Santoro Matteo
University of Aberdeen, UK
Title: Inhibition of high mobility group box 1 (HMGB1) as a neuroprotective treatment in the MPTP mouse model of Parkinson’s disease.
Biography
Biography: Santoro Matteo
Abstract
Background: 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 is implicated in the progression of numerous chronic inflammatory and autoimmune diseases. 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 cell degeneration and chronic neuroinflammation both of which underlie the mechanistic basis of PD progression.
Materials & Methods: Pharmacological trials - Male mice C57BL6J ten weeks old were randomly divided in four experimental groups (n=5 per group). i) saline control group, ii) MPTP treated groups (sub-acute regimen 30 mg/kg of MPTP intraperitoneally (i.p.) once a day for five consecutive days), iii) MPTP treated group plus i.p. dose of 50mg/kg glycyrrhizin, iv) MPTP treated group plus i.p. dose of 200 ug HMGB1 neutralizing antibody. HMGB1 nuclear translocation was assessed in mice and human brain tissue via co-immunolocalization in three different nigral cell populations: tyrosine hydroxylase (TH) positive neurons, microglia and astrocytes. Western blotting was performed on protein samples extracted from ventral midbrain.
Results: In a mouse model of PD induced by sub-acute administration of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) 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.
Conclusion: HMGB1 serves as a powerful bridge between progressive dopaminergic neurodegeneration and chronic neuroinflammation in a model of PD, and suggest that HMGB1 is a suitable target for neuroprotective trials in PD.