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Tissue concentrations of MPTP and MPP+ after administration of lethal and sublethal doses of MPTP to mice
R W Fuller1, S K Hemrick-Luecke
1Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.
Abstract:
Tissue concentrations of MPP+ (1-methyl-4-phenylpyridinium) were measured in Charles River CFW mice after administration of high doses of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) or MPP+ given subcutaneously or orally, to investigate the relationships between tissue concentrations and lethality resulting from these compounds. MPTP given subcutaneously led to much higher concentrations of MPP+ in brain and somewhat higher concentrations of MPP+ in peripheral tissues than did MPTP given orally. MPTP caused no lethality at oral doses up to 160 mg/kg whereas subcutaneous MPTP had an LD50 of 54 mg/kg. Deprenyl pretreatment antagonized the lethality of subcutaneous MPTP and reduced MPP+ concentrations in brain and in other tissues after MPTP injection. Deprenyl caused a greater and longer-lasting inhibition of MPTP oxidation than of phenylethylamine oxidation, especially in liver, although both compounds are thought to be oxidized by monoamine oxidase type B. The protective effect of deprenyl against MPTP lethality implicates MPP+ (or possibly some other metabolite) in the lethality after MPTP injection. The reduced lethality of MPTP when given orally and the relative lack of brain levels of MPTP or MPP+ after oral MPTP implicate the brain as a target organ in the lethality of MPTP. Lethality after MPP+ administration almost certainly does not involve the brain, since little or no MPP+ could be measured in brain after oral or subcutaneous dosing of MPP+.
Insights
Subcutaneous administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) resulted in higher MPP+ (1-methyl-4-phenylpyridinium) brain concentrations and lethality compared to oral dosing. Deprenyl pretreatment protected against MPTP toxicity.
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin implicated in Parkinsonism.
- 1-methyl-4-phenylpyridinium (MPP+) is the active metabolite of MPTP.
- Understanding the pharmacokinetics and toxicokinetics of MPTP and MPP+ is crucial for assessing their toxicity.
Purpose of the Study:
- To investigate the relationship between tissue concentrations of MPP+ and lethality following MPTP or MPP+ administration.
- To compare the effects of subcutaneous versus oral administration of MPTP and MPP+.
- To evaluate the protective effect of deprenyl against MPTP-induced toxicity.
Main Methods:
- Tissue concentrations of MPP+ were measured in mice after subcutaneous or oral administration of MPTP or MPP+.
- Lethality was assessed at various doses.
- Deprenyl pretreatment was used to investigate its protective effects and impact on MPP+ levels.
Main Results:
- Subcutaneous MPTP administration led to significantly higher brain MPP+ concentrations and lethality compared to oral MPTP.
- Oral MPTP caused no lethality at doses up to 160 mg/kg, with minimal brain MPP+ levels.
- Deprenyl pretreatment reduced MPP+ concentrations and antagonized MPTP-induced lethality, implicating MPP+ in toxicity.
- MPP+ administration did not result in significant brain MPP+ levels or lethality, suggesting the brain is not a primary target for MPP+ toxicity.
Conclusions:
- The route of administration significantly impacts MPTP's pharmacokinetic profile and subsequent toxicity.
- MPTP lethality is associated with brain MPP+ accumulation, highlighting the brain as a critical target organ.
- Deprenyl exhibits protective effects against MPTP toxicity, likely through inhibition of MPTP oxidation.