title: In-vivo evidence that high mobility group box 1 exerts deleterious effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model and Parkinson's disease which can be attenuated by glycyrrhizin.
abstract: High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is released during tissue damage from immune and non-immune cells - including microglia and neurons. HMGB1 can contribute to progression of numerous chronic inflammatory and autoimmune diseases which is mediated in part by interaction with the receptor for advanced glycation endproducts (RAGE). There is increasing evidence from in vitro studies that HMGB1 may link the two main pathophysiological components of Parkinson's disease (PD), i.e. progressive dopaminergic degeneration and chronic neuroinflammation which underlie the mechanistic basis of PD progression. Analysis of tissue and biofluid samples from PD patients, showed increased HMGB1 levels in human postmortem substantia nigra specimens as well as in the cerebrospinal fluid and serum of PD patients. In a mouse model of PD induced by sub-acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), systemic administration of neutralizing antibodies to HMGB1 partly inhibited the dopaminergic cell death, and reduced the increase of RAGE and tumour necrosis factor-alpha. The small natural molecule glycyrrhizin, a component from liquorice root which can directly bind to HMGB1, both suppressed MPTP-induced HMGB1 and RAGE upregulation while reducing MPTP-induced dopaminergic cell death in a dose dependent manner. These results provide first in vivo evidence that HMGB1 serves as a powerful bridge between progressive dopaminergic neurodegeneration and chronic neuroinflammation in a model of PD, suggesting that HMGB1 is a suitable target for neuroprotective trials in PD.
authors.affiliation: School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD Scotland, UK.
authors.forename: Matteo
authors.initials: M
authors.lastname: Santoro
authors.affiliation: Center of Neurology, Department of Neurodegeneration, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE) Tuebingen, Otfried-Müller-Str. 27, 72076 Tuebingen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Maetzler
authors.affiliation: School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD Scotland, UK.
authors.forename: Petros
authors.initials: P
authors.lastname: Stathakos
authors.affiliation: School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD Scotland, UK.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Martin
authors.affiliation: Center of Neurology, Department of Neurodegeneration, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE) Tuebingen, Otfried-Müller-Str. 27, 72076 Tuebingen, Germany.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Hobert
authors.affiliation: Center of Neurology, Department of Neurodegeneration, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE) Tuebingen, Otfried-Müller-Str. 27, 72076 Tuebingen, Germany.
authors.forename: Tim W
authors.initials: TW
authors.lastname: Rattay
authors.affiliation: Center of Neurology, Department of Neurodegeneration, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE) Tuebingen, Otfried-Müller-Str. 27, 72076 Tuebingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.affiliation: School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD Scotland, UK; Ocular Immunology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Western Australia 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia 6009, Australia.
authors.forename: John V
authors.initials: JV
authors.lastname: Forrester
authors.affiliation: Center of Neurology, Department of Neurodegeneration, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE) Tuebingen, Otfried-Müller-Str. 27, 72076 Tuebingen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Berg
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.affiliation: School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD Scotland, UK.
authors.forename: Gernot
authors.initials: G
authors.lastname: Riedel
authors.affiliation: School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD Scotland, UK. Electronic address: pteismann@gmx.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Teismann
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D019695:Glycyrrhizic Acid / Q000494:pharmacology*; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C582808:HMGB1 protein, mouse; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D019695:Glycyrrhizic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
keywords: High-mobility group box 1; MPTP; Parkinson's disease; receptor for advanced glycation endproducts