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Rebamipide Mitigates Impairments in Mitochondrial Function and Bioenergetics with α-Synuclein Pathology in 6-OHDA-Induced Hemiparkinson’s Model in Rats

  • Akanksha Mishra
  • Sairam KrishnamurthyEmail author
Original Article

Abstract

Parkinson’s disease (PD) is one of the widely reported neurodegenerative disorders affecting more than ten million people worldwide. Due to therapeutic limitations and several adverse effects associated with currently used drugs, it is crucial to search for safe and effective options for treatment of PD. Oxidative stress, mitochondrial dysfunction, α-synuclein oligomeric aggregates, and glucocerebrosidase (GCase) deficiency are involved in PD pathogenesis. Rebamipide, an anti-ulcer drug, is a proven free-radical scavenger and antioxidant. The drug has shown neuroprotective effects in cultured SH-SY5Y cells. Therefore, we investigated the pharmacological effect of rebamipide in 6-hydroxydopamine (6-OHDA)-induced experimental PD model. Rebamipide was given to adult male albino rats of Charles-Foster strain in 20, 40, and 80 mg/kg (R-20, R-40, and R-80) oral dose twice daily for 24 days (day 4 to day 27) after 6-OHDA intrastriatal injection. The drug inhibited 6-OHDA-induced motor deficits and nigral α-synuclein aggregates in dose-dependent manner. R-40 and R-80 dose dependently increased striatal mitochondrial complex I, II, IV, and V activities; mitochondrial bioenergetics; and nigral GCase activity. 6-OHDA-induced lipid peroxidation was decreased. Highest dose (R-80) also decreased apoptotic proteins and upregulated striatal dopamine concentration in 6-OHDA-induced hemiparkinson’s rat model. Therefore, the anti-PD effect of rebamipide may involve stabilization of mitochondrial bioenergetics, enhancement of GCase enzymatic activity as well as decreased oxidative stress with α-synuclein pathology, and apoptosis in 6-OHDA-induced hemiparkinson’s rat model. Hence, preclinical evidence indicates rebamipide to be a potential drug for management of PD.

Keywords

Rebamipide Mitochondrial bioenergetics Oxidative stress Parkinson’s disease α-Synuclein Glucocerebrosidase 

Abbreviations

4-MU

4-methylumbelliferone

6-OHDA

6-hydroxydopamine

α-Synuclein

alpha-synuclein

Aβ42

amyloid-β 1–42

ADP

adenosine diphosphate

ATP

adenosine triphosphate

β-actin

beta-actin

BSA

bovine serum albumin

CMC

carboxymethylcellulose

CNS

central nervous system

COMT

catechol-O-methyltransferase

DA

dopamine

DNA

deoxyribonucleic acid

DOPAC

3,4-dihydroxyphenylacetic acid

ECD

electrochemical detector

EGTA

ethylene glycol-bis (β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid

ELISA

enzyme-linked immunosorbent assay

ER

endoplasmic reticulum

ETC

electron transport chain

FAD

flavin adenine dinucleotide

FCCP

carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone

GC

glucocerebroside

GCase

glucocerebrosidase

h

hours

H+

Hydrogen ion

H2O2

hydrogen peroxide

HEPES

4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid

HPLC

high-performance liquid chromatography

HVA

homovanillic acid

iNOS

inducible nitric oxide synthase

kg

kilogram

KH2PO4

potassium phosphate monobasic anhydrous

LPO

lipid peroxide

MAO B

monoamine oxidase B

MDA

malondialdehyde

mg

milligram

MgCl2

magnesium chloride

Min

minute

mL

milliliter

mM

millimolar

mmol

millimoles

MMP

mitochondrial membrane potential

μL

microliter

μg

microgram

μmol

micromoles

NAD+

nicotinamide adenine dinucleotide (oxidized)

NADH

nicotinamide adenine dinucleotide (reduced)

NBT

nitroblue tetrazolium

ng

nanogram

NIH

National Institutes of Health Guide for the Care and Use of Laboratory Animals

NMDA

N-methyl-d-aspartate

nmol

nanomoles

OFT

open field test

PD

Parkinson’s disease

pg

picogram

Pi

inorganic phosphate

p.o.

per os

R-20

rebamipide 20 mg/kg

R-40

rebamipide 40 mg/kg

R-80

rebamipide 80 mg/kg

RCR

respiratory control ratio

RNA

ribonucleic acid

ROS

reactive oxygen species

S.C.

subcutaneous

SD

standard deviation

SDS-PAGE

sodium dodecyl sulfate polyacrylamide gel electrophoresis

S

seconds

SOD

superoxide dismutase

SNc

substantia nigra pars compacta

TBARS

thiobarbituric acid reactive substances

Notes

Acknowledgements

The authors wish to acknowledge Akums Drugs & Pharmaceuticals Ltd., New Delhi, India for providing rebamipide (active pharmaceutical ingredient) as gift sample. This work was supported by the teaching assistantship to Akanksha Mishra from Indian Institute of Technology (Banaras Hindu University), Varanasi-221005, U.P., India.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All the procedures performed in the study were in accordance with the ethical standards of the Institutional animal ethical committee, Banaras Hindu University (Dean/2016/CAEC/33). The experiments were performed according to the principles of National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8023, revised 1978) guidelines. The article does not contain any studies with human participants performed by any of the authors.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering & TechnologyIndian Institute of Technology (Banaras Hindu University)VaranasiIndia

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