17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) Is Neuroprotective and Reduces Motor Impairment and Neuroinflammation in a Murine MPTP Model of Parkinson’s Disease
17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) is a synthetic androstenetriol in Phase II clinical development for the treatment of inflammatory diseases. HE3286 was evaluated for blood-brain barrier (BBB) permeability in mice, and efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP...
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| Format: | Article |
| Language: | English |
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Wiley
2012-01-01
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| Series: | Parkinson's Disease |
| Online Access: | http://dx.doi.org/10.1155/2012/969418 |
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| author | Ferdinando Nicoletti Ingrid Philippens Paolo Fagone Clarence N. Ahlem Christopher L. Reading James M. Frincke Dominick L. Auci |
| author_facet | Ferdinando Nicoletti Ingrid Philippens Paolo Fagone Clarence N. Ahlem Christopher L. Reading James M. Frincke Dominick L. Auci |
| author_sort | Ferdinando Nicoletti |
| collection | DOAJ |
| description | 17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) is a synthetic androstenetriol in Phase II clinical development for the treatment of inflammatory diseases. HE3286 was evaluated for blood-brain barrier (BBB) permeability in mice, and efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson’s disease (PD). We found that HE3286 freely penetrated the BBB. HE3286 treatment significantly improved motor function compared to vehicle in the rotarod test (mean 58.2 sec versus 90.9 sec, P<0.0001), and reduced inflammatory mediator gene expression in the brain (inducible nitric oxide synthase, 20%, P=0.002; tumor necrosis factor α, 40%, P=0.038, and interleukin-1β, 33%, P=0.02) measured by reverse-transcriptase polymerase chain reaction. Brain tissue histopathology and immunohistochemistry showed that HE3286 treatment increased the numbers of tyrosine hydroxylase-positive cells by 17% compared to vehicle (P=0.003), and decreased the numbers of damaged neurons by 38% relative to vehicle (P=0.029). L-3,4-dihydroxyphenylalanine (L-DOPA) efficacy was not enhanced by concurrent administration of HE3286. HE3286 administration prior to MPTP did not enhance efficacy. Our data suggest a potential role for HE3286 in PD treatment, and provides incentive for further investigation. |
| format | Article |
| id | doaj-art-87c6993dba6844f7a3e9081dda6e9584 |
| institution | Kabale University |
| issn | 2090-8083 2042-0080 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Parkinson's Disease |
| spelling | doaj-art-87c6993dba6844f7a3e9081dda6e95842025-02-03T05:47:47ZengWileyParkinson's Disease2090-80832042-00802012-01-01201210.1155/2012/96941896941817α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) Is Neuroprotective and Reduces Motor Impairment and Neuroinflammation in a Murine MPTP Model of Parkinson’s DiseaseFerdinando Nicoletti0Ingrid Philippens1Paolo Fagone2Clarence N. Ahlem3Christopher L. Reading4James M. Frincke5Dominick L. Auci6Department of Biomedical Sciences, School of Medicine, University of Catania, Via Androne 81, 95124 Catania, ItalyDepartment of Immunobiology, Biomedical Primate Research Centre, Lange Kleiweg 161, 2288 GJ Rijswijk, The NetherlandsDepartment of Biomedical Sciences, School of Medicine, University of Catania, Via Androne 81, 95124 Catania, ItalyHarbor Therapeutics, Inc., 9191 Towne Centre Drive, Suite 409, San Diego, CA 92122, USAHarbor Therapeutics, Inc., 9191 Towne Centre Drive, Suite 409, San Diego, CA 92122, USAHarbor Therapeutics, Inc., 9191 Towne Centre Drive, Suite 409, San Diego, CA 92122, USATumor Vaccine Group, School of Medicine, University of Washington, Seattle, WA 98109, USA17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) is a synthetic androstenetriol in Phase II clinical development for the treatment of inflammatory diseases. HE3286 was evaluated for blood-brain barrier (BBB) permeability in mice, and efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson’s disease (PD). We found that HE3286 freely penetrated the BBB. HE3286 treatment significantly improved motor function compared to vehicle in the rotarod test (mean 58.2 sec versus 90.9 sec, P<0.0001), and reduced inflammatory mediator gene expression in the brain (inducible nitric oxide synthase, 20%, P=0.002; tumor necrosis factor α, 40%, P=0.038, and interleukin-1β, 33%, P=0.02) measured by reverse-transcriptase polymerase chain reaction. Brain tissue histopathology and immunohistochemistry showed that HE3286 treatment increased the numbers of tyrosine hydroxylase-positive cells by 17% compared to vehicle (P=0.003), and decreased the numbers of damaged neurons by 38% relative to vehicle (P=0.029). L-3,4-dihydroxyphenylalanine (L-DOPA) efficacy was not enhanced by concurrent administration of HE3286. HE3286 administration prior to MPTP did not enhance efficacy. Our data suggest a potential role for HE3286 in PD treatment, and provides incentive for further investigation.http://dx.doi.org/10.1155/2012/969418 |
| spellingShingle | Ferdinando Nicoletti Ingrid Philippens Paolo Fagone Clarence N. Ahlem Christopher L. Reading James M. Frincke Dominick L. Auci 17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) Is Neuroprotective and Reduces Motor Impairment and Neuroinflammation in a Murine MPTP Model of Parkinson’s Disease Parkinson's Disease |
| title | 17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) Is Neuroprotective and Reduces Motor Impairment and Neuroinflammation in a Murine MPTP Model of Parkinson’s Disease |
| title_full | 17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) Is Neuroprotective and Reduces Motor Impairment and Neuroinflammation in a Murine MPTP Model of Parkinson’s Disease |
| title_fullStr | 17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) Is Neuroprotective and Reduces Motor Impairment and Neuroinflammation in a Murine MPTP Model of Parkinson’s Disease |
| title_full_unstemmed | 17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) Is Neuroprotective and Reduces Motor Impairment and Neuroinflammation in a Murine MPTP Model of Parkinson’s Disease |
| title_short | 17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) Is Neuroprotective and Reduces Motor Impairment and Neuroinflammation in a Murine MPTP Model of Parkinson’s Disease |
| title_sort | 17α ethynyl androst 5 ene 3β 7β 17β triol he3286 is neuroprotective and reduces motor impairment and neuroinflammation in a murine mptp model of parkinson s disease |
| url | http://dx.doi.org/10.1155/2012/969418 |
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