TSPO, translocator protein (18 kDa) ligands have demonstrated consistent antidepression and anxiolytic effects in several preclinical studies. This study aimed to examine whether YL-IPA08[N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-ichlorophenyl) -7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride], a potent and selective TSPO ligand synthesized by our institute, could alleviate anxiety-related behaviors induced by electric shock (ES) and investigate its underlying mechanism. As expected, we showed that chronic treatment with YL-IPA08 significantly reversed anxiety-related behaviors induced by electrical stimulation (0.5 mA, 12 times, duration 1s, interval 10s) exposure. Using the analysis of RNA-sequencing (RNA-seq) technology, it was found that the differential genes associated with the anxiolytic effect of YL-IPA08 were mainly related to synaptic plasticity. Furthermore, YL-IPA08 restored the decreased levels of brain-derived neurotrophic factor (BDNF), synapse-related protein (e.g. synapsin-1 and post-synaptic density95, PSD95), and the number of doublecortin (DCX) + neurons in the hippocampus of post-ES mice. In addition, YL-IPA08 also enhanced the dendritic complexity and dendritic spine density of hippocampal dentate gyrus (DG) granule neurons. Meanwhile, the induction of long-term potentiation (LTP) was significantly enhanced by YL-IPA08. In summary, the findings from the current study showed that YL-IPA08 exerted a clear anxiolytic effect, which might be partially mediated by promoting hippocampal neuroplasticity.

2022-12-01·Metabolic brain disease

Correction to: Involvement of regulation of the excitation:inhibition functional balance in the mPFC in the antidepressant-anxiolytic effect of YL-IPA08, a novel TSPO ligand

作者: Fang, Xin-Xin ; Wang, Yun-Hui ; Li, Yun-Feng ; Dai, Wei ; Yuan, Jin ; Yao, Jun-Qi ; Zhang, Li-Ming

2022-10-01·Journal of psychopharmacology (Oxford, England)

Cognition-enhancing effect of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in the 5 × FAD transgenic mouse model of Alzheimer’s pathology

Article

作者: Yao, Ru-Meng ; Li, Yun-Feng ; Zhang, Li-Ming ; Dai, Wei ; Cheng, Jin-Bo ; Mi, Tian-Yue ; Wu, Hong-liang

Background::

Intracerebral translocator protein 18 kDa (TSPO) mediates the transport of cholesterol from cytoplasm to mitochondria and activation of microglia. The change of TSPO and the dysfunction of microglia are closely related to the pathogenesis of Alzheimer’s disease (AD).

Aims::

This study aimed to investigate the effects of microglial TSPO and its selective ligand YL-IPA08 on the cognitive function of transgenic mice in 5 × familial Alzheimer’s disease (FAD) mouse model of AD.

Methods::

The TSPO knockout 5 × FAD transgenic mice were bred, and tested by Morris water maze. The effects of YL-IPA08 on cognitive abilities and expression of Aβ in 5 × FAD mice were also explored into.

Results::

The latency of escape by TSPO knockout 5 × FAD mice was significantly prolonged compared with the 5 × FAD group, indicating that the cognitive impairment of mice aggravated. With the attenuated phagocytic ability of microglia, the deposition of Aβ in prefrontal cortex of TSPO knockout 5 × FAD mice increased, and the expression of proinflammatory factors (IL-1β, TNF-α, IL-6) were upregulated. In addition, YL-IPA08 significantly reduced the latency of escape by 5 × FAD mice, increased the number of times of crossing over the platform by mice, and inhibited the deposition of Aβ in the prefrontal cortex of 5 × FAD mice without affecting the cleavage of APP.

Conclusion::

Our findings suggested that TSPO knockout in 5 × FAD mice inhibited microglial phagocytosis, promoted Aβ deposition and neuroinflammation, and aggravated cognitive dysfunction in AD mice. YL-IPA08 had a significant cognition-enhancing effect in 5 × FAD transgenic mice, which might provide a new basis for potential drug candidates in AD treatment.

100 项与 YL-IPA08 相关的药物交易

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