PYM50028, a novel, orally active, nonpeptide neurotrophic factor inducer, prevents and reverses neuronal damage induced by MPP + in mesencephalic neurons and by MPTP in a mouse model of Parkinson's disease
| Autor: | Tom H. Johnston, Noelle Callizot, Kimberly Dixon, Antonia Orsi, Daryl Rees, Naomi P. Visanji, Patrick A. Howson, Jonathan M. Brotchie |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Tyrosine 3-Monooxygenase Neurotoxins Administration Oral Substantia nigra Ciliary neurotrophic factor Pharmacology Biochemistry Neuroprotection Mice chemistry.chemical_compound Parkinsonian Disorders Mesencephalon Neurotrophic factors Spirostans Genetics medicine Glial cell line-derived neurotrophic factor Animals Glial Cell Line-Derived Neurotrophic Factor Nerve Growth Factors Molecular Biology Neurons biology business.industry MPTP Neurodegeneration medicine.disease Rats Disease Models Animal Nerve growth factor nervous system chemistry 1-Methyl-4-phenyl-1 2 3 6-tetrahydropyridine Anesthesia biology.protein business Biotechnology |
| Zdroj: | The FASEB Journal. 22:2488-2497 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.07-095398 |
| Popis: | Many experimental data support the enhancement of neurotrophic factors as a means to modify neurodegeneration in Parkinson's disease. However, the translation of this to the clinic has proven problematic. This is likely due to the complex nature of the surgical gene delivery and cell-based approaches adopted to deliver proteinaceous neurotrophic factors to targets within the central nervous system. We investigated the ability of a novel, orally active, nonpeptide neurotrophic factor inducer, PYM50028 (Cogane), to restore dopaminergic function after 1-methyl-4-phenylpyridinium (MPP(+)) -induced damage to mesencephalic neurons in vitro and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -lesioned mice. In rat mesencephalic neurons, administration of PYM50028, either before or after MPP(+), significantly prevented and reversed both MPP(+)-induced neuronal atrophy and cell loss. These effects were potent and of a magnitude equivalent to those achieved by a combination of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF). Oral administration of PYM50028 (10 mg/kg/day for 60 days) to MPTP-lesioned mice, commencing after a striatal impairment was evident, resulted in a significant elevation of striatal GDNF (297%) and BDNF (511%), and attenuated the loss of striatal dopaminergic transporter levels and dopaminergic neurons in the substantia nigra. PYM50028 did not inhibit monoamine oxidase B in vitro, nor did it alter brain levels of MPP(+) in vivo. PYM50028 has neuroprotective and neurorestorative potential and is in clinical development for the treatment of neurodegenerative disorders, including Parkinson's disease. |
| Databáze: | OpenAIRE |
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