**1. Introduction**

Oxidative stress is an imbalance in cellular redox homeostasis caused by ROS overproduction and/or antioxidant system dysfunction. The brain is particularly susceptible to oxidative stress and this process is increased with aging. The brain consumes almost 20% of the total basal oxygen, it is rich in polyunsaturated *n*-3 fatty acids and redox-active transition metals, it has a low endogenous antioxidant defense (i.e., catalase), and neurotransmitters such as dopamine can auto-oxidize leading to free radicals [1,2]. Moreover, the mitochondrial electron transport chain consumes around 98% of oxygen and the residual oxygen is converted into radical superoxide (O2 •−) and the non-radical oxidant H2O2; excessive mitochondrial-derived ROS accumulation can lead to mitochondrial dysfunction [3]. Furthermore, hydrogen peroxide, the major redox metabolite, diffuses across membranes by water channels, oxidizes and damages biomolecules [4,5]. The main mechanism underlying the neurotoxic effects of hydrogen peroxide occurs through Fenton's reaction. In this reaction, ferrous iron and hydrogen peroxide react to yield hydroxyl radical. Hydroxyl radical is the most deleterious free radical, reacting with macromolecules by hydroxyl addition and hydrogen abstraction [6]. The altered cellular redox homeostasis causes oxidative injury to lipids, proteins, and DNA and modifications in cellular function that finally contribute to cell death mainly by apoptosis [3]. Oxidative stress is involved as a major pathophysiologic mechanism of age-related neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis [7].

**Citation:** Ureña-Vacas, I.;

González-Burgos, E.; Divakar, P.K.; Gómez-Serranillos, M.P. Lichen Extracts from Cetrarioid Clade Provide Neuroprotection against Hydrogen Peroxide-Induced Oxidative Stress. *Molecules* **2022**, *27*, 6520. https://doi.org/10.3390/ molecules27196520

Academic Editor: Nour Eddine Es-Safi

Received: 25 August 2022 Accepted: 30 September 2022 Published: 2 October 2022

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**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/).

Antioxidants modulate the redox state of cells through single electron transfer (SET), hydrogen atom transfer (HAT), transition metals chelation and the up-regulation of enzymatic and non-enzymatic antioxidants. Antioxidants are potentially beneficial in the prevention and treatment of central nervous system pathologies associated with oxidative stress and constitute one of the most promising therapeutical strategies [8].

Lichens have aroused great pharmacological interest in recent years because they produce compounds unique to these species. These bioactive compounds are primarily phenol derivatives such as dibenzofurans, depsidones and depsides. Lichen extracts and their secondary metabolites have shown an interesting antioxidant activity [8,9]. However, studies focusing on therapeutic and protective strategy based on the antioxidant ability of lichens are very limited [9].

Recently, in previous studies of this group, the antioxidant activity of lichen extracts from the cetrarioid clade was evaluated using different in vitro methods (1,1-Diphenyl-2 picrylhydrazyl (DPPH), oxygen radical absorbance capacity (ORAC) and ferric-reducing antioxidant power (FRAP) assays) and multivariate statistical techniques. This study revealed that the lichen species *Dactylina arctica* (Hook) Nyl., *Nephromopsis stracheyi* (C. Bab.) Müll. Arg., *Tuckermannopsis americana* (Sprengel) Hale, and *Vulpicida pinastri* (Scop.) J.-E. Mattsson & M. J. Lai. were the ones with the highest antioxidant capacities [10].

The aim of the present work is to evaluate for the first time the neuroprotective activity, based on antioxidant properties, of the methanol lichen extracts *Dactylina arctica*, *Nephromopsis stracheyi, Tuckermannopsis americana* and *Vulpicida pinastri* in a hydrogen peroxide-induced oxidative stress model in a neuroblastoma cell line.
