The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease.
c-Abl is activated in the brain of Parkinson's disease (PD) patients and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice where it inhibits parkin through tyrosine phosphorylation leading to the accumulation of parkin substrates, and neuronal cell death. In the present study, we evaluated the in vivo efficacy of nilotinib, a brain penetrant c-Abl inhibitor, in the acute MPTP-induced model of PD. Our results show that administration of nilotinib reduces c-Abl activation and the levels of the parkin substrate, PARIS, resulting in prevention of dopamine (DA) neuron loss and behavioral deficits following MPTP intoxication. On the other hand, we observe no reduction in the tyrosine phosphorylation of parkin and the parkin substrate, AIMP2 suggesting that the protective effect of nilotinib may, in part, be parkin-independent or to the pharmacodynamics properties of nilotinib. This study provides a strong rationale for testing other brain permeable c-Abl inhibitors as potential therapeutic agents for the treatment of PD.
1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Senthilkumar S
SS
Karuppagounder
1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Saurav
S
Brahmachari
1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [4] Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Yunjong
Y
Lee
1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [4] Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [5] Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Valina L
VL
Dawson
1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [4] Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [5] Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA [6].
Ted M
TM
Dawson
1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA [4].
Han Seok
HS
Ko
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism*; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D018696:Neuroprotective Agents; D011743:Pyrimidines; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D016315:Proto-Oncogene Proteins c-abl; C498826:nilotinib