Angiotensin type 1 receptor antagonist losartan, reduces MPTP-induced degeneration of dopaminergic neurons in substantia nigra

Tom N Grammatopoulos,W Michael Zawada,Lawrence D Snell,Andy M Poczobutt,Vimal V Jhaveri,Susan M Jones,Jesse Skoch,James A Weyhenmeyer,Brian R Hoover,Ferogh A Ahmadi

doi:10.1186/1750-1326-2-1

Abstract

BackgroundRecent attention has focused on understanding the role of the brain-renin-angiotensin-system (RAS) in stroke and neurodegenerative diseases. Direct evidence of a role for the brain-RAS in Parkinson's disease (PD) comes from studies demonstrating the neuroprotective effect of RAS inhibitors in several neurotoxin based PD models. In this study, we show that an antagonist of the angiotensin II (Ang II) type 1 (AT1) receptor, losartan, protects dopaminergic (DA) neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity both in primary ventral mesencephalic (VM) cultures as well as in the substantia nigra pars compacta (SNpc) of C57BL/6 mice (Fig. 1).ResultsIn the presence of exogenous Ang II, losartan reduced MPP+ (5 μM) induced DA neuronal loss by 72% in vitro. Mice challenged with MPTP showed a 62% reduction in the number of DA neurons in the SNpc and a 71% decrease in tyrosine hydroxylase (TH) immunostaining of the striatum, whereas daily treatment with losartan lessened MPTP-induced loss of DA neurons to 25% and reduced the decrease in striatal TH+ immunostaining to 34% of control.ConclusionOur study demonstrates that the brain-RAS plays an important neuroprotective role in the MPTP model of PD and points to AT1 receptor as a potential novel target for neuroprotection.

Highlights

Recent attention has focused on understanding the role of the brain-reninangiotensin-system (RAS) in stroke and neurodegenerative diseases
Angiotensin angiotensin II (II) protects dopaminergic neurons in vitro from MPP+ toxicity only in the presence of the AT1 receptor antagonist losartan To study the effects of the RAS on MPP+-induced neurotoxicity in vitro, primary rat embryonic day 15 (E15) ventral mesencephalic (VM) cultures were grown for 6 days and treated with MPP+ (1–100 μM) for 48 hrs
This analysis showed that MPP+-treated VM cultures pretreated with angiotensin II (Ang II) (100 nM), in the presence of losartan (1 μM), had a statistically significant reduction in DA neuronal loss when compared to MPP+ exposed VM cultures pretreated with Ang II alone or in the presence of PD123319 (Fig. 2)

Summary

Introduction

Recent attention has focused on understanding the role of the brain-reninangiotensin-system (RAS) in stroke and neurodegenerative diseases. Direct evidence of a role for the brain-RAS in Parkinson's disease (PD) comes from studies demonstrating the neuroprotective effect of RAS inhibitors in several neurotoxin based PD models. We show that an antagonist of the angiotensin II (Ang II) type 1 (AT1) receptor, losartan, protects dopaminergic (DA) neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity both in primary ventral mesencephalic (VM) cultures as well as in the substantia nigra pars compacta (SNpc) of C57BL/6 mice (Fig. 1). Treatment of rodents and non-human primates with neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine [6,7] and rotenone [8] have helped us understand that oxidative stress, mitochondrial respiration dysfunction and protein aggregation are primary mediators of the dopaminergic neurodegeneration [9]. This study explores the hypothesis that the reninangiotensin system (RAS) is a potential target for preventing the loss of DA neurons

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