title: Neuroprotective efficacy and pharmacokinetic behavior of novel anti-inflammatory para-phenyl substituted diindolylmethanes in a mouse model of Parkinson's disease.
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.
authors: Center for Environmental Medicine, Department of Environmental and Radiological Health Sciences, Animal Cancer Center, Colorado State University, Fort Collins, Colorado 80523-1680, USA.
authors: Briana R
authors: BR
authors: De Miranda
authors: James A
authors: JA
authors: Miller
authors: Ryan J
authors: RJ
authors: Hansen
authors: Paul J
authors: PJ
authors: Lunghofer
authors: Stephen
authors: S
authors: Safe
authors: Daniel L
authors: DL
authors: Gustafson
authors: Dorothy
authors: D
authors: Colagiovanni
authors: Ronald B
authors: RB
authors: Tjalkens
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053719:Tandem Mass Spectrometry
chemical_list: D000893:Anti-Inflammatory Agents; D007211:Indoles; D018696:Neuroprotective Agents; C016392:3,3'-diindolylmethane