What is the clinical evidence from this study?

Study design: Other. Population: Parkinson's disease (MPTP model). Intervention: Losartan vs. Saline or media (with MPTP/MPP+). Primary outcome: Loss of dopaminergic (TH+) neurons in the substantia nigra pars compacta (p=<0.05).

January 15, 2007Molecular Neurodegeneration171 citationsOpen Access

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

Q: What are the key findings of this study?

Daily treatment with the angiotensin type 1 receptor antagonist losartan significantly reduced MPTP-induced loss of dopaminergic neurons in the substantia nigra pars compacta of mice from 61.8% to 25.0%.

TGTom N. GrammatopoulosHarvard University SJSusan JonesGriffith University FAFerogh A. AhmadiDenver Health Medical Center

Key Result

Daily treatment with the angiotensin type 1 receptor antagonist losartan significantly reduced MPTP-induced loss of dopaminergic neurons in the substantia nigra pars compacta of mice from 61.8% to 25.0%.

Structured PICO

Does losartan prevent MPTP-induced degeneration of dopaminergic neurons in preclinical models of Parkinson's disease?

Population

Eight-week-old male C57BL/6 mice and primary rat ventral mesencephalic cultures used to model MPTP-induced Parkinson's disease.

Intervention

Losartan (daily treatment in vivo, and in vitro)

Comparator

MPTP/MPP+ challenge without losartan

Outcome

Dopaminergic neuronal loss in vitro and in the substantia nigra pars compacta (SNpc), and tyrosine hydroxylase (TH) immunostaining of the striatumsurrogate

Losartan demonstrates neuroprotective effects against MPTP-induced dopaminergic neuronal loss in preclinical models of Parkinson's disease.

Main Result

Absolute Event Rate: 25% vs 61.8%

p-value: p=<0.05

Limitations

Losartan reduced mean arterial blood pressure in mice, so the contribution of blood pressure reduction to neuroprotection cannot be excluded.
Nissl staining was done separately from TH immunostaining, meaning non-dopaminergic neurons and glia may have been included in total cell counts.
Animal and in vitro models may not fully replicate human Parkinson's disease pathogenesis.

Abstract

BACKGROUND: Recent 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). RESULTS: In the presence of exogenous Ang II, losartan reduced MPP+ (5 muM) 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. CONCLUSION: Our 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.

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