locomotor and cognitive functions were analysed following the treatment. The levels of gamma-aminobutyric acid (GABA), glutamate, and dopamine were measured in the larval head. The expression of genes associated with apoptosis (baxa and bcl2a), selected neurotransmitter receptors and bdnf was analysed. The protein levels of CREB and nNOS were also quantified. Tadalafil incubation reversed the HA-associated locomotor and cognitive impairments in larvae. The treatment attenuated GABA, dopamine, and glutamate levels. An upregulation in the expression of grin1a, gria2b, drd1b, drd2b, bdnf, and bcl2a, and downregulation of gabrz, gabrd, gabrg2 and baxa was observed following tadalafil treatment. The protein expression showed increased nNOS, p-CREB(Ser133), and decreased p-nNOS(Ser847) levels in the larvae incubated with tadalafil. The study concluded that tadalafil mitigates HA-induced neurological impairments by activating neuronal nitric oxide synthase. The study highlighted the possible application of tadalafil in the symptomatic management of neurological impairments in HA provided its efficacy and safety are further ensured in higher mammals.

BDNF/Cyclin D1 Signaling System and Cognitive Performance After Perampanel and Lacosamide Treatment Singly or in Combination in an Experimental Model of Temporal Lobe Epilepsy.

Epilepsy is a common brain function disorder. The present study aims to evaluate the long-term effect of perampanel (PRM) and lacosamide (LCM), administered singly in a high-dose or in a low-dose combination of both, on comorbid anxiety, cognitive impairment, BDNF, and Cyclin D1 hippocampal expression in an experimental model of temporal lobe epilepsy with lithium-pilocarpine. PRM (3 mg/kg, p.o.)/LCM (30 mg/kg, p.o.) or PRM+LCM (0.5 mg/kg + 3 mg/kg, p.o.) treatments were administered three hours after the lithium-pilocarpine-induced status epilepticus and continued for up to ten weeks in adult Wistar rats. Our study demonstrated that perampanel and lacosamide administered singly in high doses improved epilepsy-associated cognitive impairment through ameliorating anxiety and facilitating passive learning and memory, with spatial and recognition memory measured in the elevated plus maze, step-through, Y-maze, and object recognition tests, respectively. In addition, the combination of both drugs in low doses demonstrated similar anxiolytic and cognitive-improving effects compared to the singly administered drugs. Moreover, the three experimental groups enhanced the hippocampal expression of the neurotrophic factor BDNF and mitigated the increased levels of the apoptotic factor Cyclin D1. These beneficial effects could be essential mechanisms through which administered anticonvulsants preserve neuronal survival and homeostasis in the CNS and especially in the hippocampus.

Neuroprotective effect of mealworm protein hydrolysate-derived bioactive peptides in human microglial cells

Abstract The larva of Tenebrio molitor, better known as mealworm, is one of the most studied insects today, since it was recently classified as safe for human consumption. Specifically, its high protein content makes it a splendid candidate for the search for bioactive peptides, with properties ranging from anti-inflammatory to neuroprotective. In this study, the effect of a digested hydrolysate on microglia cells (which previously demonstrated high anti-inflammatory activity in intestinal CACO-2 cells) was analysed, specifically on their levels of gene expression of various cytokines, such as IL-6, IL-10, or IL-1β, among others. In addition, four chemically synthesised peptides, selected from this digested hydrolysate based on in silico analysis, including the estimation of the bioactive properties of these peptides, their physicochemical properties and their toxicokinetic, were evaluated in the microglia cells as well. In addition, molecular docking assays of the peptides were performed with two receptors relevant to inflammation. Relevant changes in the expression of IL-6, IL-1β, and BDNF were observed due to the action of the peptides, especially in the case of IYVDAVIN and SLPSLPEPV. These results provide an insight on how specific peptides found in Tenebrio molitor could be used as therapeutics agent in the immunomodulation of brain cells.

Hypothyroidism Promotes Microglia M1 Polarization by Inhibiting BDNF-Promoted PI3K-Akt Signaling Pathway

Introduction: Hypothyroidism and its induced neurological-associated disorders greatly affect the health-related quality of patients’ life. Meanwhile, microglia in brain have essential regulatory functions on neurodegeneration, but the underlying link between hypothyroidism and microglia function is largely ambiguous. Methods: We deciphered how hypothyroidism modulates the polarization of microglia by constructing methimazole-induced mice model and checking the expression pattern of biomarkers of microglia M1 polarization. Then, we used lipopolysaccharide (LPS)-treated BV2 cells to explore the effecting factors on microglia M1 polarization. Finally, global transcriptome sequencing (RNA-seq) was utilized to identify the underlying regulatory mechanisms. Results: We detected that biomarkers of microglia M1 polarization and pro-inflammatory cytokines were significantly increased in hypothyroidism mice brain; hypothyroidism could also repress the expression of BDNF and TrkB, and the anti-inflammatory cytokine such as IL-10. In BV2 cells, LPS treatment decreased expression of BDNF, IL-10, and Arg1, while BDNF overexpression (BDNF-OE) significantly reversed the inflammation induced by LPS. BDNF-OE significantly repressed expression of iNOS and TNF-α, but increased expression of IL-10 and Arg1. For mechanism, RNA-seq analysis demonstrated that BDNF-OE could globally regulate transcriptome profile by affecting gene expression. In LPS-treated BV2 cells, BDNF-OE significantly altered expression pattern of genes involved in PI3K-Akt signaling pathway, including Thbs3, Myc, Gdnf, Thbs1, and Ccnd1 as upregulated genes, and Gnb4, Fgf22, Pik3r3, Pgf, Cdkn1a, and Pdgfra as downregulated genes. Myc, Gdnf, Thbs1, and Ccnd1 showed much higher expression levels than other genes in PI3K-Akt signaling pathway and could be promising targets of BDNF in reversing microglia M1 polarization. Conclusion: Our study demonstrated a sound conclusion that hypothyroidism promotes microglia M1 polarization by inhibiting BDNF expression in brain; BDNF could inhibit the M1 polarization of microglia by activating PI3K-Akt signaling pathway, which could serve as a promising therapeutic target for microglia-induced neurodegenerative or emotional disorders in future.

VNS facilitates the neurological function recovery after ischemia/reperfusion injury by regulating the A1/A2 polarization of astrocytes through the NMU-NMUR2 pathway.

Stroke is the second leading cause of death worldwide. Although conventional treatments such as thrombolysis and mechanical thrombectomy are effective, their narrow therapeutic window limits long-term neurological recovery. Previous studies have shown that vagus nerve stimulation (VNS) enhances neurological recovery after ischemia/reperfusion (I/R) injury, and neuromedin U (NMU) has neuroprotective effects. This study used a mouse model of cerebral I/R injury to investigate the potential mechanisms of NMU in VNS-mediated neurological improvement. The study consisted of two parts: first, assessing the dynamic expression of NMU and NMUR2, which peaked on day 14 post-I/R. NMUR2 was primarily localized in astrocytes, suggesting that the NMU-NMUR2 signaling pathway plays an important role in astrocyte regulation. Next, interventions with VNS, NMU, and R-PSOP+VNS were conducted to evaluate the role of this pathway in VNS-mediated recovery. The results showed that VNS significantly upregulated NMU and NMUR2 expression, which was blocked by the NMUR2 antagonist R-PSOP. VNS and NMU treatment increased the proportion of A2 astrocytes, reduced A1 astrocytes, and enhanced the expression of VEGF and BDNF, all of which were also blocked by R-PSOP. These findings indicate that the "VNS-NMU-NMUR2-astrocyte A1/A2 polarization-VEGF/BDNF pathway" plays a crucial role in promoting neurovascular remodeling, axonal and dendritic regeneration, and synaptic plasticity, thereby contributing to functional recovery.

Experimental study on the effect of Mongolian medicine warming acupuncture on proBDNF-tPA-BDNF balance in depression rats based on thermal imaging monitoring

Depression is a kind of mental illness affecting the whole world. Its pathological mechanism is complex, involving neurobiological and psychosocial factors.The depression model rats were randomly divided into control group, warm acupuncture group and drug treatment group. In order to evaluate the local thermal effect of warm acupuncture and moxibustion, real-time temperature changes of rat forebrain were monitored by thermal imaging technology. After the experiment, immunohistochemistry and Western blot were used to detect the expression levels of tPA and BDNF in the forebrain of each group of rats, and the relationship between tPA and BDNF was analyzed. The results of thermal imaging monitoring showed that local forebrain temperature in warm acupuncture group was significantly increased compared with control group (p < 0.05). The ratio of tPA to BDNF was significantly improved in the warm acupuncture and moxibustion group, suggesting that warm acupuncture and moxibustion can effectively regulate the balance of TPA-BDNF. The experimental results based on thermal imaging monitoring suggest that warm acupuncture can improve the balance of TPA-BDNF in the forebrain of depressed rats by promoting the expression of BDNF and tPA in the forebrain, which may provide a new method and mechanism basis for the treatment of depression.

206 The reduced BDNF expression in the psoriatic non-lesional keratinocytes may inhibit keratinocyte proliferation

206 The reduced BDNF expression in the psoriatic non-lesional keratinocytes may inhibit keratinocyte proliferation

Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder

BackgroundMutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absence of Cdkl5 negatively impacts neuronal proliferation, survival, and maturation in in vitro and in vivo models, resulting in behavioral deficits in the Cdkl5 KO mouse. While there is no targeted therapy for CDD, several studies showed that treatments enabling an increase in brain BDNF levels give rise to structural and behavioral improvements in Cdkl5 KO mice. P021, a tetra-peptide derived from the biologically active region of the human ciliary neurotrophic factor (CNTF), was found to enhance neurogenesis and synaptic plasticity by promoting an increase in BDNF expression in preclinical models of brain disorders, such as Alzheimer’s disease and Down syndrome, resulting in a beneficial therapeutic effect. Considering the positive actions of P021 on brain development and cognition associated with increased BDNF expression, the present study aimed to evaluate the possible beneficial effect of treatment with P021 in an in vitro and in vivo model of CDD.MethodsWe used SH-CDKL5-KO cells as an in vitro model of CDD to test the efficacy of P021 on neuronal proliferation, survival, and maturation. In addition, both young and adult Cdkl5 KO mice were used to evaluate the in vivo effects of P021, on neuroanatomical and behavioral defects.ResultsWe found that P021 treatment was effective in restoring neuronal proliferation, survival, and maturation deficits, as well as alterations in the GSK3β signaling pathway, features that characterize a human neuronal model of CDKL5 deficiency. Unexpectedly, chronic in vivo P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 KO mice, resulting in limited behavioral benefit.ConclusionsAt present, it remains to be understood whether initiating the treatment prenatally, or prolonging the duration of treatment will be necessary in order to achieve similar results in vivo in CDD mice to those obtained in vitro.

The interaction of BDNF with estrogen in the development of hypertension and obesity, particularly during menopause.

The expression of BDNF in both neuronal and non-neuronal cells is influenced by various stimuli, including prenatal developmental factors and postnatal conditions such as estrogens, dietary habits, and lifestyle factors like obesity, blood pressure, and aging. Central BDNF plays a crucial role in modulating how target tissues respond to these stimuli, influencing the pathogenesis of hypertension, mitigating obesity, and protecting neurons from aging. Thus, BDNF serves as a dynamic mediator of environmental influences, reflecting an individual's unique history of exposure. Estrogens, on the other hand, regulate various processes to maintain overall physiological well-being. Through nuclear estrogen receptors (ERα, ERβ) and the membrane estrogen receptor (GPER1), estrogens modulate transcriptional processes and signaling events that regulate the expression of target genes, such as ERα, components of the renin-angiotensin system (RAS), and hormone-sensitive lipase. Estrogens are instrumental in maintaining the set point for blood pressure and energy balance. BDNF and estrogens work cooperatively to prevent obesity by favoring lipolysis, and counteractively regulate blood pressure to adapt to the environment. Estrogen deficiency leads to menopause in women with low central BDNF level. This review delves into the complex mechanisms involving BDNF and estrogen, especially in the context of hypertension and obesity, particularly among postmenopausal women. The insights gained aim to inform the development of comprehensive therapeutic strategies for these prevalent syndromes affecting approximately 68% of adults.

Intravenous Immunomodulatory Nanoparticles Prevent Secondary Damage after Traumatic Brain Injury.

After traumatic brain injury (TBI), monocyte/macrophage infiltration is a key early step in the development of an inflammatory cascade that leads to substantial secondary damage. Intravenous (IV) immunomodulatory nanoparticle (IMP) administration after TBI limits inflammatory cell infiltration and reduces both behavioral decline and lesion size without any noticeable toxicity. Here we show that there is a dose-response relationship between the amount of IMP administered and tissue damage which plateaus at a well-tolerated dose. There is a therapeutic window of efficacy for IMP administration of at least 6 h after injury with some benefit observed when treatment was delayed for 12 h after injury. Single cell RNA sequencing demonstrated substantial changes in gene expression after TBI in both neural and non-neural cells in the brain, and IMP administration ameliorated many of the changes. Particularly notable were significant unexpected changes in CCR1, CXCR2, and BDNF expression in vascular smooth muscle cells that may participate in injury responses after TBI. Thus, IMP treatment within 6 h after TBI limits inflammatory responses and gliosis, improves anatomical and behavioral outcomes and prevents detrimental changes in gene expression in both neural and non-neural cellular elements of the brain. IMPs are non-toxic and are made of an FDA-approved material that is stable at room temperature. They could easily be given IV immediately after TBI in the field by emergency medical technicians or in the emergency room to prevent secondary damage, thereby improving outcomes.

Multigenerational impact of chronic exposure to mercury chloride on maternal care, puberty, fertility, and hypothalamic function in female mice

Chronic exposure to low doses of mercury, one of the ten most dangerous chemicals for public health, has been associated with problems in fertility. Our study aims to investigate the effect of chronic exposure to a low dose of mercury chloride on the reproductive health of female mice and maternal behavior throughout generations using the maternal lineage for the first and second generations, either by direct exposure with F1 and F2 or via the germ cells with F2'. To our knowledge, these modalities have never been addressed before. Among the main outcomes of our research, we provide evidence that mercury exposure induces multigenerational alterations of maternal care and reproduction in female mice, respectively, through alterations of gene expression in the hypothalamus. The decline in maternal care behaviors observed in all exposed groups involved reduced nursing frequency and grooming/licking behaviors. The reproductive phenotype found across generations in our study directly exposed the F1 and F2, or even in the germline-exposed F2′, is defined by a delay in the vaginal opening, a delay in the first estrus, altered estrous cyclicity, and a decrease in interest in mating behavior observed in the two-choice preference test. These results were accompanied by a reduction in the mRNA expression of kiss1 and Gnrh1 in the hypothalamus, critical hormones in the HPG axis for initiating ovulation and estrous cycles. Furthermore, the F1, F2, and F2′ exposed mice had significantly decreased mRNA expression of Bdnf, which might indicate impaired communication within the neural circuits controlling reproduction. Additionally, increased Tnf-α and Il6 mRNA expression indicates a possible inflammatory response to mercury exposure across generations.