Brain-derived neurotrophic factor (BDNF) was previously reported as a positive modulator of zebrafish reproduction, yet the mechanism of action of BDNF that elicits this function is unknown. We hypothesized that the pro-reproductive effects of BDNF in female zebrafish are mediated by TrkB signaling. In zebrafish liver (ZFL) cells, a TrkB antagonist (ANA-12) blocked the stimulatory effect of BDNF on transcript abundance of vitellogenin (vtg1, 2, 4, and 7) and steroidogenic factor 1 (sf-1). No changes were observed in hepatocyte nuclear factor 4 alpha, specificity protein 1, cAMP response element-binding protein 1a, or forkhead box L2. Blocking the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and phospholipase C gamma (PLC-γ) pathways significantly attenuated BDNF-induced upregulation of vtg and sf-1 transcripts. Total vtg protein was increased by BDNF, an effect that was blunted when TrkB, MAPK, PI3K, or PLC-γ were blocked. The estrogen receptor alpha (Esrα) fluorescence immunoreactivity in the ZFL cells treated with BDNF was significantly reduced in the presence of ANA-12. In the zebrafish follicles, BDNF-induced oocyte maturation was attenuated by TrkB, MAPK-, and PI3K inhibitors, but not a PLC-γ blocker. Similarly, the positive effects of BDNF on maturation-related genes 3β-hydroxysteroid dehydrogenase 2 enzyme (3bhsd2), cytochrome P450 family 17, hyaluronan synthase 2, luteinizing hormone receptor, and prostaglandin synthase 2 were significantly attenuated when TrkB, MAPK, or PI3K was blocked. PLC-γ inhibition prevented the BDNF-induced upregulation of 3bhsd1 in the oocytes. This study demonstrates that BDNF promotes vitellogenesis via the TrkB-MAPK/PI3K/PLC-γ signaling pathways. Meanwhile, BNDF enhances oocyte maturation through the TrkB-MAPK/PI3K pathways in zebrafish.

2025-12-01·EUROPEAN JOURNAL OF PHARMACOLOGY

Neuroprotective effects of Gnetin H from Paeonia lactiflora via CREB-BDNF pathway restoration in a scopolamine-induced memory deficit model

Article

作者: Kim, June Hee ; Choi, Chun Whan ; Lee, Bonggi ; Lee, Elliot Hwejoon ; Kim, Min Soo ; Cho, Ik-Hyun ; Oh, Soo-Jin ; Kim, Seong-Seop ; Kang, Taek ; Hong, Gyu-Sang

Dementia, a leading cause of disability affecting older adults worldwide, is characterized by memory and cognitive decline associated with dysregulated cholinergic activity and CREB-BDNF signaling. Polyphenols have been investigated for their potential to ameliorate these deficits. Gnetin H, a resveratrol derivative from Paeonia lactiflora seeds with known bioactive properties, has not been evaluated for neuroprotection. Here, we evaluated the neuroprotective actions of Gnetin H in a scopolamine-induced memory deficit model at cellular, slice, and animal levels. In SH-SY5Y neuroblastoma cells, Gnetin H (1 or 15 μM) promoted cell survival under scopolamine treatment. In hippocampal slices, acute bath application of Gnetin H (1.7 μM) enhanced long-term potentiation (LTP) despite scopolamine challenge, indicating preserved synaptic plasticity. In mice, central administration of Gnetin H (10 or 50 ng) restored memory performance in Y-maze, novel object recognition test, and Morris water maze, accompanied by recovery of cholinergic activity and CREB-BDNF signaling. Restoration of CREB-BDNF signaling was abolished by co-treatment of TrkB antagonist ANA-12 in SH-SY5Y cells, which confirmed involvement of TrkB-dependent CREB-BDNF signaling. Finally, Gnetin H rescued scopolamine-induced reductions in DCX-positive neurogenic cells and attenuated astrocytic (GFAP) and microglial (Iba1) reactivity in the hippocampus. In conclusion, Gnetin H exerts neuroprotective effects across cellular, slice, and animal models by enhancing synaptic plasticity (LTP) and restoring CREB-BDNF signaling through TrkB cascade, thereby supporting hippocampal neurogenesis and attenuating scopolamine-induced glial reactivity, with minimal effects under basal conditions.

2025-11-01·ANESTHESIA AND ANALGESIA

The Effects of Treadmill Exercise on the Recovery of Synaptic Plasticity in Septic Mice: A Focus on Brain-Derived Neurotrophic Factor/Tropomyosin-Related Kinase B Signaling

Article

作者: Soejima, Takashi ; Morimoto, Yuji ; Hoshino, Koji

BACKGROUND::

Sepsis-associated encephalopathy causes irreversible cognitive dysfunction, yet no effective pharmacological treatments are available. The hippocampus is particularly vulnerable to sepsis-induced damage, and impairments in hippocampal synaptic plasticity, particularly late-phase long-term potentiation (L-LTP), are implicated in cognitive dysfunction. Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), play crucial roles in maintaining L-LTP. While exercise enhances cognitive function, its effects on hippocampal synaptic plasticity under conditions mimicking early rehabilitation after sepsis remain unclear. This study evaluated the impact of treadmill exercise on hippocampal L-LTP in a murine sepsis model, using a protocol resembling early clinical rehabilitation.

METHODS::

A total of 267 C57BL/6J mice (8–12 weeks old) underwent cecal ligation and puncture (CLP) or sham surgery, with or without treadmill exercise (30 min/d for 7 days postsurgery). Mice were divided into 4 groups: (1) sham + sedentary, (2) sham + exercise, (3) CLP + sedentary, and (4) CLP + exercise. The primary outcome was hippocampal L-LTP, assessed via electrophysiology. Secondary outcomes included hippocampal BDNF levels, locomotor activity, and survival curves. Additionally, the role of BDNF/TrkB signaling was examined using ANA-12, an antagonist of the BDNF receptor TrkB. Data are presented as mean ± standard deviation.

RESULTS::

L-LTP at the Schaffer collateral–CA1 synapse was significantly impaired in CLP mice 1 week after surgery (CLP + sedentary: 144% ± 15% vs sham + sedentary: 185% ± 34%; P = .008). Exercise restored L-LTP in CLP mice (CLP + exercise: 189% ± 36% vs CLP + sedentary: 144% ± 15%, P = .003), but this effect was abolished by ANA-12 (CLP + exercise + ANA-12: 155% ± 22% vs CLP + exercise + vehicle: 194% ± 37%, P < .001). Exercise also restored hippocampal BDNF levels reduced by CLP (CLP + exercise: 4190 ± 671 pg/mg protein versus CLP + sedentary: 3220 ± 647 pg/mg protein, P = .007). Locomotor activity was impaired in CLP mice but not significantly improved by exercise (P = .38). Furthermore, the survival curves differed significantly between CLP mice with and without treadmill exercise, as determined by post hoc analysis after a log-rank test (P = .003).

CONCLUSIONS::

Treadmill exercise therapy restored hippocampal L-LTP impaired by sepsis, at least partially mediated by activation of the BDNF/TrkB signaling pathway. Additionally, exercise altered the survival curve, though it had limited effects on locomotor activity. These findings suggest that exercise therapy may mitigate sepsis-induced synaptic dysfunction.

100 项与 ANA-12(Medical University of South Carolina) 相关的药物交易

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