antioxidants Article The Anxiolytic and Antidepressant Effects of Diallyl Disulfide and GYY4137 in Animals with Chronic Neuropathic Pain Xue Bai 1,2 , Gerard Batallé 1,2 and Olga Pol 1,2, *   Citation: Bai, X.; Batallé, G.; Pol, O. The Anxiolytic and Antidepressant Effects of Diallyl Disulfide and GYY4137 in Animals with Chronic Neuropathic Pain. Antioxidants 2021, 10, 1074. https://doi.org/10.3390/ antiox10071074 Academic Editor: Andreas Daiber Received: 31 May 2021 Accepted: 30 June 2021 Published: 3 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Grup de Neurofarmacologia Molecular, Institut d’Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; xue.bai@e-campus.uab.cat (X.B.); gerard.batalle@e-campus.uab.cat (G.B.) 2 Grup de Neurofarmacologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain * Correspondence: opol@santpau.es; Tel.: +34-619-757-054 Abstract: When neuropathic pain is maintained long term, it can also lead to the development of emotional disorders that are even more intense than pain perception and difficult to treat. Hydrogen sulfide (H 2 S) donors relieve chronic pain, but their effects on the associated mood disorders are not completely elucidated. We evaluated if treatment with DADS (diallyl disulfide) or GYY4137 (morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate dichloromethane complex), two slow-releasing H 2 S donors, inhibits the anxiety- and depressive-like behaviors that concur with chronic neuropathic pain generated by sciatic nerve injury in mice. The modulatory role of these drugs in the inflammatory, apoptotic, and oxidative processes implicated in the development of the affective disorders was assessed. Our results revealed the anxiolytic, antidepressant, and antinociceptive properties of DADS and GYY4137 during neuropathic pain by inhibiting microglial activation and the up-regulation of phosphoinositide 3-kinase/phosphorylated protein kinase B and BAX in the amygdala (AMG) and/or periaqueductal gray matter (PAG). Both treatments also normalized and/or activated the endogenous antioxidant system, but only DADS blocked ERK 1/2 phosphorylation. Both H 2 S donors decreased allodynia and hyperalgesia in a dose-dependent manner by activating the Kv7 potassium channels and heme oxygenase 1 signaling pathways. This study provides evidence of the anxiolytic and antidepressant properties of DADS and GYY4137 during neuropathic pain and reveals their analgesic actions, suggesting that these therapeutic properties may result from the inhibition of the inflammatory, apoptotic, and oxidative responses in the AMG and/or PAG. These findings support the use of these treatments for the management of affective disorders accompanying chronic neuropathic pain. Keywords: anxiety; apoptosis; depression; hydrogen sulfide; neuropathic pain; oxidative stress 1. Introduction Several studies have demonstrated that the prevalence of neuropathic pain in the general population is around 6.9–10% [1]. It is also well known that, when neuropathic pain is maintained long term, in addition to the symptoms of the pain itself, it is very common to develop emotional disorders that are even more intense than pain perception, making their treatment a challenge [2]. Current treatments reduce pain symptoms but have limited efficacy in reducing the mood disorders that co-occur with neuropathic pain; consequently, new therapies are urgently needed. Hydrogen sulfide (H 2 S) is a gaseous neurotransmitter that regulates numerous physi- ological and pathophysiological processes [3]. It is highly implicated in modulating the cellular redox state and protects cells from oxidative stress [4,5]. Previous works reported the anxiolytic and/or antidepressant effects of fast exogenous H 2 S donors such as sodium hydrosulfide (NaHS) [6] and sodium sulfide (Na 2 S) [7] and the improvement of the anxiety- and/or depressive-related behaviors accompanying diabetes [8–10]. In addition, the an- tidepressant effects of H 2 S donors that could release H 2 S in a more controlled manner, such Antioxidants 2021, 10, 1074. https://doi.org/10.3390/antiox10071074 https://www.mdpi.com/journal/antioxidants