Search Results (28)

Background/Objectives: Blast-induced hearing loss (BIHL) is a major concern, particularly for military personnel, and is linked to impaired auditory neuron survival and synaptic plasticity. This study investigates the potential of the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) to reduce the severity of BIHL and promote recovery in a mouse model. Methods: Eight-week-old male C57BL/6J mice were used. A custom-built, compressed air-driven system utilizing a modified paintball apparatus was employed to deliver controlled unilateral double blasts (~22 psi exposure pressure) to the left ear. The blasts were administered 30 min apart. Immediately following the second blast, mice received either 7,8-DHF (10 mg/kg) or vehicle (10% DMSO) via intraperitoneal injection. Auditory brainstem responses (ABRs) were measured in both ears at baseline (pre-blast) and at several post-exposure time points. Results: The consecutive blast exposure induced a significant elevation in ABR thresholds, indicative of hearing loss, in both the ipsilateral (exposed) and contralateral (unexposed) ears of vehicle-treated mice. Notably, mice treated with 7,8-DHF demonstrated a marked improvement in hearing recovery compared to the vehicle group. Significant reductions in ABR thresholds were observed in the ipsilateral ear at 4 weeks post-blast (p < 0.0001) and in the contralateral ear as early as 1-week post-blast (p = 0.0236). However, the recovery was partial, with ABR thresholds plateauing after 4 weeks. Conclusions: A controlled blast model demonstrates that systemic administration of the TrkB agonist 7,8-DHF exerts a protective effect, partially restoring auditory function after blast injury. This supports the therapeutic potential of targeting the BDNF-TrkB signaling pathway for managing BIHL. Full article

Hypoxia–ischemia (HI)-related brain injury impacts millions of neonates worldwide. Male neonates are two times more susceptible to developing HI. We have previously reported that the administration of the neurotrophin receptor tyrosine kinase B (TrkB) agonist 7,8-dihydroxyflavone (DHF) following neonatal HI increases hippocampal TrkB phosphorylation and improves hippocampal-dependent learning and memory in early adult life only in females. We hypothesize that sex differences in HI outcomes are due to alterations in neonatal hippocampal steroid content, mainly the neural testosterone. At postnatal day 9, C57BL/6J mice underwent sham and Vannucci’s HI surgeries and were treated either with DHF or vehicle control. Hippocampi and plasma were collected on days 1 and 3 post-HI and liquid chromatography tandem mass spectrometry was used to determine the testosterone (T), estradiol (E₂), progesterone (P₄), and corticosterone (CORT) contents in these samples. All hippocampal steroid contents were at least 10-fold higher than in plasma, suggesting neural synthesis. Males had higher hippocampal T content than females at 3 days post-HI. Treatment with DHF reduced T in the female hippocampi at 3 days post-HI, but not in males. These findings suggest that the neuroprotective effect of DHF in females may be mediated, at least in part, through the reduction in hippocampal T following HI. Full article

Aggressive behavior is regulated by intricate neural circuits and molecular mechanisms, notably through the interaction of brain-derived neurotrophic factor (BDNF) with its receptor, tropomyosin receptor kinase B (TrkB), which influences neuroplasticity and related behavioral phenotypes. We investigate the role of the BDNF signaling pathway in fish aggression using juvenile black rockfish (Sebastes schlegelii), which exhibit distinct aggressive phenotypes. The TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) was administered intraperitoneally at doses of 1.25, 2.5, and 5 mg/kg to assess its effects on the behavioral characteristics of high-aggression (H-agg) and low-aggression (L-agg) phenotypes. Our findings indicate the following: (1) The effects of 7,8-DHF are dose-dependent, with 2.5 mg/kg identified as the effective threshold dose for H-agg individuals; (2) in the H-agg group, this dose significantly reduced locomotor acceleration, angular velocity, and activity frequency, while prolonging the first movement latency; (3) in the L-agg group, only angular velocity was significantly decreased with the 2.5 mg/kg treatment, with no significant changes observed in other behavioral parameters. This study provides the first evidence for differential behavioral responses to 7,8-DHF in S. schlegelii, demonstrating dose-dependent aggression suppression in H-agg phenotypes and threshold-specific responses in L-agg phenotypes. These insights into the neuro-molecular basis of fish aggression can guide phenotype-specific management in aquaculture, potentially improving stress management, reducing injuries and mortality, and boosting productivity. Full article

The brain-derived neurotrophic factor (BDNF) has become one of the cornerstones of neuropathology, influencing synaptic plasticity, cognitive resilience, and neuronal survival. Apart from its molecular biology, BDNF is a powerful target for transformative benefit in precision medicine, leading to innovative therapeutic approaches for neurodegenerative and psychiatric diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). Nevertheless, clinical applicability is obstructed by hurdles in delivery, patient-specific diversity, and pleiotropic signaling. Here, we summarize findings in BDNF research, including its regulatory pathways and diagnostic/prognostic biomarkers and integrative therapeutic approaches. We describe innovative delivery systems, such as lipid nanoparticle-based mRNA therapies and CRISPR-dCas9-based epigenetic editing that bypass obstacles such as BBB (blood–brain barrier) and enzymatic degradation. The recent implementation of multiplex panels combining BDNF biodynamic indicators with tau and amyloid-β signaling markers showcases novel levels of specificity for both early detection and potential therapeutic monitoring. Humanized preclinical models like iPSC-derived neurons and organoids point to the key role of BDNF in neurodeveloping and neurodegenerative processes, paralleling advances in bridging preclinical observation and clinical environments. Moreover, novel therapeutic tools delivering TrkB activators or the implementation of AI-based dynamic care platforms enable tailored and scalable treatments. This review also aims to extend a framework used in the understanding of BDNF’s relevance to traditional neurodegenerative models by situating more recent work detailing BDNF’s actions in ischemic tissues and the gut–brain axis in the context of systemic health. Finally, we outline a roadmap for the incorporation of BDNF-centered therapies into worldwide healthcare, highlighting ethical issues, equity, and interdisciplinary decomposition. The therapeutic potential of BDNF heralds a new era in neuroscience and medicine, revolutionizing brain health and paving the way for the advancement of precision medicine. Full article

Dexmedetomidine (DEX) is a selective alpha-2 adrenergic receptor agonist with sedative and anxiolytic properties. Increasing evidence reports that DEX has a neuroprotective effect. In this study, we investigated the potential effects of DEX on learning and memory functions in rats with experimental cognitive impairment. In the study, 21 adult male rats were used. The rats were divided into three groups, namely control, Scopolamine (SCOP) and SCOP + DEX. Cognitive impairment was induced with 1 mg/kg SCOP daily for 21 days. DEX was administered at a dose of 10 µg/kg between days 14 and 21 of the experiment. Following the injections, a spatial memory test was performed with a Morris Water Maze (MWM). At the end of the experiment, the hippocampus was dissected. The brain-derived neurotrophic factor (BDNF), acetylcholine (ACh) and acetylcholinesterase (AChE) levels were determined by ELISA. The tropomyosin receptor kinase B (TrkB) and Cyclic AMP-Response Element-Binding Protein (CREB) levels were measured by immunohistochemistry. DEX treatment improved the learning performance of rats compared to SCOP for 5 days. However, it did not significantly change memory performance. DEX increased the BDNF and ACh levels in the hippocampus while decreasing the AChE levels. Similarly, DEX treatment significantly increased CREB phosphorylation. No significant difference was observed between the TrkB receptor levels of the groups. This study demonstrated that the role of DEX in reducing SCOP-induced cognitive impairment is partially mediated by the increase in BDNF/TrkB/CREB signaling pathway activity. Full article

Tropomyosin kinase receptor B (TrkB) has been explored as a therapeutic target for neurological and psychiatric disorders. However, the development of TrkB agonists was hindered by our poor understanding of the TrkB agonist binding location and affinity (both affect the regulation of disorder types). This motivated us to develop a combined computational and experimental approach to study TrkB binders. First, we developed a docking method to simulate the binding affinity of TrkB and binders identified by our magnetic drug screening platform from Gotu kola extracts. The Fred Docking scores from the docking computation showed strong agreement with the experimental results. Subsequently, using this screening platform, we identified a list of compounds from the NIH clinical collection library and applied the same docking studies. From the Fred Docking scores, we selected two compounds for TrkB activation tests. Interestingly, the ability of the compounds to increase dendritic arborization in hippocampal neurons matched well with the computational results. Finally, we performed a detailed binding analysis of the top candidates and compared them with the best-characterized TrkB agonist, 7,8-dyhydroxyflavon. The screening platform directly identifies TrkB binders, and the computational approach allows for the quick selection of top candidates with potential biological activities based on the docking scores. Full article

The present study examined how P2X7 receptor knockout (KO) modulates central post-stroke pain (CPSP) induced by lesions of the ventrobasal complex (VBC) of the thalamus in behaviors, molecular levels, and electrical recording tests. Following the experimental procedure, the wild-type and P2X7 receptor KO mice were injected with 10 mU/0.2 μL type IV collagenase in the VBC of the thalamus to induce an animal model of stroke-like thalamic hemorrhage. Behavioral data showed that the CPSP group induced thermal and mechanical pain. The P2X7 receptor KO group showed reduced thermal and mechanical pain responses compared to the CPSP group. Molecular assessments revealed that the CPSP group had lower expression of NeuN and KCC2 and higher expression of GFAP, IBA1, and BDNF. The P2X7 KO group showed lower expression of GFAP, IBA1, and BDNF but nonsignificant differences in KCC2 expression than the CPSP group. The expression of NKCC1, GABAa receptor, and TrkB did not differ significantly between the control, CPSP, and P2X7 receptor KO groups. Muscimol, a GABAa agonist, application increased multiunit numbers for monitoring many neurons and [Cl⁻] outflux in the cytosol in the CPSP group, while P2X7 receptor KO reduced multiunit activity and increased [Cl⁻] influx compared to the CPSP group. P2X4 receptor expression was significantly decreased in the 100 kDa but not the 50 kDa site in the P2X7 receptor KO group. Altogether, the P2X7 hypothesis of CPSP was proposed, wherein P2X7 receptor KO altered the CPSP pain responses, numbers of astrocytes and microglia, CSD amplitude of the anterior cingulate cortex and the medial dorsal thalamus, BDNF expression, [Cl⁻] influx, and P2X4 expression in 100 kDa with P2X7 receptors. The present findings have implications for the clinical treatment of CPSP symptoms. Full article

The disruption of the synaptic connection between the sensory inner hair cells (IHCs) and the auditory nerve fiber terminals of the type I spiral ganglion neurons (SGN) has been observed early in several auditory pathologies (e.g., noise-induced or ototoxic drug-induced or age-related hearing loss). It has been suggested that glutamate excitotoxicity may be an inciting element in the degenerative cascade observed in these pathological cochlear conditions. Moreover, oxidative damage induced by free hydroxyl radicals and nitric oxide may dramatically enhance cochlear damage induced by glutamate excitotoxicity. To investigate the underlying molecular mechanisms involved in cochlear excitotoxicity, we examined the molecular basis responsible for kainic acid (KA, a full agonist of AMPA/KA-preferring glutamate receptors)-induced IHC synapse loss and degeneration of the terminals of the type I spiral ganglion afferent neurons using a cochlear explant culture from P3 mouse pups. Our results demonstrated that disruption of the synaptic connection between IHCs and SGNs induced increased levels of oxidative stress, as well as altered both mitochondrial function and neurotrophin signaling pathways. Additionally, the application of exogenous antioxidants and neurotrophins (NT3, BDNF, and small molecule TrkB agonists) clearly increases synaptogenesis. These results suggest that understanding the molecular pathways involved in cochlear excitotoxicity is of crucial importance for the future clinical trials of drug interventions for auditory synaptopathies. Full article

One common event that is the most detrimental in neurodegenerative disorders, even though they have a complex pathogenesis, is the increased rate of neuronal death. Endogenous neurotrophins consist of the major neuroprotective factors, while brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor TrkB are described in a number of studies for their important neuronal effects. Normal function of this receptor is crucial for neuronal survival, differentiation, and synaptic function. However, studies have shown that besides direct activation, the TrkB receptor can be transactivated via GPCRs. It has been proven that activation of the 5-HT₄ receptor and transactivation of the TrkB receptor have a positive influence on neuronal differentiation (total dendritic length, number of primary dendrites, and branching index). Because of that and based on the main structural characteristics of LM22A-4, a known activator of the TrkB receptor, and RS67333, a partial 5-HT₄ receptor agonist, we have designed and synthesized a small data set of novel compounds with potential dual activities in order to not only prevent neuronal death, but also to induce neuronal differentiation in neurodegenerative disorders. Full article

Ketamine is a racemic mixture composed of two enantiomers, S-ketamine and R-ketamine. In preclinical studies, both enantiomers have exhibited antidepressant effects, but these effects are attributed to distinct pharmacological activities. The S-enantiomer acts as an NMDA-channel blocker and as an opioid μ-receptor agonist, whereas the R-enantiomer binds to σ1-receptors and is believed to act as an agonist. As racemate, ketamine potentially triggers four biochemical pathways involving the AGC-kinases, PKA, Akt (PKB), PKC and RSK that ultimately lead to inhibitory phosphorylation of GSK3β in microglia. In patients with major depressive disorder, S-ketamine administered as a nasal spray has shown clear antidepressant activity. However, when compared to intravenously infused racemic ketamine, the response rate, duration of action and anti-suicidal activity of S-ketamine appear to be less pronounced. The σ1-protein interacts with μ-opioid and TrkB-receptors, whereas in preclinical experiments σ1-agonists reduce μ-receptor desensitization and improve TrkB signal transduction. TrkB activation occurs as a response to NMDA blockade. So, the σ1-activity of R-ketamine may not only enhance two pathways via which S-ketamine produces an antidepressant response, but it furthermore provides an antidepressant activity in its own right. These two factors could explain the apparently superior antidepressant effect observed with racemic ketamine compared to S-ketamine alone. Full article

Oleuropein (OLE), a main constituent of olives, displays a pleiotropic beneficial dynamic in health and disease; the effects are based mainly on its antioxidant and hypolipidemic properties, and its capacity to protect the myocardium during ischemia. Furthermore, OLE activates the peroxisome proliferator-activated receptor (PPARα) in neurons and astrocytes, providing neuroprotection against noxious biological reactions that are induced following cerebral ischemia. The current study investigated the effect of OLE in the regulation of various neural plasticity indices, emphasizing the role of PPARα. For this purpose, 129/Sv wild-type (WT) and Pparα-null mice were treated with OLE for three weeks. The findings revealed that chronic treatment with OLE up-regulated the brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the prefrontal cortex (PFC) of mice via activation of the ERK1/2, AKT and PKA/CREB signaling pathways. No similar effects were observed in the hippocampus. The OLE-induced effects on BDNF and TrkB appear to be mediated by PPARα, because no similar alterations were observed in the PFC of Pparα-null mice. Notably, OLE did not affect the neurotrophic factors NT3 and NT4/5 in both brain tissues. However, fenofibrate, a selective PPARα agonist, up-regulated BDNF and NT3 in the PFC of mice, whereas the drug induced NT4/5 in both brain sites tested. Interestingly, OLE provided neuroprotection in differentiated human SH-SY5Y cells against β-amyloid and H₂O₂ toxicity independently from PPARα activation. In conclusion, OLE and similar drugs, acting either as PPARα agonists or via PPARα independent mechanisms, could improve synaptic function/plasticity mainly in the PFC and to a lesser extent in the hippocampus, thus beneficially affecting cognitive functions. Full article

The odontoblastic differentiation of dental pulp stem cells (DPSCs) associated with caries injury happens in an inflammatory context. We recently demonstrated that there is a link between inflammation and dental tissue regeneration, identified via enhanced DPSC-mediated dentinogenesis in vitro. Brain-derived neurotrophic factor (BDNF) is a nerve growth factor-related gene family molecule which functions through tropomyosin receptor kinase B (TrkB). While the roles of BDNF in neural tissue repair and other regeneration processes are well identified, its role in dentinogenesis has not been explored. Furthermore, the role of BDNF receptor-TrkB in inflammation-induced dentinogenesis remains unknown. The role of BDNF/TrkB was examined during a 17-day odontogenic differentiation of DPSCs. Human DPSCs were subjected to odontogenic differentiation in dentinogenic media treated with inflammation inducers (LTA or TNFα), BDNF, and a TrkB agonist (LM22A-4) and/or antagonist (CTX-B). Our data show that BDNF and TrkB receptors affect the early and late stages of the odontogenic differentiation of DPSCs. Immunofluorescent data confirmed the expression of BDNF and TrkB in DPSCs. Our ELISA and qPCR data demonstrate that TrkB agonist treatment increased the expression of dentin matrix protein-1 (DMP-1) during early DPSC odontoblastic differentiation. Coherently, the expression levels of runt-related transcription factor 2 (RUNX-2) and osteocalcin (OCN) were increased. TNFα, which is responsible for a diverse range of inflammation signaling, increased the levels of expression of dentin sialophosphoprotein (DSPP) and DMP1. Furthermore, BDNF significantly potentiated its effect. The application of CTX-B reversed this effect, suggesting TrkB`s critical role in TNFα-mediated dentinogenesis. Our studies provide novel findings on the role of BDNF-TrkB in the inflammation-induced odontoblastic differentiation of DPSCs. This finding will address a novel regulatory pathway and a therapeutic approach in dentin tissue engineering using DPSCs. Full article

The transcripts for Bdnf (brain-derived neurotrophic factor), driven by different promoters, are expressed in different brain regions to control different body functions. Specific promoter(s) that regulates energy balance remain unclear. We show that disruption of Bdnf promoters I and II but not IV and VI in mice (Bdnf-e1^−/−, Bdnf-e2^−/−) results in obesity. Whereas Bdnf-e1^−/− exhibited impaired thermogenesis, Bdnf-e2^−/− showed hyperphagia and reduced satiety before the onset of obesity. The Bdnf-e2 transcripts were primarily expressed in ventromedial hypothalamus (VMH), a nucleus known to regulate satiety. Re-expressing Bdnf-e2 transcript in VMH or chemogenetic activation of VMH neurons rescued the hyperphagia and obesity of Bdnf-e2^−/− mice. Deletion of BDNF receptor TrkB in VMH neurons in wildtype mice resulted in hyperphagia and obesity, and infusion of TrkB agonistic antibody into VMH of Bdnf-e2^−/− mice alleviated these phenotypes. Thus, Bdnf-e2-transcripts in VMH neurons play a key role in regulating energy intake and satiety through TrkB pathway. Full article

The causes of vestibular dysfunction include the loss of hair cells (HCs), synapses beneath the HCs, and nerve fibers. 7, 8–dihydroxyflavone (DHF) mimics the physiological functions of brain-derived neurotrophic factor. We investigated the effects of the orally-administered DHF in the guinea pig crista ampullaris after gentamicin (GM)-induced injury. Twenty animals treated with GM received daily administration of DHF or saline for 14 or 28 days (DHF (+) or DHF (−) group; N = 5, each). At 14 days after GM treatment, almost all of the HCs had disappeared in both groups. At 28 days, the HCs number in DHF (+) and DHF (−) groups was 74% and 49%, respectively, compared to GM-untreated control. In the ampullary nerves, neurofilament 200 positive rate in the DHF (+) group was 91% at 28 days, which was significantly higher than 42% in DHF (−). On day 28, the synaptic connections observed between C–terminal–binding protein 2-positive and postsynaptic density protein-95-positive puncta were restored, and caloric response was significantly improved in DHF (+) group (canal paresis: 57.4% in DHF (+) and 100% in DHF (−)). Taken together, the oral administration of DHF may be a novel therapeutic approach for treating vestibular dysfunction in humans. Full article

Misfolded aggregation of the hyperphosphorylated microtubule binding protein Tau in the brain is a pathological hallmark of Alzheimer’s disease (AD). Tau aggregation downregulates brain-derived neurotrophic factor (BDNF)/tropomycin receptor kinase B (TRKB) signaling and leads to neurotoxicity. Therefore, enhancement of BDNF/TRKB signaling could be a strategy to alleviate Tau neurotoxicity. In this study, eight compounds were evaluated for the potential of inhibiting Tau misfolding in human neuroblastoma SH-SY5Y cells expressing the pro-aggregator Tau folding reporter (ΔK280 Tau_RD-DsRed). Among them, coumarin derivative ZN-015 and quinoline derivatives VB-030 and VB-037 displayed chemical chaperone activity to reduce ΔK280 Tau_RD aggregation and promote neurite outgrowth. Studies of TRKB signaling revealed that ZN-015, VB-030 and VB-037 treatments significantly increased phosphorylation of TRKB and downstream Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase 1/2 (ERK) and AKT serine/threonine kinase (AKT), to activate ribosomal S6 kinase (RSK) and cAMP response element-binding protein (CREB). Subsequently, p-CREB enhanced the transcription of pro-survival BDNF and BCL2 apoptosis regulator (BCL2), accompanied with reduced expression of anti-survival BCL2-associated X protein (BAX) in ΔK280 Tau_RD-DsRed-expressing cells. The neurite outgrowth promotion effect of ZN-015, VB-030 and VB-037 was counteracted by a RNA interference-mediated knockdown of TRKB, suggesting the role of these compounds acting as TRKB agonists. Tryptophan fluorescence quenching analysis showed that ZN-015, VB-030 and VB-037 interacted directly with a Pichia pastoris-expressed TRKB extracellular domain, indirectly supporting the role through TRKB signaling. The results of up-regulation in TRKB signaling open up the therapeutic potentials of ZN-015, VB-030 and VB-037 for AD. Full article