Dual Molecules Targeting 5-HT₆ and GABA-A Receptors as a New Approach to Combat Depression Associated with Neuroinflammation

Abstract

While monoaminergic deficits are evident in all depressed patients, nonresponders are characterized by impaired GABA-ergic signaling and the simultaneous presence of the inflammatory component. Pharmacological agents able to curb pathological immune responses and modulate ineffective GABA-ergic neurotransmission are thought to improve therapeutic outcomes in the treatment-resistant subgroup of depressed patients. Here, we report on a set of dually acting molecules designed to simultaneously modulate GABA-A and 5-HT 6 receptor activity. The serotonin 5-HT 6 receptor was chosen as a complementary molecular target, due to its promising antidepressant-like activities reported in animal studies. Within the study we identified that lead molecule 16 showed a desirable receptor profile and physicochemical properties. In pharmacological studies, 16 was able to reduce the secretion of proinflammatory cytokines and decrease oxidative stress markers. In animal studies, 16 exerted antidepressant-like activity deriving from a synergic interplay between 5-HT 6 and GABA-A receptors. Altogether, the presented findings point to hybrid 16 as an interesting tool that interacts with pharmacologically relevant targets, matching the pathological dysfunction of depression associated with neuroinflammation.

Effects and safety of Ginkgo biloba on depression: a systematic review and meta-analysis

“…BDNF and 5-HT have a strong association in the typical human brain. 5-HT promotes BDNF production, and BDNF improves 5-HT signaling ( Popova et al, 2022 ; Marcinkowska et al, 2023 ). However, this link is disturbed when the brain is ischemic and hypoxic, which may result in decreased production of BDNF and 5-HT ( Kumar et al, 2018 ; Yadav et al, 2019 ; Kumar et al, 2020 ; Panigrahi et al, 2021 ; Mishra et al, 2022 ).…”