Pharmacokinetic, neurochemical, stereological and neuropathological studies on the potential effects of paraquat in the substantia nigra pars compacta and striatum of male C57BL/6J mice

Neurotoxicology. 2013 Jul:37:1-14. doi: 10.1016/j.neuro.2013.03.005. Epub 2013 Mar 21.

Abstract

The pharmacokinetics and neurotoxicity of paraquat dichloride (PQ) were assessed following once weekly administration to C57BL/6J male mice by intraperitoneal injection for 1, 2 or 3 weeks at doses of 10, 15 or 25 mg/kg/week. Approximately 0.3% of the administered dose was taken up by the brain and was slowly eliminated, with a half-life of approximately 3 weeks. PQ did not alter the concentration of dopamine (DA), homovanillic acid (HVA) or 3,4-dihydroxyphenylacetic acid (DOPAC), or increase dopamine turnover in the striatum. There was inconsistent stereological evidence of a loss of DA neurons, as identified by chromogenic or fluorescent-tagged antibodies to tyrosine hydroxylase in the substantia nigra pars compacta (SNpc). There was no evidence that PQ induced neuronal degeneration in the SNpc or degenerating neuronal processes in the striatum, as indicated by the absence of uptake of silver stain or reduced immunolabeling of tyrosine-hydroxylase-positive (TH(+)) neurons. There was no evidence of apoptotic cell death, which was evaluated using TUNEL or caspase 3 assays. Microglia (IBA-1 immunoreactivity) and astrocytes (GFAP immunoreactivity) were not activated in PQ-treated mice 4, 8, 16, 24, 48, 96 or 168 h after 1, 2 or 3 doses of PQ. In contrast, mice dosed with the positive control substance, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 10mg/kg/dose×4 doses, 2 h apart), displayed significantly reduced DA and DOPAC concentrations and increased DA turnover in the striatum 7 days after dosing. The number of TH(+) neurons in the SNpc was reduced, and there were increased numbers of degenerating neurons and neuronal processes in the SNpc and striatum. MPTP-mediated cell death was not attributed to apoptosis. MPTP activated microglia and astrocytes within 4 h of the last dose, reaching a peak within 48 h. The microglial response ended by 96 h in the SNpc, but the astrocytic response continued through 168 h in the striatum. These results bring into question previous published stereological studies that report loss of TH(+) neurons in the SNpc of PQ-treated mice. This study also suggests that even if the reduction in TH(+) neurons reported by others occurs in PQ-treated mice, this apparent phenotypic change is unaccompanied by neuronal cell death or by modification of dopamine levels in the striatum.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacokinetics
  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Basal Ganglia / drug effects*
  • Basal Ganglia / metabolism
  • Basal Ganglia / pathology
  • Cell Death / drug effects
  • Dopamine / metabolism
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Half-Life
  • Herbicides / administration & dosage
  • Herbicides / pharmacokinetics*
  • Herbicides / toxicity*
  • Homovanillic Acid / metabolism
  • Injections, Intraperitoneal
  • MPTP Poisoning / metabolism
  • MPTP Poisoning / pathology
  • Male
  • Metabolic Clearance Rate
  • Mice
  • Mice, Inbred C57BL
  • Microglia / drug effects
  • Microglia / metabolism
  • Microglia / pathology
  • Nerve Degeneration
  • Paraquat / administration & dosage
  • Paraquat / pharmacokinetics*
  • Paraquat / toxicity*
  • Substantia Nigra / drug effects*
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Herbicides
  • 3,4-Dihydroxyphenylacetic Acid
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Tyrosine 3-Monooxygenase
  • Paraquat
  • Dopamine
  • Homovanillic Acid