J Biochem Mol Toxicol. 2020;e22605. wileyonlinelibrary.com/journal/jbt © 2020 Wiley Periodicals LLC | 1 of 18 https://doi.org/10.1002/jbt.22605 Received: 14 February 2020 | Revised: 8 June 2020 | Accepted: 10 August 2020 DOI: 10.1002/jbt.22605 REVIEW The protective effect of natural compounds against rotenone‐induced neurotoxicity Fatemeh Yarmohammadi 1,2 | A. Wallace Hayes 3,4 | Nahid Najafi 1,2 | Gholamreza Karimi 2,5 1 Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran 2 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran 3 Institute for Integrative Toxicology, University of South Florida, Tampa, Florida 4 Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 5 Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran Correspondence Gholamreza Karimi, Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, 9177948954 Mashhad, Iran. Email: karimig@mums.ac.ir Funding information Mashhad University of Medical Sciences Abstract Rotenone is a widely used organic pesticide; its serious side effect for off‐target species is neurotoxicity. The primary mechanism of rotenone toxicity is inhibition of the mitochondrial complex I. Oxidative stress, apoptosis, and reduction of autophagy are key outcomes of the inhibition of complex I. Numerous in vitro and in vivo studies have shown antioxidant, anti‐apoptotic, and autophagy enhancement of a variety of natural compounds (NCs). In this manuscript, we reviewed several NCs, which have protective effects against rotenone‐induced neurotoxicity. KEYWORDS mitochondrial dysfunction, natural compounds, neuroprotective, rotenone 1 | INTRODUCTION Rotenone is an isoflavone lipophilic broad‐spectrum pesticide that readily crosses cellular membranes independent of a transporter. Rotenone has been classified as moderately hazardous. [1] Dopami- nergic neurons are more susceptible to the toxicity of rotenone than other neuronal cell types. [2] Therefore, exposure to rotenone may be a potential risk factor for some neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's diseases (PD), characterized by progressive deterioration of brain function. [3] Rotenone is a neurotoxin, which can replicate, in experimental models, many of the pathological features of Parkinson's disease. [4] Epidemiological evidence suggests that environmental exposure to rotenone may have a role in neurodegenerative diseases, especially PD. [5,6] The pathophysiology of rotenone in dopaminergic neurons includes aggregation of α‐synuclein in Lewy bodies, [7] proteasome Abbreviations: AA, asiatic acid; AchE, acetylcholinesterase; AD, Alzheimer's disease; ALP, autophagy‐lysosome pathway; AMPK, AMP‐activated protein kinase; Arb, arbutin; ARE, antioxidant responsive element; ATG, autophagy‐related protein; ATP, adenosine triphosphate; AUR, auraptene; BAs, Boswellic acids; BAX, Bcl2‐associated X protein; Bcl2, B‐cell lymphoma 2; BDNF, brain‐derived neurotrophic factor; beclin‐1, Bcl‐2 homology (BH3)‐only protein; CAT, catalases; CMG, curcumin monoglucoside; COX‐2, cyclooxygenase‐2; CS, citrate synthase; CUR, curcumin; Cys, cysteine; DA cell, dopaminergic cell; DM, drosophila melanogaster; ER, endoplasmic reticulum; ERK1/2, extracellular signal‐regulated kinase; FIP200, focal adhesion kinase family interacting protein of 200 kDa; FMN, flavin mononucleotide; GDNF, glial cell line‐derived neurotrophic factor; GPX, glutathione peroxidase; GS, genistein; GSH, reduced glutathione; GSK‐3β, glycogen synthase kinase‐3; GSSG, glutathione disulfide; HO‐1, heme oxygenase‐1; ILF, isolongifolene; iNOS, inducible nitric oxide synthase; JNK, c‐Jun N‐terminal protein kinases; Keap1, Kelch‐like ECH‐associated protein 1; LC3‐I, protein light chain‐1; LC3‐II, protein light chain‐3; LMP, lysosomal membrane permeability; MAPK, mitogen activated protein kinase; MDA, malondialdehyde; MMP, mitochondrial membrane potential; MPT, mitochondrial membrane permeability transition; mPTP, mitochondrial permeability transition pore; mTOR, mammalian target of rapamycin; NADH, nicotinamide adenine dinucleotide hydrate; NC, natural compound; NF‐κB, nuclear factor‐κB; NLRP3, nucleotide‐binding oligomerization domain (NOD)‐like receptor protein 3; NOS2, nitric oxide synthase‐2; NQO1, NAD (P) H: quinone oxidoreductase 1; Nrf2, nuclear factor erythroid 2‐related factor 2; Nuur1, nuclear receptor‐related 1 protein; P13K, phosphatidylinositol‐3‐kinase; PA, proanthocyanidin; PD, Parkinson's disease; PF, paeoniflorin; PGC‐1α, proliferator‐activated receptor‐γ coactivator 1‐α; PINK, PTEN‐induced kinase 1; PIP3, phosphatidylinositol‐3,4,5‐trisphosphate; PKCδ, protein kinase Cδ; PON‐1, paraoxnase 1; pro‐IL‐18, pro‐ interleukin‐18; pro‐IL‐1β, pro‐interleukin‐1β; ROS, reactive oxygen species; SFN, sulforaphane; Sirt1, mammalian silent information regulator‐2; Sirt3, sirtuin‐3; SOD, superoxide dismutase; STAT3, signal transducer and activator of transcription 3; TH, tyrosine hydroxylase; TNF‐α, tumor necrosis factor α; TrkB, tropomyosin‐receptor‐kinase B; ULK1, unc‐51‐like kinase 1; UPS, ubiquitin‐proteasome system; VDAC, voltage‐dependent anion channels; VDCC, voltage‐ dependent calcium channelw; α7 nAChR, nicotinic acetylcholine receptor of the α7 subtype; β‐Ecd, β‐ecdysterone.