Endothelin receptor type B agonist, IRL-1620, prevents beta amyloid (Aβ) induced oxidative stress and cognitive impairment in normal and diabetic rats

Seema Briyal; Cortney Shepard; Anil Gulati

doi:10.1016/j.pbb.2014.02.008

Endothelin receptor type B agonist, IRL-1620, prevents beta amyloid (Aβ) induced oxidative stress and cognitive impairment in normal and diabetic rats

Pharmacol Biochem Behav. 2014 May:120:65-72. doi: 10.1016/j.pbb.2014.02.008. Epub 2014 Feb 20.

Authors

Seema Briyal¹, Cortney Shepard², Anil Gulati³

Affiliations

¹ Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL 60515, USA.
² Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, USA.
³ Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL 60515, USA. Electronic address: AGULAT@midwestern.edu.

PMID: 24561065
DOI: 10.1016/j.pbb.2014.02.008

Abstract

Alzheimer's disease (AD) is a progressive brain disorder leading to impairment of learning and memory. Amyloid β (Aβ) induced oxidative stress has been implicated in the initiation and progression of AD. Endothelin (ET) and its receptors have been considered as therapeutic targets for AD. Recent studies indicate that stimulation of ETB receptors may provide neuroprotection. The purpose of this study was to determine the preventative effect of selectively stimulating ETB receptors on cognitive impairment and oxidative stress in Aβ treated non-diabetic and diabetic (induced by streptozotocin) rats. Rats were concurrently treated with Aβ1-40 (day 1, 7 and 14) and either saline, IRL-1620 (an ETB agonist), and/or BQ788 (an ETB antagonist) daily for 14 days in the lateral cerebral ventricles using sterotaxically implanted cannula; experiments were performed on day 15. Aβ treatment produced a significant (p<0.0001) increase of 360% and 365% in malondialdehyde levels (a marker of lipid peroxidation) in non-diabetic and diabetic rats, respectively, compared to sham group. Antioxidants (superoxide dismutase and reduced glutathione) decreased following Aβ treatment compared to sham group. Treatment with IRL-1620 reversed these effects, indicating that ETB receptor stimulation reduces oxidative stress injury following Aβ treatment. In Morris swim task, Aβ treated rats showed impairment in spatial memory. Rats treated with IRL-1620 significantly reduced the cognitive impairment induced by Aβ. BQ788 treatment completely blocked IRL-1620 induced reduction in oxidative stress and cognitive impairment. Results of the present study demonstrate that IRL-1620 improved both acquisition (learning) and retention (memory) on water maze task and reduced oxidative stress parameters. It can be speculated that ETB receptor stimulation prevents cognitive impairment and may be useful in neurodegenerative diseases.

Keywords: Alzheimer's disease; Beta amyloid; Cognitive impairment; ET(B) receptors; Endothelin; Oxidative stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid beta-Peptides / antagonists & inhibitors*
Amyloid beta-Peptides / toxicity*
Animals
Antioxidants / metabolism
Cognition Disorders / prevention & control*
Cognition Disorders / psychology*
Diabetes Mellitus, Experimental / psychology*
Diabetes Mellitus, Type 2 / psychology
Endothelins / pharmacology*
Lipid Peroxidation / drug effects
Male
Maze Learning / drug effects
Oxidative Stress / drug effects*
Peptide Fragments / pharmacology*
Rats
Rats, Sprague-Dawley
Receptor, Endothelin B / agonists*

Substances

Amyloid beta-Peptides
Antioxidants
Endothelins
Peptide Fragments
Receptor, Endothelin B
sovateltide