Brain-Derived Neurotrophic Factor as a Potential Mediator of the Beneficial Effects of Myo-Inositol Supplementation during Suckling in the Offspring of Gestational-Calorie-Restricted Rats.

This study aims to investigate the potential mechanisms underlying the protective effects of myo-inositol (MI) supplementation during suckling against the detrimental effects of fetal energy restriction described in animal studies, particularly focusing on the potential connections with BDNF signaling. Oral physiological doses of MI or the vehicle were given daily to the offspring of control (CON) and 25%-calorie-restricted (CR) pregnant rats during suckling. The animals were weaned and then fed a standard diet until 5 months of age, when the diet was switched to a Western diet until 7 months of age. At 25 days and 7 months of age, the plasma BDNF levels and mRNA expression were analyzed in the hypothalamus and three adipose tissue depots. MI supplementation, especially in the context of gestational calorie restriction, promoted BDNF secretion and signaling at a juvenile age and in adulthood, which was more evident in the male offspring of the CR dams than in females. Moreover, the CR animals supplemented with MI exhibited a stimulated anorexigenic signaling pathway in the hypothalamus, along with improved peripheral glucose management and enhanced browning capacity. These findings suggest a novel connection between MI supplementation during suckling, BDNF signaling, and metabolic programming, providing insights into the mechanisms underlying the beneficial effects of MI during lactation.

Network pharmacology and experimental evidence: ERK/CREB/BDNF signaling pathway is involved in the antidepressive roles of Kaiyu Zhishen decoction.

ETHNOPHARMACOLOGICAL RELEVANCE: Major Depressive Disorder (MDD) emerges as a complex psychosomatic condition, notable for its considerable suicidality and mortality rates. Increasing evidence suggests the efficacy of Chinese herbal medicine in mitigating depression symptoms and offsetting the adverse effects associated with conventional Western therapeutics. Notably, clinical trials have revealed the adjunctive antidepressant potential of Kaiyu Zhishen Decoction (KZD) alongside Western medication. However, the standalone antidepressant efficacy of KZD and its underlying mechanisms merit in-depth investigation. AIM OF THE STUDY: This research aims to elucidate the impact of KZD on MDD and delineate its mechanistic pathways through integrated network pharmacological assessments and empirical in vitro and in vivo analyses. MATERIALS AND METHODS: To ascertain the optimal antidepressant dosage and mechanism of KZD, a Chronic Unpredictable Mild Stress (CUMS)-induced depression model in mice was established to evaluate depressive behaviors. High-Performance Liquid Chromatography (HPLC) and network pharmacological approaches were employed to predict KZD's antidepressant mechanisms. Subsequently, hippocampal samples were subjected to 4D-DIA proteomic sequencing and validated through Western blot, immunofluorescence, Nissl staining, and pathway antagonist applications. Additionally, cortisol-stimulated PC12 cells were utilized to simulate neuronal damage, analyzing protein and mRNA levels of MAPK-related signals and cell proliferation markers. RESULTS: The integration of network pharmacology and HPLC identified kaempferol and quercetin as KZD's principal active compounds for MDD treatment. Proteomic and network pharmacological KEGG pathway analyses indicated the MAPK signaling pathway as a critical regulatory mechanism for KZD's therapeutic effect on MDD. KZD was observed to mitigate CUMS-induced upregulation of p-ERK/ERK, CREB, and BDNF protein expressions in hippocampal cells by attenuating oxidative stress, thereby ameliorating neuronal damage and exerting antidepressant effects. The administration of PD98059 counteracted KZD's improvements in depression-like behaviors and downregulated p-ERK/ERK and BDNF protein expressions in the hippocampus. CONCLUSIONS: This investigation corroborates KZD's pivotal, dose-dependent role in antidepressant activity. Both in vivo and in vitro experiments demonstrate KZD's capacity to modulate the ERK-CREB-BDNF signaling pathway by diminishing ROS expression induced by oxidative stress, enhancing neuronal repair, and thus, manifesting antidepressant properties. Accordingly, KZD represents a promising herbal candidate for further antidepressant research.

Xuefu Zhuyu decoction promotes synaptic plasticity by targeting miR-191a-5p/BDNF-TrkB axis in severe traumatic brain injury.

BACKGROUND: Xuefu Zhuyu decoction (XFZYD) is a traditional Chinese herbal formula known for its ability to eliminate blood stasis and improve blood circulation, providing neuroprotection against severe traumatic brain injury (sTBI). However, the underlying mechanism is still unclear. PURPOSE: We aim to investigate the neuroprotective effects of XFZYD in sTBI from a novel mechanistic perspective of miRNA-mRNA. Additionally, we sought to elucidate a potential specific mechanism by integrating transcriptomics, bioinformatics, and conducting both in vitro and in vivo experiments. METHODS: The sTBI rat model was established, and the rats were treated with XFZYD for 14 days. The neuroprotective effects of XFZYD were evaluated using a modified neurological severity score, hematoxylin and eosin staining, as well as Nissl staining. The anti-inflammatory effects of XFZYD were explored using quantitative real-time PCR (qRT-PCR), Western blot analysis, and immunofluorescence. Next, miRNA sequencing of the hippocampus was performed to determine which miRNAs were differentially expressed. Subsequently, qRT-PCR was used to validate the differentially expressed miRNAs. Target core mRNAs were determined using various methods, including miRNA prediction targets, mRNA sequencing, miRNA-mRNA network, and protein-protein interaction (PPI) analysis. The miRNA/mRNA regulatory axis were verified through qRT-PCR or Western blot analysis. Finally, morphological changes in the neural synapses were observed using transmission electron microscopy and immunofluorescence. RESULTS: XFZYD exhibited significant neuroprotective and anti-inflammatory effects on subacute sTBI rats' hippocampus. The analyses of miRNA/mRNA sequences combined with the PPI network revealed that the therapeutic effects of XFZYD on sTBI were associated with the regulation of the rno-miR-191a-5p/BDNF axis. Subsequently, qRT-PCR and Western blot analysis confirmed XFZYD reversed the decrease of BDNF and TrkB in the hippocampus caused by sTBI. Additionally, XFZYD treatment potentially increased the number of synaptic connections, and the expression of the synapse-related protein PSD95, axon-related protein GAP43 and neuron-specific protein TUBB3. CONCLUSIONS: XFZYD exerts neuroprotective effects by promoting hippocampal synaptic remodeling and improving cognition during the subacute phase of sTBI through downregulating of rno-miR-191a-5p/BDNF axis, further activating BDNF-TrkB signaling.

Transcutaneous auricular vagus nerve stimulation for post-stroke depression: A double-blind, randomized, placebo-controlled trial.

BACKGROUND: It is a well-established fact that post-stroke depression (PSD) is a prevalent condition that affects a significant proportion of individuals who have suffered a stroke. Hence, our research endeavors to explore the safety, efficacy and the potential molecular mechanism of transcutaneous auricular vagus nerve stimulation (ta-VNS) for the treatment of depression in PSD patients by conducting a double-blind, sham-controlled, randomized trial. METHODS: Patients who had experienced strokes and exhibited depressive symptoms, with a Hamilton Depression Scale (HAMD-17) score of ≥8 and met the DSM-IV criteria, were diagnosed with PSD. A volunteer sample of participants (N = 80) were randomly divided into either the ta-VNS group (which received ta-VNS in addition to conventional treatment) or the control group (which received conventional treatment only), in a 1:1 ratio. The effectiveness of the interventions was evaluated using the 17-item Hamilton Rating Scale for Depression (HAMD-17), Zung Self-Rating Depression Scale (SDS), and Barthel Index (BI) scores. Furthermore, Plasma BDNF, CREB1, and 5-HT levels were measured before and after treatment. RESULTS: The concomitant application of ta-VNS demonstrated a remarkable reduction in HAMD-17 and SDS scores, leading to noteworthy enhancements in patients' daily functioning, as evidenced by improved activities of daily living, at all assessed time points, in contrast to the control group (p < 0.0001). Notably, the ta-VNS group exhibited superior effects in modulating the measured neurotrophic biomarkers when compared to the control group (p < 0.05). CONCLUSIONS: The synergistic approach of combining ta-VNS with conventional treatment has demonstrated remarkable efficacy and tolerability in managing depression following a stroke.

Yi-Qi-Huo-Xue decoction alleviates intracerebral hemorrhage injury through inhibiting neuronal autophagy of ipsilateral cortex via BDNF/TrkB pathway.

BACKGROUND: Yi-Qi-Huo-Xue Decoction (YQHXD), a traditional Chinese medicine formula, has demonstrated efficacy in the clinical treatment of intracerebral hemorrhage (ICH) for over a decade. Nevertheless, the precise pharmacotherapeutic compounds of YQHXD capable of penetrating into cerebral tissue and the pharmacological underpinnings of YQHXD remain ambiguous. METHODS: The active components of YQHXD in rat brains was analyzed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. The potential targets, pathways and biological progresses of YQHXD ameliorating ICH induced injury was predicted by network pharmacology. Moreover, collagenase-induced ICH rat model, primary cortex neurons exposed to hemin and molecular docking were applied to validate the molecular mechanisms of YQHXD. RESULTS: Eleven active components of YQHXD were identified within the brains. Employing the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, our investigation concentrated on the roles of autophagy and the BDNF/TrkB signaling pathway in the pharmacological context. The pharmacological results revealed that YQHXD alleviated neurological dysfunction, brain water content, brain swelling, and pathological injury caused by ICH. Meanwhile, YQHXD inhibited autophagy influx and autophagosome in vivo, and regulated cortex neuronal autophagy and TrkB/BDNF pathway both in vivo and in vitro. Subsequently, N-acetyl serotonin (NAS), a selective TrkB agonist, was employed to corroborate the significance of the BDNF/TrkB pathway in this process. The combination of NAS and YQHXD did not further enhance the protective efficacy of YQHXD in ICH rats. Additionally, outcomes of molecular docking analysis revealed that nine compounds of YQHXD exhibited potential regulatory effects on TrkB. CONCLUSIONS: Ipsilateral neuronal autophagy and BDNF/TrkB pathway were activated 72 h after ICH. YQHXD effectively resisted injury induced by ICH, which was related with suppression of ipsilateral neuronal autophagy via BDNF/TrkB pathway. This study provides novel insights into the therapeutic mechanisms of traditional Chinese medicine in the context of ICH treatment.

Echinacoside ameliorates post-stroke depression by activating BDNF signaling through modulation of Nrf2 acetylation.

BACKGROUND: Post-stroke depression (PSD) affects approximately one-third of stroke survivors, leading to adverse outcomes in rehabilitation, reduced quality of life, and increased mortality rates. Despite these implications, the underlying causes of PSD remain unclear, posing challenges for prevention and treatment. Echinacoside (ECH), a natural compound with known neuroprotective and antidepressant properties, holds significant therapeutic potential for PSD. However, the precise mechanism of its action remains unknown. PURPOSE: To unravel the specific mechanism through which ECH alleviates PSD by exploring the intricate interplay between ECH and Nrf2, as well as its impact on the BDNF/TrkB signaling axis. STUDY DESIGN AND METHODS: A rat PSD model was established though middle cerebral artery occlusion coupled with chronic unpredictable mild stress, followed by ECH treatment. The rats' depressive state was evaluated using the sucrose preference test and force swimming test. Brain damage was assessed through TTC staining, Nissl staining, and TUNEL assay. The multifaceted mechanism of ECH in PSD was investigated using immunofluorescence, immunohistochemistry, RT-qPCR, dual-luciferase assay, and western blotting. Additionally, the interaction between ECH and Nrf2 was explored through molecular docking and microscale thermophoresis. RESULTS: Our findings unveiled a novel facet of ECH action, demonstrating its unique ability to upregulate Nrf2 through acetylation within the hippocampus of PSD-affected rats (p < 0.05). Moreover, ECH showcased its distinctive potential by enhancing BDNF transcriptional activity, activating the BDNF/TrkB signaling axis, and orchestrating a comprehensive response against oxidative stress and apoptosis, thereby alleviating PSD symptoms in rats (p < 0.05). CONCLUSIONS: This study not only provides insights into the pivotal role of Nrf2 in mediating the BDNF/TrkB axis activation by ECH but also highlights the novelty of ECH's mechanism in addressing PSD. The elucidation of these unique aspects positions ECH as a groundbreaking candidate for further exploration and development in the realm of PSD intervention.

Paeonol alleviates postmenopause-induced neuropsychiatric symptoms through the modulation of GPR30 in ovariectomized mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The Moutan cortex (MC), the root bark of Paeonia suffruticosa Anderws (Paeoniaceae), has been historically employed in traditional herbal medicine for addressing women's ailments by replenishing kidney Yin. AIM OF THE STUDY: We aimed to explore if paeonol, an active constituent of MC, could ameliorate neuropsychiatric symptoms, such as anxiety, depression, and cognitive impairments, associated with post-menopausal syndrome (PMS) in an ovariectomized (OVX) mouse model. MATERIALS AND METHODS: The experimental design comprised 6 groups, including a sham group, OVX group, paeonol administration groups (3, 10 or 30 mg/kg, p.o.), and an estradiol (E2)-treated positive control group. Behavioral tests including the open field, novel object recognition, Y-maze, elevated plus-maze, splash, and forced swimming tests were conducted. In addition, we investigated the effets of paeonol on the phosphorylated levels of phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR), as well as on the expression levels of G protein-coupled receptor (GPR30) and brain-derived neurotrophic factor (BDNF) in the prefrontal cortex and hippocampus. RESULTS: Paeonol treatment (10 and 30 mg/kg, p.o.) effectively reversed the cognitive decline in OVX mice, measured by the novel object recognition and Y-maze tests, similar to that in the positive control group. Additionally, it alleviated anxiety- and depressive-like behaviors, as evaluated by the elevated plus-maze test, splash test, and forced swimming test. Paeonol restored GPR30 expression levels in the prefrontal cortex and hippocampus, mirroring the effects of E2 administration. Furthermore, it reversed the reduced expression levels of the PI3K-Akt-mTOR signaling pathway in the prefrontal cortex and hippocampus and increased BDNF expression in the hippocampus of OVX mice. CONCLUSION: This research suggests that paeonol would be beneficial for alleviating PMS-associated cognitive impairment, anxiety and depression.

Effect of 2-Week Naringin Supplementation on Neurogenesis and BDNF Levels in Ischemia-Reperfusion Model of Rats.

BACKGROUND: Ischemic stroke is the leading cause of mortality and disability worldwide with more than half of survivors living with serious neurological sequelae; thus, it has recently attracted a lot of attention in the field of medical study. PURPOSE: The aim of this study was to determine the effect of naringin supplementation on neurogenesis and brain-derived neurotrophic factor (BDNF) levels in the brain in experimental brain ischemia-reperfusion. STUDY DESIGN: The research was carried out on 40 male Wistar-type rats (10-12 weeks old) obtained from the Experimental Animals Research and Application Center of Selçuk University. Experimental groups were as follows: (1) Control group, (2) Sham group, (3) Brain ischemia-reperfusion group, (4) Brain ischemia-reperfusion + vehicle group (administered for 14 days), and (5) Brain ischemia-reperfusion + Naringin group (100 mg/kg/day administered for 14 days). METHODS: In the ischemia-reperfusion groups, global ischemia was performed in the brain by ligation of the right and left carotid arteries for 30 min. Naringin was administered to experimental animals by intragastric route for 14 days following reperfusion. The training phase of the rotarod test was started 4 days before ischemia-reperfusion, and the test phase together with neurological scoring was performed the day before and 1, 7, and 14 days after the operation. At the end of the experiment, animals were sacrificed, and then hippocampus and frontal cortex tissues were taken from the brain. Double cortin marker (DCX), neuronal nuclear antigen marker (NeuN), and BDNF were evaluated in hippocampus and frontal cortex tissues by Real-Time qPCR analysis and immunohistochemistry methods. RESULTS: While ischemia-reperfusion increased the neurological score values, DCX, NeuN, and BDNF levels decreased significantly after ischemia in the hippocampus and frontal cortex tissues. However, naringin supplementation restored the deterioration to a certain extent. CONCLUSION: The results of the study show that 2 weeks of naringin supplementation may have protective effects on impaired neurogenesis and BDNF levels after brain ischemia and reperfusion in rats.

Salidroside directly activates HSC70, revealing a new role for HSC70 in BDNF signalling and neurogenesis after cerebral ischemia.

Salidroside, a principal bioactive component of Rhodiola crenulata, is neuroprotective across a wide time window in stroke models. We investigated whether salidroside induced neurogenesis after cerebral ischemia and aimed to identify its primary molecular targets. Rats, subjected to transient 2 h of middle cerebral artery occlusion (MCAO), received intraperitoneal vehicle or salidroside ± intracerebroventricular HSC70 inhibitor VER155008 or TrkB inhibitor ANA-12 for up to 7 days. MRI, behavioural tests, immunofluorescent staining and western blotting measured effects of salidroside. Reverse virtual docking and enzymatic assays assessed interaction of salidroside with purified recombinant HSC70. Salidroside dose-dependently decreased cerebral infarct volumes and neurological deficits, with maximal effects by 50 mg/kg/day. This dose also improved performance in beam balance and Morris water maze tests. Salidroside significantly increased BrdU+/nestin+, BrdU+/DCX+, BrdU+/NeuN+, BrdU-/NeuN+ and BDNF+ cells in the peri-infarct cortex, with less effect in striatum and no significant effect in the subventricular zone. Salidroside was predicted to bind with HSC70. Salidroside dose-dependently increased HSC70 ATPase and HSC70-dependent luciferase activities, but it did not activate HSP70. HSC70 immunoreactivity concentrated in the peri-infarct cortex and was unchanged by salidroside. However, VER155008 prevented salidroside-dependent increases of neurogenesis, BrdU-/NeuN+ cells and BDNF+ cells in peri-infarct cortex. Salidroside also increased BDNF protein and p-TrkB/TrkB ratio in ischemic brain, changes prevented by VER155008 and ANA-12, respectively. Additionally, ANA-12 blocked salidroside-dependent neurogenesis and increased BrdU-/NeuN+ cells in the peri-infarct cortex. Salidroside directly activates HSC70, thereby stimulating neurogenesis and neuroprotection via BDNF/TrkB signalling after MCAO. Salidroside and similar activators of HSC70 might provide clinical therapies for ischemic stroke.

Cerebrolysin potentiates the antidepressant effect of lithium in a rat model of depression.

RATIONALE: Depression is the most prevalent psychiatric disorder worldwide. Although numerous antidepressant treatments are available, there is a serious clinical concern due to their severe side effects and the fact that some depressed patients are resistant to them. Lithium is the drug of choice for bipolar depression and has been used as adjunct therapy with other groups of antidepressants. OBJECTIVES: The present study aims to investigate the effect of lithium augmentation with cerebrolysin on the neurochemical, behavioral and histopathological alterations induced in the reserpine model of depression. METHODS: The animals were divided into control and reserpine-induced model of depression. The model animals were further divided into rat model of depression, rat model treated with lithium, rat model treated with cerebrolysin and rat model treated with a combination of lithium and cerebrolysin. RESULTS: Treatment with lithium, cerebrolysin, or their combination alleviated most of the changes in behavior, oxidative stress parameters, acetylcholinesterase and monoamines in the cortex and hippocampus of the reserpine-induced model of depression. It also improved the alterations in brain-derived neurotrophic factor (BDNF) and histopathology induced by reserpine. CONCLUSIONS: The augmentation of lithium with cerebrolysin showed a clear beneficial effect in the present model of depression suggesting the use of cerebrolysin as an adjuvant in antidepressant treatment.

Lutein and Zeaxanthin Supplementation Improves Dynamic Visual and Cognitive Performance in Children: A Randomized, Double-Blind, Parallel, Placebo-Controlled Study.

INTRODUCTION: Supplementation with dietary neuro-pigments lutein (L) and zeaxanthin (Z) has been shown to improve many aspects of visual and cognitive function in adults. In this study, we tested whether a similar intervention could improve such outcomes in preadolescent children. METHODS: Sixty children (age range 5-12 years) were randomized in a 2:1 ratio in this double-blind, placebo-controlled clinical trial. Subjects were supplemented with gummies containing either a combination of 10 mg lutein and 2 mg zeaxanthin (LZ) or placebo for 180 days. Macular pigment optical density (MPOD) was the primary endpoint. The secondary endpoints included serum levels of L and Z, and brain-derived neurotrophic factor (BDNF), critical flicker fusion (CFF), eye strain and fatigue using visual analogue scales (VAS), Children's Sleep Habits Questionnaire-Abbreviated (CSHQ-A), and Creyos Health cognitive domains like attention, focus/concentration, episodic memory and learning, visuospatial working memory, and visuospatial processing speed. Safety was assessed throughout the study on the basis of physical examination, vital signs, clinical laboratory tests, and monitoring of adverse events. RESULTS: The LZ group showed significant increases in MPOD at all visits post-supplementation, with significant increases as early as day 42 compared to placebo. The LZ group showed significant increases in serum lutein levels, reduced eye strain and fatigue, and improved cognitive performance (focus, episodic memory and learning, visuospatial working memory) at days 90 and 180 compared to placebo. Further, the LZ group showed significant increases in processing speed (CFF), attention, visuospatial processing, and serum Z and BDNF levels on day 180 compared to placebo. No safety concerns were observed. CONCLUSIONS: Supplementing LZ resulted in increased MPOD levels, along with increased serum levels of L, Z, and BDNF. These changes were associated with improved visual and cognitive performances and reduction in eye strain and eye fatigue in the children receiving LZ gummies. The investigational product was safe and well tolerated. TRIAL REGISTRATION: http://ctri.nic.in/ Identifier CTRI/2022/05/042364.

Formulated Palmitoylethanolamide Supplementation Improves Parameters of Cognitive Function and BDNF Levels in Young, Healthy Adults: A Randomised Cross-Over Trial.

BACKGROUND: Palmitoylethanolamide (PEA) is an endocannabinoid-like lipid mediator which is naturally produced in the body and found in certain foods. The aim of this study was to assess the effect of a bioavailable formulated form of PEA (Levagen+®) on serum BDNF levels and parameters of cognitive function in healthy adults. METHODS: A randomised double-blinded placebo-controlled cross-over trial was implemented to measure the effects of a 6-week 700 mg/day course of formulated PEA supplementation versus a placebo. Participants (n = 39) completed pre- and post-assessments of a lab-based cognitive test. Serum samples were collected to measure BDNF concentrations using an immunoassay. RESULTS: A significant increase in serum BDNF levels was found following PEA supplementation compared with the placebo (p = 0. 0057, d = 0.62). The cognition test battery demonstrated improved memory with PEA supplementation through better first success (p = 0.142, d = 0.54) and fewer errors (p = 0.0287; d = -0.47) on the Paired Associates Learning test. CONCLUSION: This was the first study to report a direct beneficial effect of Levagen+® PEA supplementation on memory improvement as well as corresponding increases in circulating neurotrophic marker levels. This suggests that formulated PEA holds promise as an innovative and practical intervention for cognitive health enhancement.

Complete Restoration of Hearing Loss and Cochlear Synaptopathy via Minimally Invasive, Single-Dose, and Controllable Middle Ear Delivery of Brain-Derived Neurotrophic Factor-Poly(dl-lactic acid-co-glycolic acid)-Loaded Hydrogel.

Noise-induced hearing loss (NIHL) often accompanies cochlear synaptopathy, which can be potentially reversed to restore hearing. However, there has been little success in achieving complete recovery of sensorineural deafness using nearly noninvasive middle ear drug delivery before. Here, we present a study demonstrating the efficacy of a middle ear delivery system employing brain-derived neurotrophic factor (BDNF)-poly-(dl-lactic acid-co-glycolic acid) (PLGA)-loaded hydrogel in reversing synaptopathy and restoring hearing function in a mouse model with NIHL. The mouse model achieved using the single noise exposure (NE, 115 dBL, 4 h) exhibited an average 20 dBL elevation of hearing thresholds with intact cochlear hair cells but a loss of ribbon synapses as the primary cause of hearing impairment. We developed a BDNF-PLGA-loaded thermosensitive hydrogel, which was administered via a single controllable injection into the tympanic cavity of noise-exposed mice, allowing its presence in the middle ear for a duration of 2 weeks. This intervention resulted in complete restoration of NIHL at frequencies of click, 4, 8, 16, and 32 kHz. Moreover, the cochlear ribbon synapses exhibited significant recovery, whereas other cochlear components (hair cells and auditory nerves) remained unchanged. Additionally, the cochlea of NE treated mice revealed activation of tropomyosin receptor kinase B (TRKB) signaling upon exposure to BDNF. These findings demonstrate a controllable and minimally invasive therapeutic approach that utilizes a BDNF-PLGA-loaded hydrogel to restore NIHL by specifically repairing cochlear synaptopathy. This tailored middle ear delivery system holds great promise for achieving ideal clinical outcomes in the treatment of NIHL and cochlear synaptopathy.

Extracts of Sideritis scardica and Clinopodium vulgare Alleviate Cognitive Impairments in Scopolamine-Induced Rat Dementia.

Sideritis scardica Griseb. and Clinopodium vulgare L., belonging to the Lamiaceae family, are rich in terpenoids and phenolics and exhibit various pharmacological effects, including antioxidant, anti-inflammatory and anti-cancer activities. While the memory-enhancing impacts of S. scardica are well documented, the cognitive benefits of C. vulgare remain unexplored. This study assessed the potential effect of C. vulgare on learning and memory in healthy and scopolamine (Sco)-induced memory-impaired male Wistar rats, comparing it with the effects of S. scardica. Over a 21-day period, rats orally received extracts of cultivated S. scardica (200 mg/kg) and C. vulgare (100 mg/kg), either individually or in combination, with administration starting 10 days before and continuing 11 days simultaneously with Sco injection at a dose of 2 mg/kg intraperitoneally. The results showed that both extracts effectively mitigated Sco-induced memory impairment. Their combination significantly improved recognition memory and maintained monoaminergic function. S. scardica excelled in preserving spatial working memory, while C. vulgare exhibited comparable retention of recognition memory, robust antioxidant activity and acetylcholinesterase inhibitory activity. The extracts alleviated Sco-induced downregulation of p-CREB/BDNF signaling, suggesting neuroprotective mechanisms. The extract combination positively affected most of the Sco-induced impairments, underscoring the potential for further investigation of these extracts for therapeutic development.

Natural product Kaji-ichigoside F1 exhibits rapid antidepression via activating the AMPA-BDNF-mTOR pathway and inhibiting the NMDAR-CaMKIIα pathway.

BACKGROUND: Depression is a common and recurrent neuropsychiatric disorder. Recent studies have shown that the N-methyl-d-aspartate (NMDA) receptor (NMDAR) is involved in the pathophysiology of depression. Previous studies have found that Kaji-ichigoside F1 (KF1) has a protective effect against NMDA-induced neurotoxicity. However, the antidepressant mechanism of KF1 has not been confirmed yet. PURPOSE: In the present study, we aimed to evaluate the rapid antidepressant activity of KF1 and explore the underlying mechanism. STUDY DESIGN: First, we explored the effect of KF1 on NMDA-induced hippocampal neurons and the underlying mechanism. Second, depression was induced in C57BL/6 mice via chronic unpredictable mild stress (CUMS), and the immediate and persistent depression-like behavior was evaluated using the forced swimming test (FST) after a single administration of KF1. Third, the contributions of NMDA signaling to the antidepressant effect of KF1 were investigated using pharmacological interventions. Fourth, CUMS mice were treated with KF1 for 21 days, and then their depression-like behaviors and the underlying mechanism were further explored. METHODS: The FST was used to evaluate immediate and persistent depression-like behavior after a single administration of KF1 with or without NMDA pretreatment. The effect of KF1 on depressive-like behavior was investigated in CUMS mice by treating them with KF1 once daily for 21 days through the sucrose preference test, FST, open field test, and tail suspension test. Then, the effects of KF1 on the morphology and molecular and functional phenotypes of primary neuronal cells and hippocampus of mice were investigated by hematoxylin-eosin staining, Nissl staining, propidium iodide staining, TUNEL staining, Ca2+ imaging, JC-1 staining, ELISA, immunofluorescence analysis, RT-PCR, and Western blot. RESULTS: KF1 could effectively improve cellular viability, reduce apoptosis, inhibit the release of LDH and Ca2+, and increase the mitochondrial membrane potential and the number of dendritic spines numbers in hippocampal neurons. Moreover, behavioral tests showed that KF1 exerted acute and sustained antidepressant-like effects by reducing Glu-levels and ameliorating neuronal damage in the hippocampus. Additionally, in vivo and in vitro experiments revealed that PSD95, Syn1, α-amino-3­hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and brain-derived neurotrophic factor (BDNF) were upregulated at the protein level, and BDNF and AMPA were upregulated at the mRNA level. NR1 and NR2A showed the opposite trend. CONCLUSION: These results confirm that KF1 exerts rapid antidepressant effects mainly by activating the AMPA-BDNF-mTOR pathway and inhibiting the NMDAR-CaMKIIα pathway. This study serves as a new reference for discovering rapid antidepressants.

The Effects of Polyphenol Supplementation on BDNF, Cytokines and Cognition in Trained Male Cyclists following Acute Ozone Exposure during High-Intensity Cycling.

The neurotoxic effects of ozone exposure are related to neuroinflammation and increases in reactive oxygen species (ROS). This study aimed to assess inflammation, Brain-Derived Neurotrophic Factor (BDNF), and cognition in healthy male cyclists following polyphenol supplementation and exercise in an ozone-polluted environment. Ten male cyclists initially completed a maximal incremental test and maximal effort 4 km time trial in ambient air. Cyclists then completed two trials in an ozone-polluted environment (0.25 ppm) following 7 days of supplementation with either polyphenol (POLY) or placebo (PL). Experimental trials consisted of a three-stage submaximal test followed by a 4 km time trial. Blood samples were drawn pre- and post-exercise, and analyzed for BDNF, interleukin 6 (IL-6), interleukin 10 (IL-10) and tumor necrosis factor (TNF-α). The Stroop test and serial subtraction task were performed before ozone exposure and again after the 4 km TT. Serum BDNF increased post-exercise (p < 0.0001), and positive differences were observed post-exercise in the ozone POLY group relative to PL (p = 0.013). Plasma IL-6 increased post-exercise (p = 0.0015), and TNF-α increased post-ozone exposure (p = 0.0018). There were no differences in Stroop or serial subtraction tasks pre- or post-exercise. Exercise increases BDNF in ozone.

Unraveling the potential of vitamins C and D as adjuvants in depression treatment with escitalopram in an LPS animal model.

Depression is linked with oxidative stress and inflammation, where key players include nitric oxide (NO), nuclear factor erythroid 2-related factor 2 (Nrf2), Brain-Derived Neurotrophic Factor (BDNF), and Heme Oxidase-1 (HO-1). Augmenting the efficacy of antidepressants represents a compelling avenue of exploration. We explored the potential of vitamins C and D as adjuncts to escitalopram (Esc) in a lipopolysaccharide (LPS)-induced depression model focusing on the aforementioned biomarkers. Male Swiss albino mice were stratified into distinct groups: control, LPS, LPS + Esc, LPS + Esc + Vit C, LPS + Esc + Vit D, and LPS + Esc + Vit C + Vit D. After a 7-day treatment period, a single LPS dose (2 mg/kg), was administered, followed by comprehensive assessments of behavior and biochemical parameters. Notably, a statistically significant (p < 0.05) alleviation of depressive symptoms was discerned in the Esc + Vit C + Vit D group versus the LPS group, albeit with concomitant pronounced sedation evident in all LPS-treated groups (p < 0.05). Within the cortex, LPS reduced (p < 0.05) the expression levels of NOx, Nrf2, BDNF, and HO-1, with only HO-1 being reinstated to baseline in the LPS + Esc + Vit D and the LPS + Esc + Vit C + Vit D groups. Conversely, the hippocampal NOx, Nrf2, and HO-1 levels remained unaltered following LPS administration. Notably, the combination of Esc, Vit C, and Vit D effectively restored hippocampal BDNF levels, which had been diminished by Esc alone. In conclusion, vitamins C and D enhance the therapeutic effects of escitalopram through a mechanism independent of Nrf2. These findings underscore the imperative need for in-depth investigations.

Periplaneta Americana (L.) extract activates the ERK/CREB/BDNF pathway to promote post-stroke neuroregeneration and recovery of neurological functions in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Periplaneta americana (L.) (PA) has been used in traditional Chinese medicine for thousands of years for the effect of invigorating blood circulation and removing blood stasis. Modern pharmacological research shown that PA extract exhibits promising effects in promoting wound healing and regeneration, as well as in brain diseases such as Parkinson's disease (PD). However, whether it is effective for neuroregeneration and neurological function recovery after stroke still unknown. AIM OF THE STUDY: This study aims to investigate the potential effect of PA extract to promote brain remodeling through the activation of endogenous neurogenesis and angiogenesis, in addition, preliminary exploration of its regulatory mechanism. METHODS: Firstly, BrdU proliferation assay and immunofluorescence (IF) staining were used to evaluate the effect of PA extract on the neurogenesis and angiogenesis in vitro and in vivo. Subsequently, the effects of PA extract on brain injury in stroke rats were assessed by TTC and HE. While mNSS score, adhesive removal test, rota-rod test, and morris water maze test were used to assess the impact of PA extract on neurological function in post-stroke rats. Finally, the molecular mechanisms of PA extract regulation were explored by RNA-Seq and western blotting. RESULTS: The number of BrdU+ cells in C17.2 cells, NSCs and BMECs dramatically increased, as well as the expression of astrocyte marker protein GFAP and neuronal marker protein Tuj-1 in C17.2 and NSCs. Moreover, PA extract also increased the number of BrdU+DCX+, BrdU+GFAP+, BrdU+CD31+ cells in the SGZ area of transient middle cerebral artery occlusion model (tMCAO) rats. TTC and HE staining revealed that PA extract significantly reduced the infarction volume and ameliorated the pathological damage. Behavioral tests demonstrated that treatment with PA extract reduced the mNSS score and the time required to remove adhesive tape, while increasing the time spent on the rotarod. Additionally, in the morris water maze test, the frequency of crossing platform and the time spent in the platform quadrant increased. Finally, RNA-Seq and Western blot revealed that PA extract increased the expression of p-ERK, p-CREB and BDNF. Importantly, PA extract mediated proliferation and differentiation of C17.2 and NSCs reversed by the ERK inhibitor SCH772984 and the BDNF inhibitor ANA-12, respectively. CONCLUSION: Our study demonstrated that PA extract promoted neurogenesis and angiogenesis by activating the CREB/ERK signaling pathway and upregulating BDNF expression, thereby recovering neurological dysfunction in post-stroke.

Signaling Pathways Involved in the Neuroprotective Effect of Osthole: Evidence and Mechanisms.

Neurodegenerative diseases constitute a major threat to human health and are usually accompanied by progressive structural and functional loss of neurons. Abnormalities in synaptic plasticity are involved in neurodegenerative disorders. Aberrant cell signaling cascades play a predominant role in the initiation, progress as well as in the severity of these ailments. Notch signaling is a pivotal role in the maintenance of neural stem cells and also participates in neurogenesis. PI3k/Akt cascade regulates different biological processes including cell proliferation, apoptosis, and metabolism. It regulates neurotoxicity and mediates the survival of neurons. Moreover, the activated BDNF/TrkB cascade is involved in promoting the transcription of genes responsible for cell survival and neurogenesis. Despite significant progress made in delineating the underlying pathological mechanisms involved and derangements in cellular metabolic promenades implicated in these diseases, satisfactory strategies for the clinical management of these ailments are yet to be achieved. Therefore, the molecules targeting these cell signaling cascades may emerge as useful leads in developing newer management strategies. Osthole is an important ingredient of traditional Chinese medicinal plants, often found in various plants of the Apiaceae family and has been observed to target these aforementioned mediators. Until now, no review has been aimed to discuss the possible molecular signaling cascades involved in osthole-mediated neuroprotection at one platform. The current review aimed to explore the interplay of various mediators and the modulation of the different molecular signaling cascades in osthole-mediated neuroprotection. This review could open new insights into research involving diseases of neuronal origin, especially the effect on neurodegeneration, neurogenesis, and synaptic plasticity. The articles gathered to compose the current review were extracted by using the PubMed, Scopus, Science Direct, and Web of Science databases. A methodical approach was used to integrate and discuss all published original reports describing the modulation of different mediators by osthole to confer neuroprotection at one platform to provide possible molecular pathways. Based on the inclusion and exclusion criteria, 32 articles were included in the systematic review. Moreover, literature evidence was also used to construct the biosynthetic pathway of osthole. The current review reveals that osthole promotes neurogenesis and neuronal functioning via stimulation of Notch, BDNF/Trk, and P13k/Akt signaling pathways. It upregulates the expression of various proteins, such as BDNF, TrkB, CREB, Nrf-2, P13k, and Akt. Activation of Wnt by osthole, in turn, regulates downstream GSK-1ß to inhibit tau phosphorylation and ß-catenin degradation to prevent neuronal apoptosis. The activation of Wnt and inhibition of oxidative stress, Aß, and GSK-3ß mediated ß-catenin degradation by osthole might also be involved in mediating the protection against neurodegenerative diseases. Furthermore, it also inhibits neuroinflammation by suppressing MAPK/NF-κB-mediated transcription of genes involved in the generation of inflammatory cytokines and NLRP-3 inflammasomes. This review delineates the various underlying signaling pathways involved in mediating the neuroprotective effect of osthole. Modulation of Notch, BDNF/Trk, MAPK/NF-κB, and P13k/Akt signaling pathways by osthole confers protection against neurodegenerative diseases. The preclinical effects of osthole suggest that it could be a valuable molecule in inspiring the development of new drugs for the management of neurodegenerative diseases and demands clinical studies to explore its potential. An effort has been made to unify the varied mechanisms and target sites involved in the neuroprotective effect of osthole. The comprehensive description of the molecular pathways in the present work reflects its originality and thoroughness. The reviewed literature findings may be extrapolated to suggest the role of othole as a "biological response modifier" which contributes to neuroprotection through kinase modulatory, immunomodulatory, and anti-oxidative activity, which is documented even at lower doses. The current review attempts to emphasize the gaps in the existing literature which can be explored in the future.

Neuroprotective effect of isovaleraldehyde accompanied with upregulation of BDNF and CREB phosphorylation via the PKA pathway.

Recently, the number of patients diagnosed with dementia has increased. The World Health Organization (WHO) estimates that 50 million patients suffer from dementia. Although several therapeutic strategies have been proposed, currently, there is no curative approach for treating dementia. Neurodegeneration is an irreversible process. As this disease gradually progresses over 15-20 years, a low-cost and sustainable method for preventing these diseases is desired. Cacao nib is consumed in many countries, and a recent clinical study indicated that cocoa intake upregulates brain-derived neurotrophic factor (BDNF), which plays a significant role in memory formation and neuronal cell survival. In the present study, neural cells were treated with cacao nib extract or the 17 characteristic components of cacao nib. Treatment with Cacao nib extract upregulates BDNF mRNA expression. In addition, cacao nib extract elicits the phosphorylation of cAMP-response-element-binding protein (CREB), which regulates the transcription of BDNF. Among the 17 species screened, isovaleraldehyde (IVA), also known as an aroma component of cacao nibs extract, improved BDNF mRNA expression without SH-SY5Y cell toxicity. IVA also promoted CREB phosphorylation through a cAMP-dependent protein kinase (PKA)-dependent mechanism. In conclusion, IVA could be responsible for the BDNF upregulation effect of cacao nib, and IVA upregulated BDNF expression via the PKA-CREB axis.