TY - JOUR
T1 - Angiotensin type I receptor antagonist losartan, reduces MPTP-induced degeneration of dopaminergic neurons in substantia nigra
AU - Grammatopoulos, Tom N.
AU - Jones, Susan M.
AU - Ahmadi, Ferogh A.
AU - Hoover, Brian R.
AU - Snell, Lawrence D.
AU - Skoch, Jesse
AU - Jhaveri, Vimal V.
AU - Poczobutt, Andy M.
AU - Weyhenmeyer, James A.
AU - Zawada, W. Michael
PY - 2007
Y1 - 2007
N2 - 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 I (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 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. 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.
AB - 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 I (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 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. 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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U2 - 10.1186/1750-1326-2-1
DO - 10.1186/1750-1326-2-1
M3 - Article
AN - SCOPUS:34247893855
SN - 1750-1326
VL - 2
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
IS - 1
M1 - 1
ER -