Citation: Szilágyi, A.; Takács, B.; Szekeres, R.; Tarjányi, V.; Bombicz, M.; Priksz, D.; Kovács, A.; Juhász, B.; Frecska, E.; Szilvássy, Z.; et al. Therapeutic Properties of Ayahuasca Components in Ischemia/Reperfusion Injury of the Eye. Biomedicines 2022, 10, 997. https://doi.org/10.3390/ biomedicines10050997 Academic Editors: Melissa García Caballero and James A. Marrs Received: 21 February 2022 Accepted: 23 April 2022 Published: 26 April 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 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/). biomedicines Article Therapeutic Properties of Ayahuasca Components in Ischemia/Reperfusion Injury of the Eye Anna Szilágyi 1 , Barbara Takács 1 ,Réka Szekeres 1 , Vera Tarjányi 1 , Mariann Bombicz 1 ,Dániel Priksz 1 , Attila Kovács 2 ,Béla Juhász 1 , Ede Frecska 2 , Zoltán Szilvássy 1,† and Balázs Varga 1, * ,† 1 Department of Pharmacology and Pharmacotherapy, University of Debrecen, Nagyerdei Krt 98, H-4032 Debrecen, Hungary; dr.szilagyi.anna@med.unideb.hu (A.S.); takacs.barbara@pharm.unideb.hu (B.T.); szekeres.reka@med.unideb.hu (R.S.); tarjanyi.vera@med.unideb.hu (V.T.); bombicz.mariann@pharm.unideb.hu (M.B.); priksz.daniel@pharm.unideb.hu (D.P.); juhasz.bela@med.unideb.hu (B.J.); szilvassy.zoltan@med.unideb.hu (Z.S.) 2 Department of Psychiatry, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98, H-4032 Debrecen, Hungary; kovacsa@med.unideb.hu (A.K.); frecska.ede@med.unideb.hu (E.F.) * Correspondence: varga.balazs@pharm.unideb.hu; Tel.: +36-52-427-899 † These authors contributed equally to this work. Abstract: Ischemic eye diseases are major causes of vision impairment. Thus, potential retinoprotec- tive effects of N’N-dimethyltryptamine (DMT) were investigated. To inhibit its rapid breakdown by monoamine-oxidase A (MAO-A) enzyme, DMT was co-administered with harmaline, a β-carboline in the Amazonian Ayahuasca brew. Using ligation, 60 min of ischemia was provoked in eyes of rats, followed by 7 days of reperfusion whilst animals received harmaline alone, DMT + harmaline, or ve- hicle treatment. After 1 week of reperfusion, electroretinographical (ERG) measurements, histological analysis, and Western blot were performed. Harmaline alone exhibited retinoprotection in ischemia– reperfusion (I/R) which was, surprisingly, counterbalanced by DMT in case of co-administration. As both MAO-A inhibition and DMT increase serotoninergic tone synergistically, communicated to be anti-ischemic, thus, involvement of other pathways was investigated. Based on our experiments, DMT and harmaline exert opposite effects on important ocular proteins such as PARP1, NFκB, MMP9, or HSP70, each having a critical role in a different mechanism of eye-ischemia-related pathologies, e.g., cell death, inflammation, tissue destruction, and oxidative stress. Since DMT is proclaimed to be a promising drug candidate, its potentially undesirable effect on eye-ischemia should be further in- vestigated. Meanwhile, this experiment revealed the potential therapeutic effect of MAO-A inhibitor harmaline in I/R-related eye diseases. Keywords: DMT; harmaline; MAO-A inhibition; retinal ischemia–reperfusion injury; ERG; PARP1; NFκB; HSP70; GFAP; MMP9 1. Introduction Retinal ischemia–reperfusion (I/R) injuries occur in several pathological conditions of the retina, such as diabetic retinopathy, severe glaucoma attack, ischemic optic neuropathy, hypertensive retinopathy, and retinal arterial occlusion. The accumulation of reactive oxygen species (ROS), dysregulated neuroinflammation, and retinal ganglion cell (RGC) apoptosis are characteristic of I/R injury leading to irreversible vision impairment [1,2]. Even though reperfusion is crucial for cell survival, it is prone to cause severe damage by ox- idative stress and the following abnormal immune response [3]. Effective treatment against I/R-related eye diseases is still unavailable in clinical practice; therefore, it is essential to find a therapeutical agent for preserving retinal function [2]. Ayahuasca is a traditional South- American decoction used in religious rituals for centuries because of its hallucinogenic and assumed therapeutic effects. This psychoactive beverage consists of β-carboline-rich herbs Biomedicines 2022, 10, 997. https://doi.org/10.3390/biomedicines10050997 https://www.mdpi.com/journal/biomedicines