Anxiolytic properties of compounds that counteract oxidative stress, neuroinflammation, and glutamatergic dysfunction: a review

Abstract

Objective:Anxiety disorders are highly prevalent and the efficacy of the available anxiolytic drugs is less than desired. Adverse effects also compromise patient quality of life and adherence to treatment. Accumulating evidence shows that the pathophysiology of anxiety and related disorders is multifactorial, involving oxidative stress, neuroinflammation, and glutamatergic dysfunction. The aim of this review was to evaluate data from animal studies and clinical trials showing the anxiolytic effects of agents whose mechanisms of action target these multiple domains.Methods:The PubMed database was searched for multitarget agents that had been evaluated in animal models of anxiety, as well as randomized double-blind placebo-controlled clinical trials of anxiety and/or anxiety related disorders.Results:The main multitarget agents that have shown consistent anxiolytic effects in various animal models of anxiety, as well in clinical trials, are agomelatine, N-acetylcysteine (NAC), and omega-3 fatty acids. Data from clinical trials are preliminary at best, but reveal good safety profiles and tolerance to adverse effects.Conclusion:Agomelatine, NAC and omega-3 fatty acids show beneficial effects in clinical conditions where mainstream treatments are ineffective. These three multitarget agents are considered promising candidates for innovative, effective, and better-tolerated anxiolytics.

The effect of N-acetylcysteine on the sensory retina of male albino rats exposed prenatally to cypermethrin

“…Moreover, NAC allowed normal development of retinal blood vessels preventing neovascularization. The protective role of NAC could be explained by acting as a glutathione precursor (cysteine is required for endogenous antioxidant glutathione production), down regulator of the expression of several inflammatory cytokines genes and microglia proliferation inhibitor [20].…”

Anxiolytic Effects of 8-O-Acetyl Shanzhiside Methylester on Acute and Chronic Anxiety via Inflammatory Response Inhibition and Excitatory/Inhibitory Transmission Imbalance

“…In addition, microglial injury may lead to depression, and drugs that inhibit microglial activation, such as minocycline and tumor necrosis factor alpha (TNF-α) inhibitors, are also considered effective antidepressants (Miller and Raison 2015 ; Yirmiya et al 2015 ). In addition, microglia release and respond to several cytokines, including IL-1, IL-6, TNF-a, and IFN-c, which contribute to the maintenance of persistent pain states in autoimmune inflammation of the nervous system (Lee 2020 ; Santos et al 2019 ). In this study, we observed that the upregulation of Iba-1 expression and the release of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in the BLA after CFA injection were decreased by 8-OaS, suggesting that the anxiolytic actions of 8-OaS are linked to the inactivation of microglia.…”

Predisposition to Alcohol Drinking and Alcohol Consumption Alter Expression of Calcitonin Gene-Related Peptide, Neuropeptide Y, and Microglia in Bed Nucleus of Stria Terminalis in a Subnucleus-Specific Manner

“…It can be speculated that inherently determined anxiety-related behaviors of sP rats are linked also to subnucleus-specific changes in microglia activation. Neuroinflammation and microglia activation are emerging as factors promoting anxiety-related behaviors (see Sild et al, 2017; Stein et al, 2017; Kim and Jeon, 2018; Santos et al, 2018, for recent reviews). However, tissue-resident macrophages (as microglia in the brain) are also thought to constitute the first line of defense that can build up a homeostatic response directed toward repair of neural environment micro-damages in anxiety-related region (Medzhitov, 2008): this led to hypothesize that microglia activation can initially provide a beneficial support to maintain homeostasis in brain, but this error-prone response can be subsequently triggered to enter a chronic, harmful state that can lead to mental state alterations (Wager-Smith and Markou, 2011; Wohleb, 2016).…”