Brain-directed delivery can elaborate locally to treat various brain ailments like the globally prevalent depression. Fulfilling such a goal via oral delivery can be conceivable owing to its expedience of self-medication and non-invasiveness. In this context, the oral behavioral trend was customized via tripolyphosphate cross-linked chitosan-based shell with lipid polymer hybrid core (TPP:CS-LPH) enclosing the antidepressant drug, mirtazapine (MIR). LPH nanoparticles were made of the PLGA core and the newly investigated lipid shell of lecithin and the pegylated lipid, Tefose 1500. Considering industrial scalability and applicability, spray drying was performed with thorough characterization. The impact of a cross-linked chitosan-based shell with LPH core on the in vivo pharmacokinetic behavior in brain and blood and pharmacodynamics in stressed mice (either daily regimen or every 3 days) was assessed and correlated to daily oral MIR suspension. The coated spray-dried nanocomposites were felicitously formed, exhibiting > 95% MIR association efficiency, controlled pH-dependent MIR release, and physicochemically, structurally, and morphologically verified cross-linked CS coating. For the selected formula (SD/TPP:CS-LPHo), the cross-linked chitosan-based shell yielded a 39-fold increase in brain Cmax and extended t1/2, brain equivalent to 4.7 times compared to oral MIR suspension. The superior antidepressant efficacy of SD/TPP:CS-LPHo, especially when administered every 3days, was also accentuated in terms of considerable amelioration of behavioral response, decreased levels of brain biomarkers (brain-derived neurotrophic factor and serotonin), and histopathological findings. In conclusion, promising brain-directed oral delivery for MIR with improved bioavailability and therapeutic efficacy can be made possible by this tactic.

Bipolar disorder (BD) is a chronic and prevalent psychiatric disease that has been considered a leading cause of disability among psychiatric conditions. Taking into account that there is yet no satisfactory disease-modifying treatment, we investigated the effect of genistein on ouabain-induced BD in male C57BL/6 mice. Animals were categorized into control, genistein control, ouabain model, lithium (Li)-treated, and genistein-treated groups. BD was induced by bilateral intracerebroventricular injection of 0.625 nmol ouabain. Genistein (10mg/kg/day) was orally administered for 2 weeks following a single dose of ouabain. Open field test, sucrose preference test, and forced swim test were performed. Na⁺/K⁺-ATPase activity was evaluated through measuring the hippocampal levels of phosphorylated epidermal growth factor receptor, proto-oncogene tyrosine-protein kinase, extracellular signal-regulated kinase, and cAMP response element-binding protein (p-CREB) by western blot analysis. The levels of brain-derived neurotrophic factor (BDNF), serotonin, oxidative stress, and inflammatory markers were quantified by ELISA. The BCL-2-associated X protein (BAX) to B-cell Lymphoma/Leukemia (BCL2) ratio was assessed by qRT-PCR. Genistein reduced manic and anxious behaviors during the manic phase and showed an antidepressant effect during the depression phase, all while maintaining an effective metabolic balance on body weight. Additionally, genistein increased serotonin, p-CREB, and BDNF levels while decreasing inflammation and apoptosis produced by ouabain. Furthermore, genistein restored the normal architecture in both hippocampal and cortical H&E-stained sections. Taken together, genistein was able to activate the Na⁺/K⁺-ATPase signalosome via a multifaceted mode of action, exerting a neuroprotective effect in an animal model of BD, promoting genistein as a therapeutic candidate for BD.

Ultrasound stimulation is a promising non-invasive strategy for neuropathic pain, yet its sustained effects and underlying mechanisms remain poorly understood. We investigated brainwave-patterned low-intensity continuous theta-burst ultrasound stimulation (LI-cTBUS) in a mouse model of partial sciatic nerve crush injury (PCI). LI-cTBUS substantially alleviated mechanical allodynia during and after treatment. Mechanistically, PCI upregulated brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling, while LI-cTBUS enhanced extracellular BDNF uptake by spinal astrocytes, thereby normalizing the BDNF/TrkB pathway and restoring potassium chloride cotransporter 2 (KCC2) function. Furthermore, LI-cTBUS attenuated reactive astrogliosis via activation of the transient receptor potential ankyrin 1 (TRPA1) channel, indicating a glial mechanism for ultrasound-induced analgesia. Transcriptomic profiling revealed that PCI altered the spinal transcriptome, whereas LI-cTBUS reversed inflammatory signatures, corrected aberrant BDNF/TrkB signaling, and restored GABAergic transmission. Collectively, these findings demonstrate that LI-cTBUS reprograms reactive astrocytes, suppresses nociceptive signaling, and provides sustained relief from neuropathic pain, underscoring its therapeutic potential for non-invasive spinal neuromodulation.

The incidence of osteoporosis is increased in Alzheimer's disease (AD). The pathogenesis of AD with osteoporosis is still unknown, there is no ideal treatment as yet for it. 7,8-Dihydroxyflavone (7,8-DHF), a functional brain-derived neurotrophic factor (BDNF) mimetic, shows therapeutic potential for neurological and orthopedic disorders. This research investigated the molecular mechanisms by which 7,8-DHF mitigates bone loss and cognitive dysfunction in osteoporotic AD mice. Micro-CT analysis quantified bone loss in AD mice. The Morris water maze (MWM) assessed mouse cognitive function, and immunohistochemical analysis measured Aβ plaque deposition. qPCR and Western blotting measured expression levels of APP, Aβ42, TRKB, and FOXO3a in osteoblasts isolated from femoral bone marrow mesenchymal stem cells (BMSCs) and brain tissue. ELISA determined the levels of IL-1β, IL-6, osteocalcin (OCN), fibroblast growth factor 23 (FGF23) and sclerostin. For in vitro experiments, osteoblast differentiation was monitored in MC3T3-E1 cells co-cultured with Aβ42, with concurrent measurement of TRKB, AKT, and FOXO3a expression. The efficacy of 7,8-DHF against bone loss and osteoblast differentiation was systematically evaluated. Cognitive impairment and bone loss manifested in APP/PS1 mice. 7,8-DHF treatment ameliorated bone mass reduction, decreased Aβ42 expression in bone tissue, and enhanced TRKB expression. Concurrently, 7,8-DHF improved cognitive function and accelerated clearance of [¹²⁵I]-Aβ42 from the brain. In in-vitro, Aβ42 increased inflammatory cytokine levels, suppressed TRKB expression, and impaired osteoblast differentiation. 7,8-DHF reduced the levels of AKT and pFOXO3a by TRKB. 7,8-DHF could alleviate bone mass loss in AD mice by regulating the TRKB/AKT/FOXO3a pathway. This finding provides new ideas for the treatment strategy of AD with osteoporosis and is beneficial to the health of the elderly.

Cortico-subcortical dysfunction from dopaminergic depletion is a hallmark of Parkinson's disease (PD). Modulating primary motor cortex (M1) excitability with intermittent theta burst stimulation (iTBS) may restore network integrity in PD by targeting neurobiological changes at excitatory, structural, and serological levels. This study aimed to demonstrate the clinical and neurobiological effects of bilateral M1 iTBS in patients with PD. Seventeen patients with Hoehn-Yahr stage II-III PD in the on-medication state underwent daily bilateral M1 iTBS sessions for 5 consecutive days in a randomized, double-blind, placebo-controlled, crossover design. The primary clinical outcomes were the relative change from baseline at four follow-up points after the final iTBS session, measured by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II, III, and IV. Changes in corticospinal excitability, structural brain imaging, and serum biomarkers of neurodegeneration, astrocytic activation, and neuroplasticity were also assessed. Real iTBS induced a significant improvement in MDS-UPDRS Part III scores, yielding more than twice the therapeutic benefit observed with sham stimulation. Responders (> 20% improvement) showed a mean 9-point improvement. Similarly, real iTBS stimulation resulted in an increase in corticospinal excitability of the clinically most affected hemisphere. In responders, serum brain-derived neurotrophic factor levels increased along with an increase in left ventral diencephalon volume, which was the strongest predictor of clinical response. Bilateral M1 iTBS may represent a valuable adjunctive therapeutic option for pharmacological treatment of motor symptoms in patients with PD by promoting structural brain changes and enhancing synaptic plasticity in intermediate disease stages. https://clinicaltrials.gov/ : NCT06840145, retrospectively registered on September 9, 2023.

Diabetes mellitus-induced mood disorders have physiologically demanding outcomes. Despite the severe outcomes of these comorbidities, the pathogenic mechanisms remain unclear. Hyperglycemia and hypoxia are key features of these conditions. Research indicates that brain-derived neurotrophic factor (BDNF), mainly secreted by microglial cells in response to neuronal stress, plays a role. Encephalic heat shock proteins (HSPs) may protect neurons by preventing death and promoting survival. Therefore, this study investigates (i) the effects of increased glucose concentrations (IGCs) on BDNF expression, (ii) the effects of hypoxia on BDNF expression, (iii) the combined effects of IGCs and hypoxia on BDNF expression, and (iv) the expression of HSPs-27, -32, and -70 under various conditions of IGCs and hypoxia.In-vitro experiments were conducted on Murine BV2 microglial cells to assess cell viability and expression of BDNF and HSPs under different conditions. These included IGCs of 30-, 60-, 90-, 120-mM glucose, hypoxia, and exposure times of 4-, 8-, and 24-h. Results showed short-term IGCs increased cell viability (p < 0.05), while long-term exposure decreased the viability. Combined IGCs and hypoxia had similar effects, with significant increases followed by decreases over time, and increased BDNF expression suggested a protective role. A significant decrease in pro-BDNF at 90 mM glucose after 8 h (p < 0.0001) was noted. Hypoxia-Inducible Factor 1-alpha (HIF1-α) expression in hypoxia-exposed cells decreased over time. HSP70 decreased significantly between 4 and 24 h (p < 0.05), while HSP32 gene expression increased over time. BDNF expression dynamically responded to IGC and hypoxia, which regulated by HIF-1α, with significant HSP involvement, particularly HSP-32, in the glial cell activation.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12035-025-05378-3.

Background: Recent research has focused on identifying innovative, non-invasive sources of migraine biomarkers, such as tear fluid and saliva, that may reflect underlying pathogenetic mechanisms, such as neurogenic inflammation. This study aimed to analyze the levels of interleukin (IL)-1β, IL-20, tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), and calcitonin gene-related peptide (CGRP) in the tear fluid of patients with migraine. Methods: Consecutive patients with a diagnosis of migraine were included. Tear fluid was collected from migraine patients and healthy controls (HCs) through Schirmer test strips; cytokines (IL-10, IL-1β, and TNF-α) and BDNF were measured using the automated EllaTM (Bio-Techne) multiplex Enzyme-Linked Immunosorbent Assay (ELISA) platform, while CGRP concentrations were quantified using a CGRP sandwich ELISA kit. Clinical characteristics of migraine patients, severity, and disability scores were collected. Results: Fifty-one patients with migraine (9 [17.6%] chronic, 16 with aura [31.4%]) and 17 age-matched HCs were included. Tear fluid CGRP concentrations were significantly elevated in migraine patients (7.4±7.6 pg/mL) compared to HCs (3.1±3.7 pg/mL; p=0.014). In the migraine group, tear CGRP levels were higher in the ictal phase (10.5±7.7 pg/mL) compared to the interictal phase (5.8±7.3 pg/mL) (p=0.021) and in patients with (10.4±9.2 pg/mL) vs. without (6.1±6.4 pg/mL) aura (p=0.042). BDNF tear levels did not differ between patients with migraine and HCs, but were higher in patients with chronic migraine (4.1±7.5 pg/mL) compared to episodic (0.6±2.5 pg/mL; p=0.018). Similarly, TNF-α tear levels did not differ between patients with migraine and HCs, but were higher in patients with chronic migraine (0.15±0.12 pg/mL) compared to episodic migraine (0.05±0.07 pg/mL; p=0.009). TNF-α levels were correlated with IL-10 (ρ=0.426, p&lt;0.001), IL-1β (ρ=0.350, p=0.017), and BDNF (ρ=0.364, p=0.010). Additionally, IL-10 levels were correlated with BDNF levels (ρ=0.481, p&lt;0.001). CGRP levels were negatively correlated with BDNF (ρ=−0.377, p=0.006). Conclusions: Elevated CGRP levels were found in patients with migraine as compared to HCs. Correlations observed among changes in tear fluid IL-10, IL-1β, and BDNF levels suggest common regulatory mechanisms. Furthermore, the increase in both tear fluid BDNF and TNF-α in patients with chronic migraine suggests a role for these biomarkers in the chronicization of the disease. While measuring biomarkers in tear fluid represents a rapid and promising non-invasive approach, it requires supporting evidence from future larger studies.

Oxidative-stress-induced neuronal injury is a major contributor to neurodegenerative diseases, underscoring the need for novel neuroprotective strategies. Natural products with antioxidant and mitochondrial-stabilizing properties are increasingly recognized as promising multi-target therapeutics. Ficus benjamina L., a member of the Moraceae family, is rich in flavonoids and traditionally used in Asian ethnomedicine for wound healing, inflammation, and weakness, with related Ficus species documented in the Bencao Gangmu (Compendium of Materia Medica) for circulation and detoxification disorders. However, its neuroprotective potential has not been systematically evaluated. In this study, we explored the neuroprotective potential of a flavonoid-enriched 80% methanolic leaf extract of F. benjamina by evaluating its capacity to mitigate oxidative stress in neuronal cells and a murine optic nerve crush (ONC) injury model. We observed in SH-SY5Y cells that cell viability was preserved after pre-treatment using the extract, mitochondrial respiration and the membrane potential were maintained, and gene expression was modulated by upregulation of BCL-2 (B-cell lymphoma 2), BCL-xL (B-cell lymphoma-extra large), X) SOD2 (Superoxide Dismutase), CAT (Catalase), and BDNF (Brain-Derived Neurotrophic Factor). Intravitreal delivery of the extract in vivo resulted in a marked increase in the survival of retinal ganglion cells following ONC injury. Caffeic acid, quercetin-3-O-rutinoside, and kaempferol-3-O-rutinoside were identified as major constituents in phytochemical profiling. These results indicate that F. benjamina exerts multi-target neuroprotective actions, mediated via mitochondrial regulation, enhancement of antioxidation defenses, and modulation of apoptotic pathways. The findings also substantiate the contemporary pharmacological relevance underscoring the ethnomedicinal use of Ficus species and highlight the potential of F. benjamina as a promising candidate for developing integrative therapeutic approaches to target neurodegenerative diseases driven by oxidative stress.

Objective: Our study aims to explore the application of low-frequency repetitive transcranial magnetic stimulation (rTMS) in patients with sleep disorders after traumatic brain injury (TBI). Methods: 47 patients with sleep disorders after TBI, who received rTMS combined with conventional treatment in our hospital from January 2022 to May 2023, were allocated into the observation group, and 43 patients with sleep disorders after TBI receiving conventional treatment during the same period were assigned into the control group. The clinical efficacy and adverse reaction in the two groups were compared, and the differences of sleep disorder score and neurotrophic factor expression before and after treatment were observed. Results: The total effective rate of clinical efficacy was significantly higher and the total incidence of adverse reaction was obviously lower in observation group than those in control group (p &lt; 0.05). After treatment, pittsburgh sleep quality index was visibly decreased in both groups (p &lt; 0.05), and that in the observation group was significantly lower than that in the control group (p &lt; 0.05). The levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor were markedly increased in both groups (p &lt; 0.05), and those in the observation group was significantly higher than those in the control group (p &lt; 0.05). Conclusion: RTMS has a good clinical efficacy in the treatment of sleep disorders after TBI, which has a good effect in improving sleep disorders and expressions of neurotrophic factors, with high safety.

proBDNF-SorCS2 Axis Suppresses Osteogenesis and Augments Inflammation of Human Periodontal Ligament Stem Cells in Inflammatory Conditions.

Background Agricultural or gardening activity (also known as hobby farming) is a simple strategy that may be effective for maintaining health and preventing lifestyle-related diseases. However, its preventive effect on the development of conditions associated with neurovascular aging (e.g., stroke and dementia) remains unclear. Objective To comprehensively investigate the preventive role of regular agricultural or gardening physical activity (AGPA) in neurovascular aging and its underlying mechanisms using two approaches. Methods We conducted an experimental study in which we assessed arterial stiffness, cognitive performance (Flanker and Stroop tests), and circulating biomarkers (e.g., plasmin-α2-plasmin inhibitor complexes, nitric oxide, brain-derived neurotrophic factor) in 12 male students (average age: 22 ± 1 years) before and after three 40-min interventions (resting, cycling, and simulated AGPA) under controlled conditions. We also conducted a cross-sectional study, in which we recruited 161 (79 in the AGPA group and 82 in the control group) hospital-based older individuals (average age: 78 ± 5 years) and assessed their history of stroke, cognitive function, and brain magnetic resonance imaging (MRI) findings. Results In the experimental study, simulated AGPA reduced arterial stiffness, improved executive cognitive function, and elevated circulating plasmin-α2-plasmin inhibitor complexes, nitric oxide, and brain-derived neurotrophic factor. Brain MRI-assessed cerebral white matter hyperintensities caused by reduced blood flow to brain tissue and stroke prevalence were lower, and cognitive scores (as assessed by the Hasegawa Dementia Scale-Revised) were higher in the AGPA group than in the control group. Conclusion Our findings suggest that regular AGPA is associated with markers of slower neurovascular aging in older individuals. AGPA induces a combination of general physical activity-related and specific AGPA-related effects; moreover, it may offer similar or even greater benefits than physical activity alone. Therefore, habitual AGPA may serve as an effective preventive strategy for neurovascular aging.

Yueju pill and its active component- Myricetin attenuate the reinstatement of methamphetamine-seeking behavior in mice.

Intranasal LAG3 antibody infusion induces microglia-dependent antidepressant effect by mobilizing astrocytic P2Y1R-mediated BDNF synthesis in the hippocampus.

Enhanced neurogenic differentiation of human dental pulp stem cells via BDNF-loaded oxidized alginate hydrogel.

Esketamine improves postoperative sleep quality in women undergoing gynecological laparoscopy: A prospective, randomized, double-blind, and controlled trial.

Presynaptic BDNF-TrkB signaling contributes to mechanical allodynia in a mouse model of chronic neuropathic pain.

Comparative efficacy of antidepressant augmentation with amantadine vs pramipexole in treatment-resistant unipolar depression: A randomised controlled trial.

Comparative neuroprotective efficacy of N-acetylcysteine and naringin in lead-induced neurotoxicity: Restoration of BDNF, neurotransmitters, and cognitive function.

Blood-based biomarkers in ketamine treatment: A blueprint for translational drug development in mood disorders.

Effects of heat environments on depressive disorders: Neurogenesis-mediated mechanisms.