Neuroprotective Efficacy of a New Brain-Penetrating C-Abl Inhibitor in a Murine Parkinson's Disease Model

Syed Z. Imam, William Trickler, Shinya Kimura, Zbigniew K. Binienda, Merle G. Paule, William Slikker, Senlin Li, Robert A Clark, Syed F. Ali

Research output: Contribution to journalArticle

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Abstract

Experimental evidence suggests that oxidative and nitrative mechanisms account for much of the dopaminergic neuronal injury in Parkinson's disease (PD). The ubiquitously expressed non-receptor tyrosine kinase c-Abl is activated by oxidative stress and thus, may play a role in redox-mediated neurodegeneration. Recently, we reported that c-Abl is activated in PD and that a c-Abl inhibitor mitigated neuronal damage in a PD animal model, suggesting a novel neuroprotective therapeutic approach. In the studies presented here, we evaluated the efficacy of a potent and clinically relevant second-generation irreversible Abl kinase inhibitor, INNO-406, as a therapeutic agent for PD. Our studies reveal that INNO-406 is capable of preventing the progression of dopaminergic neuronal damage in a toxin-induced C57 mouse model of PD. Using bovine brain microvessel endothelium as an in vitro blood-brain barrier (BBB) model, we detected rapid and significant transfer of INNO-406. Additionally, pharmacokinetic analyses demonstrated significant nanomolar concentrations of INNO-406 in brain in the presence or absence of MPTP administration, however, INNO-406 did not alter the brain levels of MPP+ in MPTP-treated mice. Finally, we showed that 10 mg/kg of INNO-406 given to C57 mice for one week before MPTP treatment (4×20 mg/kg i.p., every 2 h) and then for one week after MPTP treatment decreased the loss of dopamine in the striatum by 45% and the loss of TH+ neurons in substantia nigra pars compacts by 40%. This treatment regimen also abrogated activation of c-Abl, tyrosine phosphorylation of the Abl substrate and E3-ubiquitin ligase parkin, and accumulation of the toxic parkin substrate AIMP2. We propose that compounds of the INNO-406 class of Abl inhibitors will be useful new neuroprotective drugs for the treatment of PD-like pathology in preclinical systems that should be easily translated to the clinic.

Original languageEnglish (US)
Article numbere65129
JournalPLoS One
Volume8
Issue number5
DOIs
StatePublished - May 31 2013

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disease models
Parkinson disease
Parkinson Disease
Brain
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
brain
mice
tyrosine
phosphotransferases (kinases)
animal models
therapeutics
ubiquitin-protein ligase
blood-brain barrier
Phosphorylation
Oxidative stress
Pharmacokinetics
Ubiquitin-Protein Ligases
endothelium
dopamine
Poisons

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Imam, S. Z., Trickler, W., Kimura, S., Binienda, Z. K., Paule, M. G., Slikker, W., ... Ali, S. F. (2013). Neuroprotective Efficacy of a New Brain-Penetrating C-Abl Inhibitor in a Murine Parkinson's Disease Model. PLoS One, 8(5), [e65129]. https://doi.org/10.1371/journal.pone.0065129

Neuroprotective Efficacy of a New Brain-Penetrating C-Abl Inhibitor in a Murine Parkinson's Disease Model. / Imam, Syed Z.; Trickler, William; Kimura, Shinya; Binienda, Zbigniew K.; Paule, Merle G.; Slikker, William; Li, Senlin; Clark, Robert A; Ali, Syed F.

In: PLoS One, Vol. 8, No. 5, e65129, 31.05.2013.

Research output: Contribution to journalArticle

Imam, SZ, Trickler, W, Kimura, S, Binienda, ZK, Paule, MG, Slikker, W, Li, S, Clark, RA & Ali, SF 2013, 'Neuroprotective Efficacy of a New Brain-Penetrating C-Abl Inhibitor in a Murine Parkinson's Disease Model', PLoS One, vol. 8, no. 5, e65129. https://doi.org/10.1371/journal.pone.0065129
Imam, Syed Z. ; Trickler, William ; Kimura, Shinya ; Binienda, Zbigniew K. ; Paule, Merle G. ; Slikker, William ; Li, Senlin ; Clark, Robert A ; Ali, Syed F. / Neuroprotective Efficacy of a New Brain-Penetrating C-Abl Inhibitor in a Murine Parkinson's Disease Model. In: PLoS One. 2013 ; Vol. 8, No. 5.
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abstract = "Experimental evidence suggests that oxidative and nitrative mechanisms account for much of the dopaminergic neuronal injury in Parkinson's disease (PD). The ubiquitously expressed non-receptor tyrosine kinase c-Abl is activated by oxidative stress and thus, may play a role in redox-mediated neurodegeneration. Recently, we reported that c-Abl is activated in PD and that a c-Abl inhibitor mitigated neuronal damage in a PD animal model, suggesting a novel neuroprotective therapeutic approach. In the studies presented here, we evaluated the efficacy of a potent and clinically relevant second-generation irreversible Abl kinase inhibitor, INNO-406, as a therapeutic agent for PD. Our studies reveal that INNO-406 is capable of preventing the progression of dopaminergic neuronal damage in a toxin-induced C57 mouse model of PD. Using bovine brain microvessel endothelium as an in vitro blood-brain barrier (BBB) model, we detected rapid and significant transfer of INNO-406. Additionally, pharmacokinetic analyses demonstrated significant nanomolar concentrations of INNO-406 in brain in the presence or absence of MPTP administration, however, INNO-406 did not alter the brain levels of MPP+ in MPTP-treated mice. Finally, we showed that 10 mg/kg of INNO-406 given to C57 mice for one week before MPTP treatment (4×20 mg/kg i.p., every 2 h) and then for one week after MPTP treatment decreased the loss of dopamine in the striatum by 45{\%} and the loss of TH+ neurons in substantia nigra pars compacts by 40{\%}. This treatment regimen also abrogated activation of c-Abl, tyrosine phosphorylation of the Abl substrate and E3-ubiquitin ligase parkin, and accumulation of the toxic parkin substrate AIMP2. We propose that compounds of the INNO-406 class of Abl inhibitors will be useful new neuroprotective drugs for the treatment of PD-like pathology in preclinical systems that should be easily translated to the clinic.",
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