Astrocytes underlie a faster-onset antidepressant effect of hypidone hydrochloride (YL-0919)

Abstract

Introduction: Major depression disorder (MDD) is a common and potentially life-threatening mental illness; however, data on its pathogenesis and effective therapeutic measures are lacking. Pathological changes in astrocytes play a pivotal role in MDD. While hypidone hydrochloride (YL-0919), an independently developed antidepressant, has shown rapid action with low side effects, its underlying astrocyte-specific mechanisms remain unclear.Methods: In our study, mice were exposed to chronic restraint stress (CRS) for 14 days or concomitantly administered YL-0919/fluoxetine. Behavioral tests were applied to evaluate the depression model; immunofluorescence and immunohistochemistry staining were used to explore morphological changes in astrocytes; astrocyte-specific RNA sequencing (RNA-Seq) analysis was performed to capture transcriptome wide alterations; and ATP and oxygen consumption rate (OCR) levels of primary astrocytes were measured, followed by YL-0919 incubation to appraise the alteration of energy metabolism and mitochondrial oxidative phosphorylation (OXPHOS).Results: YL-0919 alleviated CRS-induced depressive-like behaviors faster than fluoxetine and attenuated the number and morphologic deficits in the astrocytes of depressed mice. The changes of gene expression profile in astrocytes after CRS were partially reversed by YL-0919. Moreover, YL-0919 improved astrocyte energy metabolism and mitochondrial OXPHOS in astrocytes.Conclusion: Our results provide evidence that YL-0919 exerted a faster-onset antidepressant effect on CRS-mice possibly via astrocyte structural remodeling and mitochondria functional restoration.

Human pluripotent stem cells as a translational toolkit in psychedelic research in vitro

“…Interestingly, mitochondrial function has been postulated as an astrocyte-specific mechanism underlying the potential efficacy of a novel candidate for a faster-onset antidepressant, hypidone hydrochloride (YL-0919). 123 Notably, distinct variations in mitochondrial physiology further differentiate human and mouse astrocytes. 124 Human astrocytes are more vulnerable to oxidative stress and, therefore, should be the first choice when studying the molecular underpinnings of these metabolic changes in humans at the cellular level.…”

Astroglial Dysfunctions in Mood Disorders and Rodent Stress Models: Consequences on Behavior and Potential as Treatment Target

“…However, this may need to be systematically tested for a few antidepressants of each class, as it was shown that fluoxetine treatment can reverse the chronic stress-induced GFAP reductions [ 124 ], but not citalopram [ 126 ]. Interestingly, recent work suggested that the fast-acting properties of some antidepressants may coincide with the reversal of chronic stress effects on the astroglial density or function [ 214 ] or rely on astroglia for their long-lasting effects [ 214 , 215 ]…”

“…However, this may need to be systematically tested for a few antidepressants of each class, as it was shown that fluoxetine treatment can reverse the chronic stress-induced GFAP reductions [124], but not citalopram [126]. Interestingly, recent work suggested that the fast-acting properties of some antidepressants may coincide with the reversal of chronic stress effects on the astroglial density or function [214] or rely on astroglia for their long-lasting effects [214,215] As evidence of the beneficial effects of enhancing key astroglial functions on emotionrelated effects is growing, interest in targeting astroglia for treatment is rising. Less advanced avenues of investigation for antidepressant development include drugs that promote endogenous ATP release from astrocytes [146] or glutamine supplementation, which can reverse stress-induced depressive-like behaviors [137].…”