Inhibition of platelet aggregation by 1-methyl-4-phenyl pyridinium ion (MPP+) through ATP depletion: Evidence for the reduced platelet activities in Parkinson's disease.
Neuronal accumulation of 1-methyl-4-phenylpyridinium ion (MPP(+)), the metabolite of neural toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP), induces a rapid depletion of cellular ATP level and loss of neuronal cell viability which simulates human Parkinson's disease (PD). Since ATP plays an important role in the physiology and function of platelets, which share many biochemical and physiological features with neuronal cells, we examined the effect of MPP(+) on platelet aggregation and viability using freshly isolated rat platelets. While the treatment of MPP(+) to platelets did not induce cytotoxicity, it significantly attenuated agonist-induced platelet aggregation in a concentration dependent manner. The inhibition of aggregation by MPP(+) was mediated by the depletion of the cytoplasmic ATP pool and resultant decreased ATP secretion. Different from the previous reports in neuronal cells, MPP(+) did not affect intracellular levels of glutathione and cytoplasmic Ca(2+) in platelets. The combined treatment with MPP(+) and 2-deoxyglucose, a glycolysis inhibitor, showed the additive effect in the decrease of ATP secretion and intracellular content. Consistent with these findings, inhibitory effects of MPP(+) on platelet aggregation was significantly enhanced by the treatment with 2-deoxyglucose. In conclusion, these results suggested that MPP(+) can induce ATP depletion in platelets and attenuate platelet aggregation providing a new theory on the reduced platelet activities in PD patients.
College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Kyung-Min
KM
Lim
Hyun-Hee
HH
Kim
Ok-Nam
ON
Bae
Ji-Yoon
JY
Noh
Keun-Young
KY
Kim
Sae-Hwan
SH
Kim
Seung-Min
SM
Chung
Sue
S
Shin
Hyeon-Yeong
HY
Kim
Jin-Ho
JH
Chung
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000097:blood; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D005978:Glutathione / Q000097:blood; D066298:In Vitro Techniques; D010300:Parkinson Disease / Q000097:blood*; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000255:Adenosine Triphosphate; D003094:Collagen; D003847:Deoxyglucose; D005978:Glutathione; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium