PMID- 18364399
OWN - NLM
STAT- MEDLINE
DCOM- 20080812
LR  - 20131121
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 22
IP  - 7
DP  - 2008 Jul
TI  - 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.
PG  - 2488-97
LID - 10.1096/fj.07-095398 [doi]
AB  - 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.
FAU - Visanji, Naomi P
AU  - Visanji NP
AD  - Toronto Western Research Institute, MCL 11-419, Toronto, Ontario, M5T 2S8, 
      Canada.
FAU - Orsi, Antonia
AU  - Orsi A
FAU - Johnston, Tom H
AU  - Johnston TH
FAU - Howson, Patrick A
AU  - Howson PA
FAU - Dixon, Kimberly
AU  - Dixon K
FAU - Callizot, Noelle
AU  - Callizot N
FAU - Brotchie, Jonathan M
AU  - Brotchie JM
FAU - Rees, Daryl D
AU  - Rees DD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080325
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Glial Cell Line-Derived Neurotrophic Factor)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Neurotoxins)
RN  - 0 (Spirostans)
RN  - 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
RN  - CFS802C28F (sarsasapogenin)
RN  - EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
SB  - IM
MH  - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology
MH  - Administration, Oral
MH  - Animals
MH  - Disease Models, Animal
MH  - Glial Cell Line-Derived Neurotrophic Factor/pharmacology
MH  - Male
MH  - Mesencephalon/drug effects/*pathology
MH  - Mice
MH  - Nerve Growth Factors/administration & dosage/*therapeutic use
MH  - Neurons/drug effects/*pathology
MH  - Neurotoxins/toxicity
MH  - Parkinsonian Disorders/*chemically induced/*prevention & control
MH  - Rats
MH  - Spirostans/*therapeutic use
MH  - Tyrosine 3-Monooxygenase/drug effects/metabolism
EDAT- 2008/03/28 09:00
MHDA- 2008/08/13 09:00
CRDT- 2008/03/28 09:00
PHST- 2008/03/28 09:00 [pubmed]
PHST- 2008/08/13 09:00 [medline]
PHST- 2008/03/28 09:00 [entrez]
AID - fj.07-095398 [pii]
AID - 10.1096/fj.07-095398 [doi]
PST - ppublish
SO  - FASEB J. 2008 Jul;22(7):2488-97. doi: 10.1096/fj.07-095398. Epub 2008 Mar 25.