PT  - JOURNAL ARTICLE
AU  - Briana R. De Miranda
AU  - James A. Miller
AU  - Ryan J. Hansen
AU  - Paul J. Lunghofer
AU  - Stephen Safe
AU  - Daniel L. Gustafson
AU  - Dorothy Colagiovanni
AU  - Ronald B. Tjalkens
TI  - Neuroprotective Efficacy and Pharmacokinetic Behavior of Novel Anti-Inflammatory <em>Para</em>-Phenyl Substituted Diindolylmethanes in a Mouse Model of Parkinson’s Disease
AID  - 10.1124/jpet.112.201558
DP  - 2013 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 125--138
VI  - 345
IP  - 1
4099  - http://jpet.aspetjournals.org/content/345/1/125.short
4100  - http://jpet.aspetjournals.org/content/345/1/125.full
SO  - J Pharmacol Exp Ther2013 Apr 01; 345
AB  - 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.