Role of neurosteroids in experimental 3-nitropropionic acid induced neurotoxicity in rats.

Abstract

Huntington's disease is an autosomal dominant, progressive, and fatal neurodegenerative disease characterized by motor and non-motor symptoms. Systemic administration of 3-nitropropionic acid, a complex II inhibitor of the electron transport chain induces selective striatal lesions in rodents. Neurosteroids are synthesized in central nervous system, able to modulate GABAA receptor function and has been reported to have neuroprotective action. The present study has been designed to investigate the role of neurosteroids such as progesterone and pregnenolone which are positive and negative modulators of GABA respectively against 3-nitropropionic acid induced experimental Huntington's disease. Systemic administration of 3-nitropropionic acid (10mg/kg i.p.) for 14 days significantly reduced body weight, locomotor activity, motor coordination, balance beam walk performance, antioxidant defense enzymes (reduced glutathione and catalase) and significantly increase oxidative stress markers (lipid peroxidation and nitrite level) in striatum and cortex. 3-Nitropropionic acid treatment also increases pro-inflammatory cytokines (TNF-α and IL-1β) level in striatum. Progesterone (10, 20mg/kg/day i.p.) treatments for 14 days significantly reversed the behavioral, antioxidant defense enzymes, oxidative stress marker and pro-inflammatory cytokines as compared to the 3-Nitropropionic acid treated group. Pregnenolone (1 and 2mg/kg i.p.), a negative modulator of GABAA pretreatment significantly reversed the protective effect of progesterone on behavioral and biochemical parameters. The results of the present study suggest that the positive GABAergic modulation may be beneficial for the treatment of motor disorder.

• Authors: Pushpender Kumar, Puneet Kumar, Aamir Khan, Rahul Deshmukh, Pyare Lal Sharma
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 723 Pg. 38-45 (Jan 15 2014) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 24333475 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Published by Elsevier B.V.

Chemical References

• Interleukin-1beta
• Neuroprotective Agents
• Neurotoxins
• Nitrites
• Nitro Compounds
• Propionates
• Tumor Necrosis Factor-alpha
• Progesterone
• Pregnenolone
• Catalase
• Glutathione
• 3-nitropropionic acid

Topics

• Animals
• Behavior, Animal (drug effects)
• Brain (drug effects, metabolism)
• Catalase (metabolism)
• Glutathione (metabolism)
• Huntington Disease (drug therapy)
• Interleukin-1beta (metabolism)
• Lipid Peroxidation (drug effects)
• Male
• Motor Activity (drug effects)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Neurotoxicity Syndromes (drug therapy, etiology, metabolism)
• Neurotoxins
• Nitrites (metabolism)
• Nitro Compounds
• Oxidative Stress (drug effects)
• Pregnenolone (pharmacology)
• Progesterone (pharmacology, therapeutic use)
• Propionates
• Rats
• Rats, Wistar
• Rotarod Performance Test
• Tumor Necrosis Factor-alpha (metabolism)