Neuroprotective efficacy and pharmacokinetic behavior of novel anti-inflammatory para-phenyl substituted diindolylmethanes in a mouse model of Parkinson's disease

Document Type

Article

Abstract

There are currently no registered drugs that slow the progression of neurodegenerative diseases, in part because translation from animal models to the clinic has been hampered by poor distribution to the brain. The present studies examined a selected series of para-phenyl-substituted diindolylmethane (C-DIM) compounds that display anti-inflammatory and neuroprotective efficacy in vitro. We postulated that the pharmacokinetic behavior of C-DIM compounds after oral administration would correlate with neuroprotective efficacy in vivo in a mouse model of Parkinson's disease. Pharmacokinetics and metabolism of 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane (C-DIM5), 1,1-bis(3'-indolyl)-1-(phenyl)methane, 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (C-DIM8), and 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) were determined in plasma and brain of C57Bl/6 mice after oral and intravenous administration at 10 and 1 mg/Kg, respectively. Putative metabolites were measured in plasma, liver, and urine. C-DIM compounds given orally displayed the highest area under the curve, Cmax, and Tmax levels, and C-DIM12 exhibited the most favorable pharmacokinetics of the compounds tested. Oral bioavailability of each compound ranged from 6% (C-DIM8) to 42% (C-DIM12). After pharmacokinetic studies, the neuroprotective efficacy of C-DIM5, C-DIM8, and C-DIM12 (50 mg/Kg per oral) was examined in mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid for 14 days, a model of progressive neurodegeneration with a strong neuroinflammatory component. C-DIM5 and C-DIM12 given orally once daily after one week of exposure to MPTP and probenecid prevented further loss of dopaminergic neurons in the substantia nigra pars compacta and striatal dopamine terminals, indicating that these compounds could be effective therapeutic agents to prevent neurodegeneration.

Medical Subject Headings

Administration, Oral; Animals; Anti-Inflammatory Agents (chemistry, pharmacology, therapeutic use); Chromatography, High Pressure Liquid; Corpus Striatum (drug effects, pathology); Dopaminergic Neurons (drug effects, pathology); Indoles (chemistry, pharmacokinetics, therapeutic use); Injections, Intravenous; Male; Mice; Mice, Inbred C57BL; Microsomes, Liver (drug effects, metabolism); Molecular Structure; Neuroprotective Agents (chemistry, pharmacokinetics, therapeutic use); Parkinsonian Disorders (drug therapy, metabolism, pathology); Tandem Mass Spectrometry

Publication Date

4-1-2013

Publication Title

The Journal of pharmacology and experimental therapeutics

E-ISSN

1521-0103

Volume

345

Issue

1

First Page

125

Last Page

38

PubMed ID

23318470

Digital Object Identifier (DOI)

10.1124/jpet.112.201558

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