ABSTRACT
Depression has become a serious global public health concern. Almost all the current first-line antidepressants developed are based on the classical "monoamine hypothesis (strategy)". These drugs commonly possess a series of defects, including slow-onset, lower response, cognitive injury and suicidal tendencies. So, by breaking through the classical monoamine strategy framework, developing new antidepressants with fast-onset, cognitive-enhancement and less adverse reactions is a major global demand. In 2019, fast-onset antidepressants S-ketamine(S-Ket) and brexanolone were approved by the FDA of USA, which opened up a new field for the non-monoamine strategy mainly based on the N-methyl-D-aspartic acid (NMDA) and y-aminobutyric acid A (GABAA) receptors. There are currently two main trends in the research and development of rapid onset antidepressants: the optimized multi-target monoamine strategy (modem monoamine strategy) and the non-monoamine strategy based on glutamate(Glu)-GABA balance regulation. According to the research of our laboratory and foreign colleagues, we propose a candidate hypothesis of the "monoamine (5-HT)-nonmonoamine (Glu/ GABA) long feedback neural circuit". It is believed that both monoamine regulatory mechanisms (such as 5-HT neurons located in raphe nucleus) and non-monoamine regulatory mechanisms (Glu/GABA neurons located in the prefrontal cortex and other brain regions) are all part of the rapid-acting antidepressant mechanisms, and both of them form a long-feedback neural loop mediating the fast synaptogenesis of the brain regions including the prefrontal cortex and hippocampus. Based on this hypothesis, we propose five candidate strategies for rapid onset of antidepressant development. (1) By relieving the inhibition of GABA interneurons on glutamatergic pyramidal neurons or directly activating glutamatergic pyramidal neurons, the rapid excitation/inhibition (E/l) balance can be achieved; (2) simultaneous regulation of 5-HT neuronal activity and E/l balance by 5-HT transporter and 5-HT receptors such as 5-HT1A (that means simultaneous enhancement of monoamine and nonmonoamine links); (3) direct activation of mammalian sirolimus (rapamycin) target protein complex 1 (mTORCI) and rapid enhance ment of the brain- derived neurotrophic factor (BDNF)- mTOR signaling; (4) stimulation of the fast release of BDNF in the brain; (5) positive allosteric modulator of GABAA receptor. We hope that these ideas and strategies will bring about a breakthrough for the development of a new generation of antidepressants in China in the future, and provide useful reference for further discovery of candidate targets for rapid antidepressant therapy.
ABSTRACT
OBJECTIVE To investigate the protective effect of selective 18 ku translocator protein (TSPO) ligand YL-IPA08 on corticosterone(CORT)-induced apoptosis of BV-2 cells and its potential mecha?nisms. METHODS BV-2 Cells were pretreated with selective TSPO ligand YL-IPA08 1-100 nmol · L-1 and(or) TSPO antagonist PK11195 100 nmol · L-1 for 2 h,and then co-incubated with CORT for another 24 h. The apoptosis rate was measured by flow cytometry. CCK-8 kit was used to test BV-2 cell viability. The protein expression of TSPO was determined by Western blotting. The level of allopreg?nanolone was detected by ELISA kit. RESULTS In line with positive drug-AC-5216, the cell apoptosis rate decreased in YL-IPA08 1-100 nmol · L-1 and CORT co-treatment groups(P<0.01), which was antago?nized by PK11195 100 nmol · L-1 treatment(P<0.05). Cell viability increased in YL-IPA08 100 nmol · L-1and CORT co-treatment groups (P<0.01), which was blocked by PK11195 100 nmol·L-1 treatment(P<0.01). The expression of TSPO and the level of allopregnanolone(P<0.01) were enhanced by YL-IPA08 100 nmol · L-1 pretreatment followed by CORT treatment. The enhancement of allopregnanolone level was blocked by PK11195 100 nmol·L-1 treatment(P<0.05). CONCLUSION YL-IPA08 can protect BV-2 cells from CORT induced apoptosis. The protective effect of YL-IPA08 may be conferred by the increasing level of TSPO expression and allopregnanolone.
ABSTRACT
Objective To explore the role of 18 ku translocator protein (TSPO) in the anti-post-traumatic-stress-disorder(PTSD) effects of YL-IPA08 and the value of TSPO as a potential pharmacological target using gene knock out mice.Methods The PCR method was used to genotype TSPO wild type (WT) mice and knock out (KO) mice.Foot shock was used to establish a well-accepted mouse model of PTSD,the open field test (OFT) was used to evaluate the locomotor activity in mice,and freezing measurement was used to evaluate the PTSD-like fear behavior in mice.Results Compared with TSPO WT mice,KO mice had no expressible TSPO gene,but showed similar locomotor activity to WT mice after PTSD modeling.On day 1,day 5 and day 16 after PTSD modeling (day-1-day 0),both WT and KO mice showed significant PTSD-like behavior with enhanced freezing time.However,8 d treatment (day 0-day 7) of YL-IPA08 (0.3 mg/kg,once daily) or positive drug sertraline (15 mg/kg,once daily) after PTSD modeling significantly reduced freezing time selectively in WT mice,but not in KO mice.Conclusion It has been found for the first time that TSPO WT and KO mice can show the same sensitivity to PTSD modeling (namely the same PTSD-like behavior performance).Interestingly,TSPO can mediate the anti-PTSD effects of YL-IPA08.Therefore,the present study provides direct evidence for the value of TSPO as an potential pharmacological target for PTSD.