Brain-derived Neurotrophic Factor Overexpression Research Articles

Treadmill running on neuropathic pain: via modulation of neuroinflammation.

Neuropathic pain is a type of chronic pain caused by an injury or somatosensory nervous system disease. Drugs and exercise could effectively relieve neuropathic pain, but no treatment can completely stop neuropathic pain. The integration of exercise into neuropathic pain management has attracted considerable interest in recent years, and treadmill training is the most used among exercise therapies. Neuropathic pain can be effectively treated if its mechanism is clarified. In recent years, the association between neuroinflammation and neuropathic pain has been explored. Neuroinflammation can trigger proinflammatory cytokines, activate microglia, inhibit descending pain modulatory systems, and promote the overexpression of brain-derived neurotrophic factor, which lead to the generation of neuropathic pain and hypersensitivity. Treadmill exercise can alleviate neuropathic pain mainly by regulating neuroinflammation, including inhibiting the activity of pro-inflammatory factors and over activation of microglia in the dorsal horn, regulating the expression of mu opioid receptor expression in the rostral ventromedial medulla and levels of γ-aminobutyric acid to activate the descending pain modulatory system and the overexpression of brain-derived neurotrophic factor. This article reviews and summarizes research on the effect of treadmill exercise on neuropathic pain and its role in the regulation of neuroinflammation to explore its benefits for neuropathic pain treatment.

Impaired synaptic plasticity and decreased glutamatergic neuron excitability induced by SIRT1/BDNF downregulation in the hippocampal CA1 region are involved in postoperative cognitive dysfunction

BackgroundPostoperative cognitive dysfunction (POCD) is a common complication after anesthesia/surgery, especially among elderly patients, and poses a significant threat to their postoperative quality of life and overall well-being. While it is widely accepted that elderly patients may experience POCD following anesthesia/surgery, the exact mechanism behind this phenomenon remains unclear. Several studies have indicated that the interaction between silent mating type information regulation 2 homologue 1 (SIRT1) and brain-derived neurotrophic factor (BDNF) is crucial in controlling cognitive function and is strongly linked to neurodegenerative disorders. Hence, this research aims to explore how SIRT1/BDNF impacts cognitive decline caused by anesthesia/surgery in aged mice.MethodsOpen field test (OFT) was used to determine whether anesthesia/surgery affected the motor ability of mice, while the postoperative cognitive function of 18 months old mice was evaluated with Novel object recognition test (NORT), Object location test (OLT) and Fear condition test (FC). The expressions of SIRT1 and other molecules were analyzed by western blot and immunofluorescence staining. The hippocampal synaptic plasticity was detected by Golgi staining and Long-term potentiation (LTP). The effects of SIRT1 and BDNF overexpression as well as chemogenetic activation of glutamatergic neurons in hippocampal CA1 region of 18 months old vesicular glutamate transporter 1 (VGLUT1) mice on POCD were further investigated.ResultsThe research results revealed that older mice exhibited cognitive impairment following intramedullary fixation of tibial fracture. Additionally, a notable decrease in the expression of SIRT1/BDNF and neuronal excitability in hippocampal CA1 glutamatergic neurons was observed. By increasing levels of SIRT1/BDNF or enhancing glutamatergic neuron excitability in the CA1 region, it was possible to effectively mitigate synaptic plasticity impairment and ameliorate postoperative cognitive dysfunction.ConclusionsThe decline in SIRT1/BDNF levels leading to changes in synaptic plasticity and neuronal excitability in older mice could be a significant factor contributing to cognitive impairment after anesthesia/surgery.Graphical

Urinary Bladder Dysfunction in a Novel Model of Neuroendocrine Stress

Chronic stress can lead to urinary bladder dysfunction and pain either through actions within the central nervous system or by mechanisms that are locally induced in the bladder. Prolonged upregulation of brain-derived neurotrophic factor (BDNF) in the paraventricular nucleus of the hypothalamus (PVN) has been shown to induce hypertension and chronically elevate activities of the sympathetic nervous system and hypothalamus-pituitary-adrenal axis. Taking advantage of this mechanism, we created a novel model of chronic neuroendocrine stress by subjecting male Sprague Dawley rats to bilateral PVN injections of AAV2 viral vectors expressing either BDNF or GFP (for control). We tested the hypothesis that model-induced chronic neuroendocrine stress would impair bladder function. Bladder activity was assessed 10 weeks post-injections by monitoring the number of urinary voids and average urinary void volume along with water intake over a 48-hour period. To further characterize changes in the urinary bladder, bladder weights were recorded, and in vitro bladder strip experiments were conducted 14 weeks after viral vector injections. BDNF overexpression in the hypothalamus led to significantly lower daily urine output even though water intake remained unaffected, suggesting that BDNF-treated animals showed a significantly higher non-urine-related fluid compared to GFP controls (daily urine output = GFP: 33.85±4.94, BDNF: 14.82±2.18, p < 0.01. Interestingly, despite a lower total daily urine volume, BDNF-treated animals had a significantly higher number of urinary voids (GFP: 7.50±1.42, BDNF: 15.38±2.76; GFP vs. BDNF: p < 0.001) and lower average void volume (GFP: 1.19±0.15, BDNF: 0.27±0.07; GFP vs. BDNF: p < 0.01), thus emulating the overactive bladder phenotype, a common complication in humans with chronic stress. These findings were complemented by in vitro experiments where bladder strips from BDNF rats showed significantly higher contractility as tested with high K+ concentration and electric field stimulation. Moreover, Carbachol-induced stimulation of muscarinic receptors in BDNF bladder strips also trended towards higher contractility. However, urinary bladder weights were unaffected by BDNF overexpression. In summary, we demonstrated that prolonged hypothalamic BDNF overexpression, a model of chronic neuroendocrine stress, leads to significant alterations in bladder function such that BDNF-treated rats exhibited a higher number of urinary voids and lower average void volume compared to GFP controls, and bladder strip experiments suggest that enhanced smooth muscle contractility may contribute to this overactive bladder phenotype. These findings from our novel experimental model will help elucidate pathways through which neuroendocrine stress mechanisms contribute to the development of the overactive bladder syndrome. Funded by R01HL166464, R03AG072016 and R01DK125543. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Enhancing nerve regeneration in infraorbital nerve injury rat model: effects of vitamin B complex and photobiomodulation.

Orofacial nerve injuries may result in temporary or long-term loss of sensory function and decreased quality of life in patients. B vitamins are required for DNA synthesis and the repair and maintenance of phospholipids. In particular, vitamins B1, B6, and B12 are essential for neuronal function. Deficiency in vitamin B complex (VBC) has been linked to increased oxidative stress, inflammation and demyelination. Photobiomodulation (PBM) has antioxidant activity and is neuroprotective. In addition, a growing literature attests to the positive effects of PBM on nerve repair. To assess the effect of PBM and VBC on regenerative process we evaluated the expression of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), myelin basic protein (MBP), laminin and neurofilaments (NFs) using Western blotting to identify regenerative pattern after chronic constriction injury of the infraorbital nerve (CCI IoN) treated by PBM, VBC or its combination. After CCI IoN, the rats were divided into six groups naive, sham, injured (CCI IoN), treated with photobiomodulation (904nm, 6.23J/cm2, CCI IoN + PBM), treated with VBC (containing B1, B6 and B12) 5 times, CCI IoN + VBC) and treated with PBM and VBC (CCI IoN + VBC + PBM). The treatments could revert low expression of BDNF, MBP and laminin. Also reverted the higher expression of neurofilaments and enhanced expression of NGF. PBM and VBC could accelerate injured infraorbital nerve repair in rats through reducing the expression of neurofilaments, increasing the expression of BDNF, laminin and MBP and overexpressing NGF. These data support the notion that the use of PBM and VBC may help in the treatment of nerve injuries. This finding has potential clinical applications.

Abstract 5414: BDNF/TrKB signaling may lead to higher incidence of perineural invasion in men with prostate cancer

Abstract Perineural invasion (PNI) is a crucial mechanism facilitating prostate cancer metastasis. PNI encompasses perineural, circumferential, and intraneural invasion, with cancer cells closely interacting with nerves. Evidence suggests that cancer cells utilize the nervous system for metastasis through signaling pathways. PNI is associated with poor prognoses in various cancers, but its role in prostate cancer remains unclear. PCa primarily metastasizes through systemic routes, such as lymphatic and circulatory systems. Metastasizing cancer cells undergo epithelial-mesenchymal transition (EMT), enhancing their motility. SNAIL1, a transcriptional repressor, induces EMT and promotes cancer cell migration, including towards nerves, termed neurite outgrowth. Neurite outgrowth involves intricate signaling between tumor cells and nerves, possibly facilitating cancer cell infiltration into nerve sheaths and PNI. Our lab has shown SNAIL1 in interactions with neurotrophic factors like Brain-Derived Neurotrophic Factor (BDNF) and Tyrosine Kinase Receptor Beta (TrkB), modulating cancer cell behavior. TrkB is overexpressed in various cancers, while BDNF signaling contributes to EMT via the Twist-Snail axis. BDNF may also play a role in PNI pathogenesis. Our hypothesis posits the BDNF-TrkB axis drives aggressive prostate cancer and PNI. This study employed prostate cancer cell lines for comprehensive analysis. We assessed BDNF expression in different cell lines, particularly those with high Snail levels, and analyzed BDNF transcript levels via real-time quantitative PCR following RNA extraction and reverse transcription. We explored whether BDNF overexpression enhanced cancer cell migration towards nerves, employing migration assays. Our findings indicated heightened migration in BDNF-high cell lines, C42, PC3, and MDA-2b, compared to BDNF knockdown cells. Additionally, a TrkB inhibitor, K252a, attenuated migration due to BDNF-induced TrkB phosphorylation. Our study establishes that BDNF/TrkB signaling promotes prostate cancer cell migration towards nerves, a phenomenon reversible with K252a, offering a potential strategy to impede prostate cancer progression and metastasis. Citation Format: Gabrielle Joy Edwards, Valerie Odero-Marah. BDNF/TrKB signaling may lead to higher incidence of perineural invasion in men with prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5414.

Locus Coeruleus-Dorsolateral Septum Projections Modulate Depression-Like Behaviors via BDNF But Not Norepinephrine.

Locus coeruleus (LC) dysfunction is involved in the pathophysiology of depression; however, the neural circuits and specific molecular mechanisms responsible for this dysfunction remain unclear. Here, it is shown that activation of tyrosine hydroxylase (TH) neurons in the LC alleviates depression-like behaviors in susceptible mice. The dorsolateral septum (dLS) is the most physiologically relevant output from the LC under stress. Stimulation of the LCTH -dLSSST innervation with optogenetic and chemogenetic tools bidirectionally can regulate depression-like behaviors in both male and female mice. Mechanistically, it is found that brain-derived neurotrophic factor (BDNF), but not norepinephrine, is required for the circuit to produce antidepressant-like effects. Genetic overexpression of BDNF in the circuit or supplementation with BDNF protein in the dLS is sufficient to produce antidepressant-like effects. Furthermore, viral knockdown of BDNF in this circuit abolishes the antidepressant-like effect of ketamine, but not fluoxetine. Collectively, these findings underscore the notable antidepressant-like role of the LCTH -dLSSST pathway in depression via BDNF-TrkB signaling.

Brain-Derived Neurotrophic Factor (BDNF) in Mechanisms of Autistic-like Behavior in BTBR Mice: Crosstalk with the Dopaminergic Brain System.

Disturbances in neuroplasticity undoubtedly play an important role in the development of autism spectrum disorders (ASDs). Brain neurotransmitters and brain-derived neurotrophic factor (BDNF) are known as crucial players in cerebral and behavioral plasticity. Such an important neurotransmitter as dopamine (DA) is involved in the behavioral inflexibility of ASD. Additionally, much evidence from human and animal studies implicates BDNF in ASD pathogenesis. Nonetheless, crosstalk between BDNF and the DA system has not been studied in the context of an autistic-like phenotype. For this reason, the aim of our study was to compare the effects of either the acute intracerebroventricular administration of a recombinant BDNF protein or hippocampal adeno-associated-virus-mediated BDNF overexpression on autistic-like behavior and expression of key DA-related and BDNF-related genes in BTBR mice (a widely recognized model of autism). The BDNF administration failed to affect autistic-like behavior but downregulated Comt mRNA in the frontal cortex and hippocampus; however, COMT protein downregulation in the hippocampus and upregulation in the striatum were insignificant. BDNF administration also reduced the receptor TrkB level in the frontal cortex and midbrain and the BDNF/proBDNF ratio in the striatum. In contrast, hippocampal BDNF overexpression significantly diminished stereotypical behavior and anxiety; these alterations were accompanied only by higher hippocampal DA receptor D1 mRNA levels. The results indicate an important role of BDNF in mechanisms underlying anxiety and repetitive behavior in ASDs and implicates BDNF-DA crosstalk in the autistic-like phenotype of BTBR mice.

Activation of mTOR signaling in the paraventricular nucleus of the hypothalamus (PVN) contributes to stress- and BDNF-induced hypertensive responses

The paraventricular nucleus of the hypothalamus (PVN) integrates afferent inputs from limbic, medullary and hypothalamic regions to orchestrate cardiovascular stress responses via its medullary and spinal projections. Brain-derived neurotrophic factor (BDNF) is an important pro-hypertensive regulator in the PVN upregulated during stress that transforms the PVN neurocircuitry to facilitate responsiveness to hypertensive stimuli by shifting the balance of excitatory/inhibitory synaptic mechanisms. Mechanistic target of rapamycin (mTOR), as part of mTOR complex-1 (mTORC1), is stimulated by trophic factors, such as BDNF, in other brain regions to induce changes in neuronal morphology and increases in neuronal excitability. We tested the hypothesis that activation of mTORC1 in the PVN by BDNF and acute stress plays a key role in stimulating hypertensive responses. Male Sprague Dawley (SD) rats (n=4/group) received bilateral PVN injections of AAV2 viral vectors expressing myc-tagged BDNF (BDNFmyc), shRNA against TSC1 (a repressor of mTORC1) to stimulate mTORC1, shRNA against Raptor (a key component of the mTORC1) to inhibit mTORC1 or GFP for control. Blood pressure and heart rate were monitored by telemetry for 4 wks, and cardiovascular responses to restraint (60min) and water stress (15 minutes, 1-cm deep, 25°C water) were recorded 4-5 wks after vector injections. Vector injections were confirmed and neuronal morphology as well as pS6 levels (a marker of mTOR activity) were analyzed with immunofluorescence. Activation mTORC1 with TSC1 knock-down significantly increased resting blood pressure compared with control, but inhibition of mTORC1 with Raptor knock-down had no effect. BDNF overexpression significantly elevated blood pressure, as we have shown previously, and these increases were completely abolished by Raptor knock-down (daytime mean arterial pressure: shTSC1: 108.0±1.4*; BDNFmyc: 131.4±2.5*; shRaptor: 101.8±0.9; BDNF+shRaptor: 102.7±2.8#, GFP: 96.5±1.8 mmHg at week 4, *p<0.05 vs GFP; #p<0.05 vs. BDNFmyc). In addition, mTORC1 inhibition with Raptor knock-down also significantly diminished stress-induced hypertensive responses. Maximum blood pressure increase in shRaptor rats was 30.3±1.3 mmHg during restraint and 26.0±3.4 mmHg during water stress vs 43.8±2.2 and 37.4±2.5 mmHg in control rats (p<0.05). Immunofluorescence of pS6, an indicator of mTOR activity, and neuronal soma size were significantly elevated by both TSC1 knock-down and BDNF overexpression in the PVN, whereas Raptor knock-down reduced pS6 intensity and soma size and completely abolished the effects of BDNF. In summary, we demonstrated that mTOR activation in the PVN significantly increased blood pressure both during baseline conditions and during acute stress, and mediated hypertensive responses and neuronal morphological changes elicited by BDNF. Supported by R01 HL133211. R01 HL133211 (BE), R03 AG072016 (BE) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Brain-derived neurotrophic factor promotes airway smooth muscle cell proliferation in asthma through regulation of transient receptor potential channel-mediated autophagy

ObjectiveIncreased proliferation of airway smooth muscle cells (ASMCs) is a key feature of airway remodeling in asthma. This study aims to determine whether brain-derived neurotrophic factor (BDNF) regulates ASMC proliferation and airway remodeling via the transient receptor potential channels (TRPCs)/autophagy axis. MethodsHuman ASMCs were isolated and passively sensitized with human asthmatic serum. Protein levels of BDNF and its receptor TrkB, TRPC1/3/6, autophagy markers, intracellular Ca2+ concentration ([Ca2+]i), LC3 immunofluorescence, cell proliferation, cell cycle population were examined. Wistar rats were sensitized with OVA to establish asthma models. ResultsIn asthmatic serum-sensitized human ASMCs, BDNF overexpression or recombinant BDNF (rhBDNF) increased TrkB/TRPC1/3/6 axis, [Ca2+]i, autophagy level, cell proliferation, cell number in the S+G2/M phase and decreased cell number in the G0/G1 phase, whereas BDNF knockdown exerted the opposite effects. Furthermore, TRPC channel blocker SKF96365 and TRPC1/3/6 knockdown reversed the effects of the rhBDNF-mediated induction of [Ca2+]i, autophagy level, cell proliferation and cell number in the S+G2/M phase. Moreover, the autophagy inhibitor (3-MA) rescued the rhBDNF-mediated induction of cell proliferation and cell number in the S+G2/M phase. Further in vivo assays revealed that BDNF altered the pathology of airway remodeling, promoted the infiltration of inflammatory cells, promoted the proliferation of ASMCs, and upregulated the protein levels of TrkB, TRPC1/3/6, and autophagy markers in asthma model rats. ConclusionWe conclude that BDNF promotes ASMCs proliferation in asthma through TRPC-mediated autophagy induction.

Effects of brain-derived neurotrophic factor and adeno-associated viral vector on morphine-induced condition through target concentration changes in the ventral tegmental area and nucleus accumbens

Morphine remains the standard analgesic for severe pain. However, the clinical use of morphine is limited by the innate tendency of opiates to become addictive. Brain-derived neurotrophic factor (BDNF) is a growth factor that is protective against many mental disorders. This study aimed to evaluate the protective function of BDNF on morphine addiction based on the behavioural sensitisation (BS) model and assess potential changes in downstream molecular tropomyosin-related kinase receptor B (TrkB) and cyclic adenosine monophosphate response element binding protein (CREB) expression caused by overexpression of BDNF. We divided 64 male C57BL/6 J mice into saline, morphine, morphine plus adeno-associated viral vector (AAV), and morphine plus BDNF groups. After administering the treatments, behavioural tests were conducted during the development and expression phases of BS, followed by a western blot analysis. All data were analysed by one- or two-way analysis of variance. The overexpression of BDNF in the ventral tegmental area (VTA) caused by BDNF-AAV injection decreased the total distance of locomotion in mice who underwent morphine-induced BS and increased the concentrations of BDNF, TrkB, and CREB in the VTA and nucleus accumbens (NAc). BDNF exerts protective effects against morphine-induced BS by altering target gene expression in the VTA and NAc.

Identification of key genes involved in neural regeneration and the repairing effect of BDNF-overexpressed BMSCs on spinal cord ischemia-reperfusion injury in rats

Bone marrow mesenchymal stem cells (BMSCs) can repair spinal cord ischemia-reperfusion injury (SCII); however, only a few BMSCs are usually located in the injured spinal cord. Since the brain-derived neurotrophic factor (BDNF) can promote neural development and maturation, we hypothesised that BDNF-overexpressed BMSCs can ameliorate SCII more effectively than BMSCs alone. To determine the effect of BDNF overexpression on SCII repair, BDNF-overexpressed BMSCs and BMSCs were transplanted into SCII rats. Our results revealed that BDNF-overexpressed BMSCs can better promote the recovery of damaged spinal cords than BMSCs alone. Gene chip detection of spinal cord tissues showed 803 differentially expressed genes in all groups. BTG anti-proliferation factor 2 (Btg2), FOS like 2 (Fosl2), early growth response protein 1 (Egr1), and serpin family E member 1 (Serpine1) were identified as key interrelated genes based on their expression trends, as validated via quantitative PCR and protein–protein interaction network analysis. A co-expression network was constructed to further explore the role of the candidate key genes using Pearson correlation analysis. Cluster 5 was identified as the key cluster using community discovery algorithms. Functional analysis of Cluster 5 genes revealed that this cluster was mainly involved in the stress-activated MAPK cascade, p38MAPK cascade, and apoptosis. Notably, Egr1 may play an important role in SCII repair as the top hub gene in Cluster 5. Therefore, the repair activity of transplanted BDNF-overexpressed BMSCs in SCII rats is better than that of BMSCs alone, which may be regulated by the interactions between Btg2, Fosl2, Egr1, Serpine1, and BDNF.

EA participates in pain transition through regulating KCC2 expression by BDNF-TrkB in the spinal cord dorsal horn of male rats

The pathogenesis of chronic pain is complex and poorly treated, seriously affecting the quality of life of patients. Electroacupuncture (EA) relieves pain by preventing the transition of acute pain into chronic pain, but its mechanism of action is still unclear. Here, we aimed to investigate whether EA can inhibit pain transition by increasing KCC2 expression via BDNF-TrkB. We used hyperalgesic priming (HP) model to investigate the potential central mechanisms of EA intervention on pain transition. HP model male rats showed significant and persistent mechanically abnormal pain. Brain derived neurotrophic factor (BDNF) expression and Tropomyosin receptor kinase B (TrkB) phosphorylation were upregulated in the affected spinal cord dorsal horn (SCDH) of HP model rats, accompanied by K+-Cl-- Cotransporter-2 (KCC2) expression was down-regulated. EA significantly increased the mechanical pain threshold in HP model male rats and decreased BDNF and p-TrkB overexpression and upregulated KCC2 expression. Blockade of BDNF with BDNF neutralizing antibody attenuated mechanical abnormal pain in HP rats. Finally, administration of exogenous BDNF by pharmacological methods reversed the EA-induced resistance to abnormal pain. In all, these results suggest that BDNF-TrkB contributes to mechanical abnormal pain in HP model rats and that EA ameliorates mechanical abnormal pain through upregulation of KCC2 by BDNF-TrkB in SCDH. Our study further supports EA as an effective treatment to prevent the transition of acute pain into chronic pain.

BDNF and its signaling in cancer.

Brain-derived neurotrophic factor (BDNF) belongs to the family of neurotrophic factors that can potentiallyincrease cancer cell growth, survival, proliferation, anoikis, and migration by tyrosine kinase receptors TrkB and thep75NTR death receptor. The activation of BDNF/TrkB pathways leads to several downstream signaling pathways,including PI3K/Akt, Jak/STAT, PLCγ, Ras-Raf-MEK-ERK, NF-kB, and transactivation of EGFR. The current reviewaimed to provide an overview of the role of BDNF and its signaling in cancer. We searched a majormedical database, PubMed, to identify eligible studies for a narrative synthesis. Pathological examinationsdemonstrate BDNF overexpression in human cancer, notably involving the prostate, lung, breast, and underlyingtissues, associated with a higher death rate and poor prognosis. Therefore, measurement of BDNF, either foridentifying the disease or predicting response to therapy, can be helpful in cancer patients. Expression profilingstudies have recognized the role of microRNAs (miR) in modulating BDNF/TrkB pathways, such as miR-101, miR-107, miR-134, miR-147, miR-191, miR-200a/c, miR-204, miR-206, miR-210, miR-214, miR-382, miR-496, miR-497, miR-744, and miR-10a-5p, providing a potential biological mechanism by which targeted therapies may correlatewith decreased BDNF expression in cancers. Clinical studies investigating the use of agents targeting BDNFreceptors and related signaling pathways and interfering with the related oncogenic effect, including Entrectinib,Larotrectinib, Cabozantinib, Repotrectinib, Lestaurtinib, and Selitrectinib, are in progress. The aberrantsignaling of BDNF is implicated in various cancers. Well-designed clinical trials are needed to clarify the BDNF rolein cancer progression and target it as a therapeutic method.

Brain-derived neurotrophic factor overexpression in taste buds diminishes chemotherapy induced taste loss.

Vismodegib is used in patients suffering from advanced basal cell carcinoma (BCC), but 100% of the patients taking it report dysgeusia and 50% discontinue the treatment. Treatment with neurotrophic factors can stimulate neuronal survival and functional improvement in injured organs. Here, we analysed novel transgenic mouse lines in which brain-derived neurotrophic factor (BDNF) is overexpressed in taste buds, to examine whether higher levels of BDNF would reduce or prevent negative side effects of vismodegib in the taste system. BDNF plays crucial roles for development, target innervation, and survival of gustatory neurons and taste buds. The behavioural test in this study showed that vehicle-treated wild-type mice prefered 10 mM sucrose over water, whereas vismodegib treatment in wild-type mice caused total taste loss. Gustducin-BDNF mice had a significantly increased preference for low concentration of sucrose solution over water compared to wild-type mice, and most importantly the transgenic mice were able to detect low concentrations of sucrose following vismodegib treatment. We evaluated taste cell morphology, identity, innervation and proliferation using immunohistochemistry. All drug-treated mice exhibited deficits, but because of a possible functional upcycled priming of the peripheral gustatory system, GB mice demonstrated better morphological preservation of the peripheral gustatory system. Our study indicates that overexpression of BDNF in taste buds plays a role in preventing degeneration of taste buds. Counteracting the negative side effects of vismodegib treatment might improve compliance and achieve better outcome in patients suffering from advanced BCC.

Regulation of inflammation by VEGF/BDNF signaling in mouse retinal Müller glial cells exposed to high glucose.

The inflammatory changes seem to play an important role in the development of diabetic retinopathy (DR). Anti-VEGF therapy has been testified to inhibit inflammation in animal models of diabetes, but the detailed mechanisms during this process are not yet clear. Müller glial cells (MGCs) in the mammalian retina are deeply involved in DR, while the BDNF overexpression reduces inflammation in diabetic mice. In this research, we aimed to explore the relationship between VEGF and BDNF in mouse retinal MGCs during inflammation of diabetes. We examined the expression of glutamine-synthetase (GS), glial fibrillary acidic protein (GFAP), vascular-endothelial growth factor (VEGF), interleukin-1beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) at different time points after mouse retinal MGCs exposed to high glucose (25mM). We also explored changes in the expression of brain-derived neurotrophic factor (BDNF), nuclear factor kappa B (NF-κB), IL-1β, and TNF-α in MGCs after treatments with anti-VEGF, VEGF siRNA, BDNF siRNA, BDNF recombination protein, and NF-κB inhibitor. In mouse retinal MGCs exposed to high glucose, BDNF was increased after treatments with anti-VEGF or VEGF siRNA. BDNF was decreased in MGCs from VEGF overexpressed mice. Moreover, the expressions of NF-κB, IL-1β, and TNF-α changed with BDNF: NF-κB, IL-1β, and TNF-α were increased after treatments with BDNF siRNA; NF-κB, IL-1β, and TNF-α were decreased after treatments with BDNF recombination protein. VEGF may regulate cytokines (IL-1β and TNF-α) by BDNF/NF-κB signaling pathway. The regulation of the VEGF/BDNF/NF-κB signaling pathway may be a significant therapeutic strategy for DR.

Gastrodin promotes the regeneration of peripheral nerves by regulating miR-497/BDNF axis

BackgroundGastrodin (GAS), is a kind of phenolic compound extracted from the traditional Chinese herbal medicine Gastrodia elata Blume (GEB). This study was aimed at probing into the protective effect of GAS on peripheral nerve injury (PNI) and the underlying mechanism.MethodsA rat model with PNI was established, followed by intraperitoneal injection of GAS (20 mg/kg/day). Sciatic nerve function index (SFI) was used to analyze the function of sciatic nerve. The amplitude and latency of compound muscle action potential (CMAP) were examined by electrophysiology. Schwann cells (SCs) were isolated from fetal rats and treated with GAS 200 μg/mL, and H2O2-induced model of oxidative stress injury was established. EdU and Transwell assays were adopted to detect the viability and migration of SCs. Dual-luciferase reporter gene assays were applied to verify the binding site between miR-497 and brain-derived neurotrophic factor (BDNF) 3’UTR. MiR-497 expression was probed by quantitative real-time polymerase chain reaction (qRT-PCR). BDNF, neurofilament-200 (NF-200) and myelin basic protein (MBP) expression levels were detected by Western blotting. Malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, glutathione content (GSH) and catalase (CAT) activity in SCs were also measured.ResultsGAS treatment could significantly increase the SFI and amplitude of CMAP, shorten the refractory period, and ameliorate muscle atrophy of the rats with PNI. GAS treatment could markedly restrain miR-497 expression and increase the expression levels of BDNF, NF-200 and MBP in SCs. BDNF was confirmed as the target of miR-497 and BDNF overexpression could reverse the impacts of miR-497 overexpression on the proliferation, migration, and oxidative stress response of SCs.ConclusionsGAS promotes the recovery of PNI via modulating miR-497 / BDNF axis and inhibiting oxidative stress.Graphical abstract

Suppressive Effects of Gelsemine on Anxiety-like Behaviors Induced by Chronic Unpredictable Mild Stress in Mice.

Gelsemine is an active principle and a major alkaloid found in Gelsemium genus of plants belonging to the Loganiaceae family. The aim of the present study was to explore whether gelsemine exerts anxiolytic effects on a mouse model of chronic-unpredictable-mild-stress (CUMS)-induced anxiety-like behaviors. NOD-like receptor protein 3 (NLRP3) inflammasome, downregulated cAMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were also evaluated as potential mechanisms. First, gelsemine reversed a CUMS-induced decrease in body-weight gain in mice. Next, gelsemine alleviated CUMS-induced anxiety-like behaviors, as evidenced by the increased distance traveled in the central zone of the open-field test, both the increased percentage of time spent and distance traveled in the light compartment, the increased number of transitions between compartments in the light/dark-transition test, and the increased percentage of entries and time spent in the open arm of the elevated plus-maze. In addition, gelsemine decreased the levels of pro-inflammatory cytokines, including interleukin (IL)-1β and IL-6, in the hypothalamus and hippocampus of CUMS mice. Interestingly, further investigations revealed that gelsemine inhibited the CUMS-induced activation of NLRP3-inflammasome pathways and downregulated CREB and BDNF overexpression in the hypothalamus. In summary, gelsemine alleviated anxiety-like behaviors in the CUMS-induced mouse model. Gelsemine exerted its anxiolytic effects by modulating the NLRP3 and CREB/BDNF pathways.

The overexpression of GDNF in nucleus accumbens suppresses alcohol-seeking behavior in group-housed C57Bl/6J female mice

BackgroundCraving for alcohol, in other words powerful desire to drink after withdrawal, is an important contributor to the development and maintenance of alcoholism. Here, we studied the role of GDNF (glial cell line-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) on alcohol-seeking behavior in group-housed female mice.MethodsWe modeled alcohol-seeking behavior in C57Bl/6J female mice. The behavioral experiments in group-housed female mice were performed in an automated IntelliCage system. We conducted RT-qPCR analysis of Gdnf, Bdnf, Manf and Cdnf expression in different areas of the female mouse brain after alcohol drinking conditioning. We injected an adeno-associated virus (AAV) vector expressing human GDNF or BDNF in mouse nucleus accumbens (NAc) after ten days of alcohol drinking conditioning and assessed alcohol-seeking behavior. Behavioral data were analyzed by two-way repeated-measures ANOVA, and statistically significant effects were followed by Bonferroni’s post hoc test. The student’s t-test was used to analyze qPCR data.ResultsThe RT-qPCR data showed that Gdnf mRNA level in NAc was more than four times higher (p < 0.0001) in the mice from the sweetened alcohol group compared to the water group. Our data showed a more than a two-fold decrease in Manf mRNA (p = 0.04) and Cdnf mRNA (p = 0.02) levels in the hippocampus and Manf mRNA in the VTA (p = 0.04) after alcohol consumption. Two-fold endogenous overexpression of Gdnf mRNA and lack of CDNF did not affect alcohol-seeking behavior. The AVV-GDNF overexpression in nucleus accumbens suppressed alcohol-seeking behavior while overexpression of BDNF did not.ConclusionsThe effect of increased endogenous Gdnf mRNA level in female mice upon alcohol drinking has remained unknown. Our data suggest that an increase in endogenous GDNF expression upon alcohol drinking occurs in response to the activation of another mesolimbic reward pathway participant.

Brain-derived neurotrophic factor attenuates cognitive impairment and motor deficits in a mouse model of Parkinson's disease.

BackgroundParkinson's disease (PD) is one of the most common neurodegenerative disorders that seriously impair the life quality and survival of patients. Herein, we aim to investigate the neuroprotective roles of brain‐derived neurotrophic factor (BDNF) in PD mice and reveal the underlying mechanisms. BDNF overexpression was achieved via the injection of adeno‐associated viruses (AAV) with BDNF gene.MethodsPD mouse model was established by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) treatment. Tests of rotarod, pole, open field, and novel object recognition were conducted to evaluate the motor and cognitive functions of treated mice.ResultsMitochondrial impairment, mitochondrial respiratory chain enzymes, and tyrosine hydroxylase (TH)‐positive dopaminergic neurons were detected to uncover the molecular mechanism. BDNF overexpression attenuated motor deficits and cognitive impairment in MPTP‐induced PD mice. Mechanistically, BDNF mitigated mitochondrial impairment increased the activity of respiratory chain Complex I and Ⅱ+III, and finally alleviated TH‐positive dopaminergic neuron loss in MPTP‐induced PD mice.ConclusionThis study highlights the potential of BDNF as a therapeutic candidate for the treatment of mitochondrial impairment‐associated neurodegenerative diseases.

BDNF promotes neuronal survival after neonatal hypoxic-ischemic encephalopathy by up-regulating Stx1b and suppressing VDAC1

Neonatal hypoxic-ischemic encephalopathy (HIE), is a major cause of neurologic disorders in terms of neonates, with the unclear underlying mechanisms. In the study, triphenyl tetrazolium chloride (TTC) staining and Zea-longa score were performed to examine the neurologic damage in hypoxia and ischemia (HI) rats. The results showed that HI induced obviously infarct and serious neurologic impairment in neonatal rats. Then, protein chip was applied to detect the differential expression genes in cortex and hippocampus and found the brain-derived neurotrophic factor (BDNF) down-regulated both in cortex and hippocampus. Moreover, low expression of BDNF after HI in right cortex and hippocampus was validate by immunohistochemistry (IHC) and Western Blotting (WB). Afterwards, overexpressing and interfering HSV vector were produced, then verified by immunofluorescent staining and real-time quantitative polymerase chain reaction (qRT-PCR). The results of Tuj1 staining indicated that overexpression of BDNF could promote axonal regeneration and inhibit neuron swelling, whereas BDNF interference take an opposite effect after Oxygen glucose deprivation (OGD) injury. Finally, the interaction network among BDNF and associated proteins as examined by Genemania and confirmed by qRT-PCR. We found that the expression of VDAC1 was decreased and Stx1b was increased when BDNF overexpressing, which indicated that BDNF promoted neurite regrowth after OGD might be related to downregulation of VDAC1 and upregulation of Stx1b. Our results might provide novel strategy for the treatment of neurological defects induced by cerebral ischemia and hypoxia.