Amiloride is neuroprotective in an MPTP model of Parkinson's disease.
The diuretic amiloride has recently proven neuroprotective in models of cerebral ischemia, a property attributable to the drug's inhibition of central acid-sensing ion channels (ASICs). Given that Parkinson's disease (PD), like ischemia, is associated with cerebral lactic acidosis, we tested amiloride in the MPTP-treated mouse, a model of PD also manifesting lactic acidosis. Amiloride was found to protect substantia nigra (SNc) neurons from MPTP-induced degeneration, as determined by attenuated reductions in striatal tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunohistochemistry, as well as smaller declines in striatal DAT radioligand binding and dopamine levels. More significantly, amiloride also preserved dopaminergic cell bodies in the SNc. Administration of psalmotoxin venom (PcTX), an ASIC1a blocker, resulted in a much more modest effect, attenuating only the deficits in striatal DAT binding and dopamine. These findings represent the first experimental evidence of a potential role for ASICs in the pathogenesis of Parkinson's disease.
Arias
Robert L
RL
Wyeth Discovery Neuroscience, Princeton, New Jersey 08543-8000, USA. ariasr@wyeth.com
Sung
Mei-Li A
ML
Vasylyev
Dmytro
D
Zhang
Mei-Yi
MY
Albinson
Kristin
K
Kubek
Katie
K
Kagan
Natasha
N
Beyer
Chad
C
Lin
Qian
Q
Dwyer
Jason M
JM
Zaleska
Margaret M
MM
Bowlby
Mark R
MR
Dunlop
John
J
Monaghan
Michael
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D062565:Acid Sensing Ion Channels; D000140:Acidosis, Lactic / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D000584:Amiloride / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D010455:Peptides; D011869:Radioligand Assay; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism; D013111:Spider Venoms / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D000978:Antiparkinson Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C413209:PcTX1 protein, Psalmopoeus cambridgei; D010455:Peptides; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013111:Spider Venoms; D000584:Amiloride; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine