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HERO ID
2845032
Reference Type
Journal Article
Title
Potential of protease inhibitor in 3-nitropropionic acid induced Huntington's disease like symptoms: Mitochondrial dysfunction and neurodegeneration
Author(s)
Hariharan, A; Shetty, S; Shirole, T; Jagtap, AG
Year
2014
Is Peer Reviewed?
1
Journal
NeuroToxicology
ISSN:
0161-813X
EISSN:
1872-9711
Volume
45
Page Numbers
139-148
Language
English
PMID
25445565
DOI
10.1016/j.neuro.2014.10.004
Web of Science Id
WOS:000346955100015
Abstract
Huntington's disease (HD) is a genetic, neurodegenerative disorder mainly characterized by motor dysfunction, cognitive decline and psychiatric disturbances. 3-Nitropropionic acid (3-NP) is an inhibitor of succinate dehydrogenase (Complex II) of the mitochondrial respiratory chain, which thereby reduces production of ATP. It induces neurotoxicity by causing striatal degeneration, energy deficit and oxidative stress. Angiotensin converting enzyme (ACE) is an important protease in the renin angiotensin system (RAS) responsible for the conversion of Angiotensin I to Angiotensin II. Angiotensin-II stimulates mitochondrial oxidant release leading to depression of energy metabolism. ACE inhibitors have shown promise in disorders like stress, anxiety, and depression in addition to showing beneficial effects in cognitive disorders like Alzheimer's. Angiotensin-II inhibition enhances energy production by lowering mitochondrial oxidant production, and hence protects mitochondrial structure. Trandolapril is a centrally active ACE inhibitor. 3-NP administered systematically (20 mg/kg, i.p) for 4 days consecutively induced HD like symptoms - loss of body weight, neurobehavioral alterations like memory dysfunction (elevated plus maze, Morris water maze performance), Hind-limb impairment (Narrow beam test), motor incoordination (locomotor activity). Biochemical studies on brain tissue showed increased lipid peroxidation, nitrite levels and acetylcholinesterase activity along with decreased levels of reduced glutathione, catalase activity. Mitochondrial enzyme complex activities (I, II, IV and MTT assay) were found to be significantly lowered in brain mitochondria. Administration of Trandolapril (4 and 6 mg/kg, p.o) daily for 12 days showed significant improvement in body weight, neurobehavioral parameters, oxidative stress and mitochondrial enzyme activities in rat brain. These findings were further confirmed by histopathological studies which showed improvement in 3-NP induced brain lesions. This study indicates that Trandolapril could be an effective treatment option for the management of HD. (C) 2014 Elsevier Inc. All rights reserved.
Keywords
3-Nitropropionic acid; Huntington's disease; Renin angiotensin system (RAS); Trandolapril; Mitochondrial stress
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Nitrate/Nitrite
Supplemental LitSearch Update 1900-2015
PubMed
WoS
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