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.
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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
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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.
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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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Mishra, A., Krishnamurthy, S. Rebamipide Mitigates Impairments in Mitochondrial Function and Bioenergetics with α-Synuclein Pathology in 6-OHDA-Induced Hemiparkinson’s Model in Rats. Neurotox Res 35, 542–562 (2019). https://doi.org/10.1007/s12640-018-9983-2
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DOI: https://doi.org/10.1007/s12640-018-9983-2