Novel Compositions to Protect Against Neurodegenerative Inflammation

Background

Parkinson’s disease (PD) is a severely debilitating movement disorder resulting from progressive degeneration of dopaminergic neurons. Unfortunately, pharmacologic treatment for PD has not progressed beyond the use of dopamine mimetics, such as L-dopa, that only transiently alleviate motor symptoms.  Furthermore, chronic use of L-dopa is associated with its own array of resultant pathologies. Ultimately, individuals suffering from PD will progress to the end stage of the disease, which is characterized by significant gait abnormalities and frequent falls, as well as a deficit in non-motor functions resulting in dementia, psychosis, and other autonomic disturbances. Over 1.5 million individuals are currently diagnosed with PD, with an additional 50,000 expected diagnoses annually, making this disease the second most prevalent neurological disorder behind Alzheimer’s disease.

While the reason for selective neuronal loss in PD remains poorly explained, chronic inflammation and activation of glial cells has been consistently observed in PD models as well as following postmortem evaluation and provide a realistic target for slowing the progression of neuronal injury.

Benefits

• Protection of neuronal cells by reducing inflammatory activation of glial cells
• Diindolylmethane-class compounds are derived from cruciferous vegetables and have demonstrated very low toxicities
• Protection against neurodegenerative inflammation by targeting the nuclear receptor, Nurr1
• Pre-clinical data includes in vivo efficacy, molecular target verification, pharmacokinetic and safety studies

Publications

Popichak, Katriana A., et al. “Compensatory Expression of Nur77 and Nurr1 Regulates NF-ΚB–Dependent Inflammatory Signaling in Astrocytes.” Molecular Pharmacology, American Society for Pharmacology and Experimental Therapeutics, 1 Oct. 2018, molpharm.aspetjournals.org/content/94/4/1174.

Afzali MF, Popichak KA, Burton LH, Klochak AL, Wilson WJ, Safe S, Tjalkens RB, Legare ME. A novel diindolylmethane analog, 1,1-bis(3′-indolyl)-1-(p-chlorophenyl) methane, inhibits the tumor necrosis factor-induced inflammatory response in primary murine synovial fibroblasts through a Nurr1-dependent mechanism. Mol Immunol. 2018 Sep;101:46-54. doi: 10.1016/j.molimm.2018.05.024. Epub 2018 Jun 2. PMID: 29870816; PMCID: PMC6138555.

Hammond, Sean L., et al. “The Nurr1 Ligand,1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane, Modulates Glial Reactivity and Is Neuroprotective in MPTP-Induced Parkinsonism.” Journal of Pharmacology and Experimental Therapeutics, American Society for Pharmacology and Experimental Therapeutics, 1 June 2018, jpet.aspetjournals.org/content/365/3/636.

Hammond, Sean L., et al. “A Novel Synthetic Activator of Nurr1 Induces Dopaminergic Gene Expression and Protects against 6-Hydroxydopamine Neurotoxicity in Vitro.” Neuroscience Letters, Elsevier, 14 Sept. 2015, www.sciencedirect.com/science/article/pii/S0304394015301415?via%3Dihub.

Miranda, Briana R. De, et al. “The Nurr1 Activator 1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane Blocks Inflammatory Gene Expression in BV-2 Microglial Cells by Inhibiting Nuclear Factor ΚB.” Molecular Pharmacology, American Society for Pharmacology and Experimental Therapeutics, 1 June 2015, molpharm.aspetjournals.org/content/87/6/1021.

Safe, Stephen, et al. “Nuclear Receptor 4A (NR4A) Family – Orphans No More.” The Journal of Steroid Biochemistry and Molecular Biology, Pergamon, 23 Apr. 2015, www.sciencedirect.com/science/article/pii/S0960076015001132?via%3Dihub.

De Miranda, Briana R., et al. “Novel Para -Phenyl Substituted Diindolylmethanes Protect Against MPTP Neurotoxicity and Suppress Glial Activation in a Mouse Model of Parkinson’s Disease.” OUP Academic, Oxford University Press, 17 Nov. 2014, academic.oup.com/toxsci/article/143/2/360/1676838.

De Miranda BR, Miller JA, Hansen RJ, Lunghofer PJ, Safe S, Gustafson DL, Colagiovanni D, Tjalkens RB. Neuroprotective efficacy and pharmacokinetic behavior of novel anti-inflammatory para-phenyl substituted diindolylmethanes in a mouse model of Parkinson’s disease. J Pharmacol Exp Ther. 2013 Apr;345(1):125-38. doi: 10.1124/jpet.112.201558. Epub 2013 Jan 14. Erratum in: J Pharmacol Exp Ther. 2019 Apr;369(1):66. PMID: 23318470; PMCID: PMC6067390.

Last updated: Sept 2021