Involvement of dopamine D(2)/D(3) receptors and BDNF in the neuroprotective effects of S32504 and pramipexole against 1-methyl-4-phenylpyridinium in terminally differentiated SH-SY5Y cells.

Abstract

Anti-parkinsonian agents possessing both D(2) and D(3) receptor agonist properties are neuroprotective against 1-methyl-4-phenylpyridinium (MPP(+)) toxicity in a variety of in vitro models. The mechanisms underlying protection by these D(2)/D(3) receptor agonists remain poorly defined. To test if the D(3) receptor preferring agonists S32504 and pramipexole act through D(2) or D(3) receptors and via brain-derived neurotrophic factor (BDNF)-dependent pathways, we utilized a terminally differentiated neuroblastoma SH-SY5Y cell line exhibiting a dopaminergic phenotype. The cytotoxic effects of MPP(+) (LD(50) of 100 microM) were stereospecifically antagonized by S32504 (EC(50) = 2.0 microM) and, less potently, by pramipexole (EC(50) = 64.3 microM), but not by their inactive stereoisomers, R(+) pramipexole and S32601, respectively. Neuroprotective effects afforded by EC(50) doses of S32504 and pramipexole were antagonized by the selective D(3) antagonists S33084, U99194A, and SB269652, and by the D(2)/D(3) antagonist raclopride. However, the preferential D(2) receptor antagonist LY741626 was ineffective as was the D1 antagonist SCH23390. BDNF (1 nM) potently protected against MPP(+)-induced neurotoxicity. Antibody directed against BDNF concentration-dependently blocked both the neuroprotective effects of BDNF and those of pramipexole and S32504 against MPP(+). The protection afforded by BDNF was blocked by the P3K-AKT pathway inhibitor LY249002 and less so by the MEK/MAPKK pathway inhibitor PD98059. LY249002, but not PD98059, blocked the neuroprotective effects of pramipexole and S32504 against MPP(+) toxicity. In conclusion, S32504 and, less potently, pramipexole show robust, stereospecific, and long-lasting neuroprotective effects against MPP(+) toxicity that involve D(3) receptors. Their actions also reflect downstream recruitment of BDNF and via a PK3-AKT pathway.

• Authors: Steve P Presgraves, Sabine Borwege, Mark J Millan, Jeffrey N Joyce
• Journal: Experimental neurology (Exp Neurol) Vol. 190 Issue 1 Pg. 157-70 (Nov 2004) ISSN: 0014-4886 [Print] United States
• PMID: 15473989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies
• Benzothiazoles
• Brain-Derived Neurotrophic Factor
• DRD3 protein, human
• Dopamine Agonists
• Dopamine Antagonists
• Dopamine D2 Receptor Antagonists
• Enzyme Inhibitors
• Neuroprotective Agents
• Oxazines
• Receptors, Dopamine D2
• Receptors, Dopamine D3
• S 32504
• Thiazoles
• Tretinoin
• Pramipexole
• Tetradecanoylphorbol Acetate
• 1-Methyl-4-phenylpyridinium

Topics

• 1-Methyl-4-phenylpyridinium (antagonists & inhibitors, toxicity)
• Antibodies (pharmacology)
• Benzothiazoles
• Brain-Derived Neurotrophic Factor (antagonists & inhibitors, metabolism, pharmacology)
• Cell Differentiation (drug effects)
• Cell Line
• Dopamine Agonists (pharmacology)
• Dopamine Antagonists (pharmacology)
• Dopamine D2 Receptor Antagonists
• Enzyme Inhibitors (pharmacology)
• Humans
• Neuroblastoma
• Neurons (cytology, drug effects, metabolism)
• Neuroprotective Agents (pharmacology)
• Oxazines (antagonists & inhibitors, pharmacology)
• Pramipexole
• Receptors, Dopamine D2 (agonists, metabolism)
• Receptors, Dopamine D3
• Tetradecanoylphorbol Acetate (pharmacology)
• Thiazoles (antagonists & inhibitors, pharmacology)
• Tretinoin (pharmacology)