Contents lists available at ScienceDirect Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull Molecular targets and therapeutic interventions for iron induced neurodegeneration Siddhi Bagwe-Parab, Ginpreet Kaur* Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’s NMIMS, Mumbai-400056, Maharashtra, India ARTICLE INFO Keywords: Mitochondrial dysfunction Cognitive decline Alzheimer disease Iron-Sulfur clusters Flavonoids ABSTRACT Iron overload due to repeated blood transfusions in β-thalassemia patients or in predisposed diseases like he- mochromatosis may prove lethal. Regulation and deposition of iron is a significant process, which is been ex- plored extensively in the past decade. Iron deposition in the body can cause cellular dysregulation, including neuronal damage. Significant research has been conducted in understanding how iron accumulation in the brain leads to neurodegeneration. Iron chelators have been tested pre-clinically and are in clinical trials for de- termining their potential role in the treatment of neurodegenerative diseases like Alzheimerös (AD) and Parkinsonös (PD). It has been reported that iron chelators show promising effects pre-clinically in the ameli- oration of neurodegenerative disorders. In the clinical setup, the main challenge for any drug is to penetrate the blood brain barrier (BBB) and to show therapeutic action. Smaller anti-oxidant molecules that cross BBB, can be expended for the treatment of neurodegenerative disorders. This review exclusively presents an assessment of original research articles published from year 2017–2019. It also addresses the mechanism of brain iron accu- mulation focusing more on AD and PD, their genetic predispositions, the detrimental effects of iron overload leading to neurodegeneration, iron-induced neuronal apoptosis and treatment strategies for the same. 1. Introduction Atypical iron accumulation in the brain has been detected in various neurodegenerative disorders. The mechanism of neurodegeneration caused by iron overload remains partially unclear. The diseases which are caused by genes responsible for iron overload are cumulatively termed as “neurodegeneration with brain iron accumulation' (NBIA) diseases” (Rouault, 2016). However, some reports claim that, diseases like AD and PD also have iron accumulation as one of the causative factors for pathogenesis (Nikseresht et al., 2019; Qu et al., 2019). Recent studies have displayed the postmortem MRI reports of patients with early or late-onset AD to demonstrate the presence of iron in the amyloid plaques and cortical region of the brain (Bulk et al., 2018; Chen et al., 2018; Gong et al., 2019). Also, a study on parkinsonian patients suggests the severity of the disease associating it with high iron content in the motor-related subcortical nuclei and nigral iron content with dopaminergic neurodegeneration (Martin-Bastida et al., 2017). https://doi.org/10.1016/j.brainresbull.2019.12.011 Received 19 August 2019; Received in revised form 14 December 2019; Accepted 17 December 2019 Abbreviations: AD, Alzheimer disease; ADP, Adenosine diphosphate; AKT/PKB, Protein kinase B; APAF1, Apoptotic protease activating factor 1; APP, Amyloid precursor protein; ATP, Adenosine triphosphate; Aβ, Amyloid beta; BAX, BCL2 Associated X, Apoptosis Regulator; BBB, Blood Brain Barrier; C19orf12, Chromosome 19 Open Reading Frame 12; CBD, Cannabidiol; COASY, Coenzyme A Synthase protein gene; CP, Ceruloplasmin gene; CUL4, Cullin 4 gene; DCAF17, DDB1 and CUL4 Associated Factor 17 gene; DDB1, Damage Specific DNA Binding Protein 1; Dex, Dexmedetomidine; DFO, Desferrioxamine; DNA, Deoxyribonucleic acid; DNA, deoxyribose nucleic acid; EDTA, Ethylenediaminetetraacetic acid; FA2H, Fatty Acid 2-Hydroxylase protein gene; Fe, S– Iron sulfur clusters; Fpn, Feroportin; Ft, Ferritin; FTL1, Ferritin Light chain 1 gene; FXN, Frataxin gene; GLRX5, Glutaredoxin-related protein 5 gene; GSK3β, Glycogen synthase kinase 3 beta; GTPB2, GTP- binding proteins 2 gene; HSPA9, Heat Shock Protein Family A (Hsp70) Member 9 gene; IL, Interleukin; IRE, Iron response element; IRP, Iron response proteins; ISCU, Iron-sulfur cluster assembly enzyme gene; LYRM4, LYR motif containing 4 protein gene; MAPK, Mitogen-activated protein kinase; MFRN2, Mitoferrin-2; MRI, Magnetic resonance imaging; mTOR, Mammalian target of rapamycin; NBIA, Neurodegeneration with brain iron accumulation; NFS1, Cysteine desulfurase enzyme gene; NFT, Neurofibrillary tangles; P13K, Phosphoinositide 3-kinase; PANK2, Pantothenate kinase 2 protein gene; PARP, Poly (ADP-ribose) polymerase; PLA2G6, Phospholipase A2, Group VI protein gene; RNA, Ribonucleic acid; ROS, Reactive Oxygen species; SCP2, Sterol Carrier protein 2 gene; TNF, Tumor necrosis factor; TPP, Triphenylphosphonium; UTR, Untranslated region; WDR45, WD repeat-containing protein 45 gene ⁎ Corresponding author at: Department of Pharmacology, SPP School of Pharmacy & Technology Management, Narsee Monjee Institute of Management Studies, V.L. Mehta road, Vile Parle (W), Mumbai, 400056, India. E-mail address: Ginpreet.Kaur@nmims.edu (G. Kaur). Brain Research Bulletin 156 (2020) 1–9 Available online 19 December 2019 0361-9230/ © 2019 Elsevier Inc. All rights reserved. T