Decoupling SERT-nNOS Interaction to Generate Fast-Onset Antidepressants

How Oxidative Stress Induces Depression?

“…Classical antidepressants usually target on the monoamine system and elevate their synaptic concentration in the brain, such as the TCAs, MAOIs and SSRIs, which generally require at least two weeks of continuous treatment, and moreover, have a variety of side effects (Cipriani et al, 2018;Malhi & Mann, 2018). However, recent studies demonstrated the possibility of designing fast-onset monoamine-based antidepressants, by dissociating 5-HTT from neuronal NOS in the DRN of mice (Guan & Pang, 2023;Kingwell, 2022;Sun et al, 2022;Ye et al, 2023). Another study further showed Propofol rapidly relieved the core depressive symptom anhedonia in mice, through inhibiting dopamine transporter (but not the 5-HTT) and evoking long-lasting dopamine accumulation in the NAc (X. N. .…”

“…For the interaction between 5-HT and OS (Figure 1E-OS), studies found 5-HT presented antioxidant properties in vitro, as indicted by the inhibited generations of ROS and iNOS (Vašíček et al, 2020), while N-acetyl 5-HT showed antioxidant and anti-apoptosis actions, by activating TrkB/CREB/BDNF pathway and antioxidant enzyme expression, in vitro and in vivo (Yoo et al, 2017). Recent studies demonstrated the possibility of designing fast-onset antidepressant, by dissociating 5-HTT from neuronal NOS in the DRN of mice, which indicates the critical involvement of 5-HT and OS interaction in depression pathogenesis (Guan & Pang, 2023;Kingwell, 2022;Sun et al, 2022;Ye et al, 2023). In turn, OS could cause central 5-HT deficiency through inducing neuroinflammation (Catena-Dell'Osso et al, 2013) and MGB disturbance (Stasi et al, 2019), by activating IDO/TDO enzymes and promoting KP of tryptophan metabolism, as expounded in the above sections correspondingly.…”