PMID- 14975705
OWN - NLM
STAT- MEDLINE
DCOM- 20041209
LR  - 20141120
IS  - 0014-2999 (Print)
IS  - 0014-2999 (Linking)
VI  - 486
IP  - 2
DP  - 2004 Feb 20
TI  - Neurotrophic actions of the novel AMPA receptor potentiator, LY404187, in rodent 
      models of Parkinson's disease.
PG  - 163-74
AB  - Recent developments in the molecular biology and pharmacology of 
      alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has 
      led to the discovery of selective, potent and systemically active AMPA receptor 
      potentiators. These molecules enhance synaptic transmission and evidence suggests 
      that they play important roles in plasticity and cognitive processes. Activation 
      of AMPA receptors also increases neuronal activation and activity-dependent 
      signalling, which may increase brain-derived neurotrophic factor (BDNF) 
      expression and enhance cell proliferation in the brain. We therefore hypothesised 
      that an AMPA receptor potentiator may provide neurotrophic effects in rodent 
      models of Parkinson's disease. In the present studies we report that the potent 
      and selective AMPA receptor potentiator, R,S-N-2-(4-(4-Cyanophenyl)phenyl)propyl 
      2-propanesulfonamide (LY404187), provides both functional, neurochemical and 
      histological protection against unilateral infusion of 6-hydroxydopamine into the 
      substantia nigra or striatum of rats. The compound also reduced 
      1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in mice. 
      Interestingly, we were also able to observe large functional and histological 
      effects when we delayed treatment until after cell death had occurred (3 or 6 
      days after 6-hydroxydopamine infusion), supporting a neurotrophic mechanism of 
      action. In addition, LY404187 provided a dose-dependent increase in 
      growth-associated protein-43 expression in the striatum. Therefore, we propose 
      that AMPA receptor potentiators offer the potential of a new therapy to halt the 
      progression and perhaps repair the degeneration in Parkinson's disease.
FAU - O'Neill, Michael J
AU  - O'Neill MJ
AD  - Eli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey 
      GU20 6PH, UK. Oneill_Michael_J@Lilly.com
FAU - Murray, Tracey K
AU  - Murray TK
FAU - Whalley, Katherine
AU  - Whalley K
FAU - Ward, Mark A
AU  - Ward MA
FAU - Hicks, Caroline A
AU  - Hicks CA
FAU - Woodhouse, Sandra
AU  - Woodhouse S
FAU - Osborne, David J
AU  - Osborne DJ
FAU - Skolnick, Phil
AU  - Skolnick P
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (GAP-43 Protein)
RN  - 0 (LY 404187)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Receptors, AMPA)
RN  - 0 (Sulfonamides)
RN  - 8HW4YBZ748 (Oxidopamine)
RN  - 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
SB  - IM
MH  - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
MH  - Animals
MH  - Corpus Striatum/metabolism/pathology
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - GAP-43 Protein/biosynthesis
MH  - In Vitro Techniques
MH  - Injections, Subcutaneous
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Motor Activity/drug effects
MH  - Neuroprotective Agents/administration & dosage/pharmacology/*therapeutic use
MH  - Oxidopamine
MH  - Parkinson Disease, Secondary/chemically induced/*drug therapy/pathology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, AMPA/*agonists
MH  - Substantia Nigra/metabolism/pathology
MH  - Sulfonamides/administration & dosage/*pharmacology
EDAT- 2004/02/21 05:00
MHDA- 2004/12/16 09:00
CRDT- 2004/02/21 05:00
PHST- 2003/12/10 00:00 [accepted]
PHST- 2004/02/21 05:00 [pubmed]
PHST- 2004/12/16 09:00 [medline]
PHST- 2004/02/21 05:00 [entrez]
AID - S0014299903027912 [pii]
AID - 10.1016/j.ejphar.2003.12.023 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2004 Feb 20;486(2):163-74. doi: 10.1016/j.ejphar.2003.12.023.