The potentiating effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on paraquat-induced neurochemical and behavioral changes in mice.
Although the etiology of Parkinson's disease (PD) is not fully understood, there are numerous studies that have linked the increased risk for developing PD to pesticides exposure including paraquat (PQ). Moreover, the exposure to a combination of compounds or chemical mixtures has been suggested to further increase this risk. In the current study, the effects of PQ on the nigrostriatal dopaminergic system in male C57BL6 mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were examined to assess the impact of toxic substance mixtures exposure on neurochemical and behavioral changes. In this study, a low non-toxic dose of MPTP (10mg/kg) was injected once a day for 5 days and was followed by PQ (7 mg/kg) once a day for 6 days (subacute protocol) or once a week for 10 weeks (chronic protocol). The results from the subacute protocol showed that PQ reduced the turnover of dopamine (DA) as indicated by a 21% and a 22.3% decrease in dihydroxyphenyl acetic acid (DOPAC), homovanillic acid and increased S-adenosyl methionine/S-adenosyl homocysteine index (SAM/SAH) by 100%. However, the administration of PQ to MPTP primed mice resulted in the decrease of DOPAC, HVA, DA, by 35.8%, 35.2% and 22.1%, respectively. In addition, PQ decreased the total number of movements (TM) by 28% but MPTP plus PQ decreased TM by 41%. The SAM/SAH index showed that MPTP increased methylation by 33.3%, but MPTP plus PQ increased methylation by 81%. In the chronic protocol, the data showed that MPTP administration did not affect DA, DOPAC, and HVA levels. The administration of PQ led to significant decrease in DOPAC, HVA, and TD by 31.6%, 19.9%, and 21.2% respectively with no effect on DA levels. The MPTP plus PQ group showed reduced DA, DOPAC, HVA, and total distance traveled by 58.4%, 82.8%, 55.8%, and 83.9%, respectively. Meanwhile, PQ administration caused a reduction in tyrosine hydroxylase immunoreactivity in the substantia nigra, and this effect was more pronounced in MPTP pretreated mice. It was concluded from this study that prior treatment with MPTP potentiated the effects of PQ in reducing DA, DOPAC, HVA, TH immunoreactivity, locomotor activity, and increasing the methylation index. The enhanced effects of PQ following MPTP administration further support the role of toxic substance mixtures in causing Parkinson's disease.
College of Pharmacy and Pharmaceutical Sciences Florida A&M University, Tallahassee, FL 32307, USA. krsheph@emory.edu
K Raviie
KR
Shepherd
Eun-Sook Y
ES
Lee
Larry
L
Schmued
Yun
Y
Jiao
Syed F
SF
Ali
Ebenezer T
ET
Oriaku
Nazarius S
NS
Lamango
Karam F A
KF
Soliman
Clivel G
CG
Charlton
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism; D004357:Drug Synergism; D006540:Herbicides / Q000008:administration & dosage / Q000633:toxicity; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D020267:MPTP Poisoning / Q000209:etiology* / Q000378:metabolism / Q000523:psychology*; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009498:Neurotoxins / Q000008:administration & dosage / Q000633:toxicity*; D010269:Paraquat / Q000008:administration & dosage / Q000633:toxicity*
D006540:Herbicides; D009498:Neurotoxins; D015102:3,4-Dihydroxyphenylacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D010269:Paraquat; D004298:Dopamine; D006719:Homovanillic Acid