Sex-Specific Differences in Redox Homeostasis in Brain Norm and Disease

Journal of Molecular Neuroscience volume 67, pages 312–342 (2019)Cite this article

Abstract

Sex differences in brain physiology and by inference various pathologies are generally recognized, however frequently ignored in epidemiological and experimental studies, leading to numerous data gaps. As a consequence, the mechanisms underlying sexual dimorphism of neurological diseases remain largely unknown. Several cellular and molecular pathways linked to the etiology and pathogenesis of various brain disorders have been recently described as sex-specific. Here, we review the evidence for sex differences in brain redox homeostasis, which is an important factor in brain physiology and disease. First, we focus on sex-specific differences in the healthy brain regarding popular redox balance markers, including reactive oxygen and nitrogen species, oxidative damage, and antioxidant status. We also review the modulatory effect of steroid sex hormones on these markers. Lastly, we approach the sex-specific changes in brain redox homeostasis in disease and discuss the possibility that differential redox response contributes to the sexual dimorphism of neurological disorders.

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Abbreviations

AA:

Ascorbic acid

Aβ:

β-Amyloid peptide

AD:

Alzheimer disease

ADHD:

Attention deficit hyperactivity disorder

ALS:

Amyotrophic lateral sclerosis

AP-1:

Activator protein-1

APP:

Amyloid precursor protein

ARE:

Antioxidant response element

As:

Arsenic

ASD:

Autism spectrum disorder

ATP:

Adenosine triphosphate

BOAA:

β-N-Oxalyl-amino-L-alanine

BPA:

Bisphenol A

CAT:

Catalase

CB:

Cerebrum

CCI:

Controlled cortical impact

CN:

Caudate nucleus

CNS:

Central nervous system

COX:

Cytochrome c oxidase

CP:

Caudate putamen

CPF:

Chlorpyrifos

CREB:

Cyclic AMP response element binding protein

CSF:

Cerebrospinal fluid

CV:

Cerebellum

CX:

Cortex

DBL:

Lewy body dementia

DE:

Diesel exhaust

DHT:

Dihydrotestosterone

E2:

17β-estradiol

ED:

Embryonic day

EDC:

Endocrine disrupting chemical

ER:

Estrogen receptor

ETC:

Electron transport chain

EtOH:

Ethanol

EW:

Ethanol withdrawal

F2-IsoP:

F2-isoprostane

FALS:

Familial ALS

FC:

Frontal cortex

Fe:

Iron

FMO:

Flavin-containing monooxygenase

FRAP:

Ferric reducing antioxidant power

GCL:

Glutamate-cysteine ligase

GDX:

Gonadectomy

γGT:

γ-Glutamyl transferase

GSH:

Glutathione reduced

GSSH:

Glutathione oxidized

GPX:

Glutathione peroxidase

GR:

Glutathione reductase

GRX:

Glutaredoxin

GS:

Glutathione synthase

GST:

Glutathione S-transferase

Hcy:

Homocysteine

HD:

Huntington’s disease

HI:

Hypoxia-ischemia

HIE:

Hypoxic-ischemic encephalopathy

4-HNE:

4-hydroxynonenal

HO-1:

Heme oxygenase 1

HP:

Hippocampus

HT:

Hypothalamus

ICH:

Intracerebral hemorrhage

iNOS:

Inducible nitric oxide synthase

IQ:

Intelligence quotient

KEAP 1:

Kelch-like ECH-associated protein 1

KI:

Knock-in

LPO:

Lipid peroxidation

MB:

Midbrain

MCAO:

Middle cerebral artery occlusion

MDD:

Major depressive disorder

MeHg:

Methylmercury

Mn:

Manganese

MO:

Medulla oblongata

MPP+ :

1-methyl-4-phenylpyridinium

MPTP:

1-methyl-4-phenyl-1, 2, 3, 6, tetrahydro-pyridine

NA:

Nucleus accumbens

NADH/NAD:

Nicotinamide adenine dinucleotide

NF-κB:

Nuclear factor-κB

NIH:

National Institutes of Health

nNOS:

Neuronal nitric oxide synthase

NO:

Nitric oxide

NOS:

Nitric oxide synthase

NOx:

Stable nitric oxide metabolites, nitrite (NO2-) + nitrate (NO3-)

NRF2:

Nuclear factor erythroid 2-related factor 2

3-NT:

3-nitrotyrosine

NQO1:

NAD(P)H dehydrogenase (quinone) 1

OB:

Olfactory bulb

6-OHDA:

6-hydroxydopamine

ONS:

Oxidative -nitrosative stress

OP:

Organophosphate pesticide

OVX:

Ovariectomy

PCB:

Polychlorinated biphenyl

PD:

Parkinson disease

PFAS:

Poly- and perfluoroalkyl substances

PFC:

Prefrontal cortex

PFOA:

Perfluorooctanoic acid

PFOS:

Perfluorooctane sulfonate

PND:

Postnatal day

Poly(I:C):

Polyinosinic/polycytidylic acid

PON:

Paraoxonase

PROG:

Progesterone

PRX:

Peroxiredoxin

PUS:

Peripubertal unpredictable stress

rNPCs:

Rat neural progenitor cells

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SCZ:

schizophrenia

SE:

status epilepticus

SN:

substantia nigra

SOD:

Superoxide dismutase

SOD1:

Cu/Zn-superoxide dismutase

SOD2:

Mn-superoxide dismutase

ST:

Striatum

TAC:

Total antioxidant capacity

TBARS:

Thiobarbituric acid reactive substances

TBBPA:

Tetrabromobisphenol A

TBI:

Traumatic brain injury

TCDD:

2,3,7,8-tetrachlorodibenzo-p-dioxin

TEST:

Testosterone

Tg:

Transgenic

TRX:

Thioredoxin

TRXR:

Thioredoxin reductase

TP:

Testosterone propionate

UA:

Uric acid

VDR:

Vitamin D receptor

wt:

Wild-type

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Funding

MA was supported by grants from the National Institute of Environmental Health Sciences, NIEHS R01ES07331, NIEHS R01ES10563, and NIEHS R01ES020852.

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Affiliations

  1. Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer 209, Bronx, NY, 10461, USA

    Joanna A. Ruszkiewicz & Michael Aschner

  2. Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain

    Antonio Miranda-Vizuete

  3. Yaroslavl State University, Yaroslavl, Russia

    Alexey A. Tinkov & Anatoly V. Skalny

  4. Peoples’ Friendship University of Russia (RUDN University), Moscow, Russia

    Alexey A. Tinkov, Margarita G. Skalnaya & Anatoly V. Skalny

  5. All-Russian Research Institute of Medicinal and Aromatic Plants (VILAR), Moscow, Russia

    Margarita G. Skalnaya & Anatoly V. Skalny

  6. Department of Forensic Sciences and Toxicology, School of Medicine, University of Crete, Heraklion, Greece

    Aristides Tsatsakis

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  1. Joanna A. Ruszkiewicz
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  2. Antonio Miranda-Vizuete
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Ruszkiewicz, J.A., Miranda-Vizuete, A., Tinkov, A.A. et al. Sex-Specific Differences in Redox Homeostasis in Brain Norm and Disease. J Mol Neurosci 67, 312–342 (2019). https://doi.org/10.1007/s12031-018-1241-9

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Keywords

  • Oxidative stress
  • Antioxidant
  • Sex
  • Brain
  • Neurodegeneration
  • Neurotoxicity