PYM50028, a novel, orally active, nonpeptide neurotrophic factor inducer, prevents and reverses neuronal damage induced by MPP <sup>+</sup> in mesencephalic neurons and by MPTP in a mouse model of Parkinson's disease
Bibliographic record
Abstract
ABSTRACT 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 admin istration 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 treat ment of neurodegenerative disorders, including Parkinson's disease.—Visanji, N. P., Orsi, A., Johnston, T. H., Howson, P. A., Dixon, K., Callizot, N., Brotchie, J. M., Rees, D. D. 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. FASEB J. 22, 2488–2497 (2008)
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".