γ-Aminobutyric acid(GABA) neurotransmission alterations have been implicated to play a role in depression pathogenesis. While GABA_(A) receptor positive allosteric modulators are emerging as promising in clinical pra...γ-Aminobutyric acid(GABA) neurotransmission alterations have been implicated to play a role in depression pathogenesis. While GABA_(A) receptor positive allosteric modulators are emerging as promising in clinical practice, their precise antidepressant mechanism remains to be further elucidated. The aim of the present study was to investigate the effects of LY-02, a novel compound derived from the metabolite of timosaponin, on depression in animals and its mechanism. The results of behavioral tests showed that LY-02 exhibited better antidepressant effects in both male C57BL/6 mice and Sprague Dawley(SD) rats. The results of cellular voltage clamp experiments showed that LY-02 enhanced GABA-mediated currents in HEK293T cells expressing recombinant α6β3δ subunitcontaining GABA_(A) receptors. Electrophysiological recording from brain slices showed that LY-02 decreased the amplitude of spontaneous inhibitory postsynaptic current(sIPSC) and increased action potentials of pyramidal neurons in the medial prefrontal cortex(mPFC) of C57BL/6 mice. Western blot results showed that LY-02 dose-dependently up-regulated the protein expression levels of brain-derived neurotrophic factor(BDNF), tropomyosin related kinase B(TrkB) and postsynaptic density protein 95(PSD-95) in m PFC of mice. The above results suggest that LY-02, as a positive modulator of GABA_(A) receptors, reduces inhibitory neurotransmission in pyramidal neurons. It further activates the BDNF/TrkB signaling pathway, thus exerting antidepressant effects. It suggests that LY-02 is a potential novel therapeutic agent for depression treatment.展开更多
文摘γ-Aminobutyric acid(GABA) neurotransmission alterations have been implicated to play a role in depression pathogenesis. While GABA_(A) receptor positive allosteric modulators are emerging as promising in clinical practice, their precise antidepressant mechanism remains to be further elucidated. The aim of the present study was to investigate the effects of LY-02, a novel compound derived from the metabolite of timosaponin, on depression in animals and its mechanism. The results of behavioral tests showed that LY-02 exhibited better antidepressant effects in both male C57BL/6 mice and Sprague Dawley(SD) rats. The results of cellular voltage clamp experiments showed that LY-02 enhanced GABA-mediated currents in HEK293T cells expressing recombinant α6β3δ subunitcontaining GABA_(A) receptors. Electrophysiological recording from brain slices showed that LY-02 decreased the amplitude of spontaneous inhibitory postsynaptic current(sIPSC) and increased action potentials of pyramidal neurons in the medial prefrontal cortex(mPFC) of C57BL/6 mice. Western blot results showed that LY-02 dose-dependently up-regulated the protein expression levels of brain-derived neurotrophic factor(BDNF), tropomyosin related kinase B(TrkB) and postsynaptic density protein 95(PSD-95) in m PFC of mice. The above results suggest that LY-02, as a positive modulator of GABA_(A) receptors, reduces inhibitory neurotransmission in pyramidal neurons. It further activates the BDNF/TrkB signaling pathway, thus exerting antidepressant effects. It suggests that LY-02 is a potential novel therapeutic agent for depression treatment.
