Toxicological Sciences, Vol 48, 107-116, Copyright © 1999 by Society of Toxicology
AC Kuhlmann and TR Guilarte
We used the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP) to evaluate the sensitivity and specificity of
the peripheral benzodiazepine receptor (PBR) as a biomarker of
chemical-induced neurotoxicity. Receptor autoradiography of [3H]- PK11195,
a PBR selective ligand, indicated dose-dependent increases throughout the
nigrostriatal dopaminergic system as early as 24 h after MPTP
administration (10-80 mg/kg), which persisted for at least 21 days. The
binding of [3H]-PK11195 was increased as much as 98% in the corpus striatum
and 114% in the substantia nigra, following MPTP exposure. The integrity of
nigrostriatal dopaminergic terminals in the corpus striatum was assessed by
measuring high affinity dopamine transporter (DAT) levels and dopamine
content. DAT levels were measured by [3H]-WIN 35,428 autoradiography, and
dopamine content decreased with increasing MPTP dose. Reductions of both
indices of dopaminergic terminal integrity correlated with increased levels
of [3H]-PK11195- binding in the striatum (r2 = 0.84 for DAT and 0.93 for
dopamine content). Tyrosine hydroxylase (TH) immunohistochemistry
demonstrated dose-dependent reductions of dopaminergic neurons in the
substantia nigra pars compacta, with a 67% loss measured 7 days after
treatment with 80 mg/kg MPTP. The loss of TH-positive neurons was
correlated (r2 = 0.95) with increased levels of [3H]-PK11195 binding in the
substantia nigra. These findings demonstrate that the PBR is both sensitive
and specific for identifying brain regions involved in MPTP neurotoxicity.
ARTICLES
Regional and temporal expression of the peripheral benzodiazepine receptor in MPTP neurotoxicity
Department of Environmental Health Sciences, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland, USA.
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