Neuroprotective Efficacy of a New Brain-Penetrating C-Abl Inhibitor in a Murine Parkinson’s Disease Model
- Publication Date
- May 31, 2013
- Journal
- PLOS ONE
- Authors
- Syed Z. Imam, William Trickler, Shinya Kimura, Zbigniew K. Binienda, et al
- Volume
- 8
- Issue
- 5
- Pages
- e65129
- DOI
- https://dx.plos.org/10.1371/journal.pone.0065129
- Publisher URL
- http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0065129
- PubMed
- http://www.ncbi.nlm.nih.gov/pubmed/23741470
- PubMed Central
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669292
- Europe PMC
- http://europepmc.org/abstract/MED/23741470
- Web of Science
- 000319799900183
- Scopus
- 84878549593
- Mendeley
- http://www.mendeley.com/research/neuroprotective-efficacy-new-brainpenetrating-cabl-inhibitor-murine-parkinsons-disease-model
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Mendeley | Further Information
{"title"=>"Neuroprotective Efficacy of a New Brain-Penetrating C-Abl Inhibitor in a Murine Parkinson's Disease Model", "type"=>"journal", "authors"=>[{"first_name"=>"Syed Z.", "last_name"=>"Imam", "scopus_author_id"=>"7005207147"}, {"first_name"=>"William", "last_name"=>"Trickler", "scopus_author_id"=>"6506936883"}, {"first_name"=>"Shinya", "last_name"=>"Kimura", "scopus_author_id"=>"56784882900"}, {"first_name"=>"Zbigniew K.", "last_name"=>"Binienda", "scopus_author_id"=>"7003598683"}, {"first_name"=>"Merle G.", "last_name"=>"Paule", "scopus_author_id"=>"7005861411"}, {"first_name"=>"William", "last_name"=>"Slikker", "scopus_author_id"=>"35451025600"}, {"first_name"=>"Senlin", "last_name"=>"Li", "scopus_author_id"=>"7409243672"}, {"first_name"=>"Robert A.", "last_name"=>"Clark", "scopus_author_id"=>"35433151300"}, {"first_name"=>"Syed F.", "last_name"=>"Ali", "scopus_author_id"=>"7403089562"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"369052212", "sgr"=>"84878549593", "issn"=>"19326203", "pmid"=>"23741470", "scopus"=>"2-s2.0-84878549593", "doi"=>"10.1371/journal.pone.0065129", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"7baf4e51-a214-3e83-b7c7-21d1f7ef1b7e", "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.", "link"=>"http://www.mendeley.com/research/neuroprotective-efficacy-new-brainpenetrating-cabl-inhibitor-murine-parkinsons-disease-model", "reader_count"=>25, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Researcher"=>6, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>2, "Student > Master"=>3, "Other"=>2, "Student > Bachelor"=>6, "Lecturer"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Researcher"=>6, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>2, "Student > Master"=>3, "Other"=>2, "Student > Bachelor"=>6, "Lecturer"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>9, "Medicine and Dentistry"=>6, "Neuroscience"=>2, "Physics and Astronomy"=>1, "Psychology"=>1, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Neuroscience"=>{"Neuroscience"=>2}, "Chemistry"=>{"Chemistry"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"Egypt"=>2, "Australia"=>1}, "group_count"=>0}CrossRef
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Scopus | Further Information
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Relative Metric
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