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.
Highlights
The small natural molecule glycyrrhizin, a component from liquorice root which can directly bind to High-mobility group box 1 (HMGB1), both suppressed MPTP-induced HMGB1 and receptor for advanced glycation endproducts (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 Parkinson's disease (PD), suggesting that HMGB1 is a suitable target for neuroprotective trials in PD
Levels of a RAGE co-ligand, S100B (Sathe et al, 2012), were not significantly altered. This is, to the best of our knowledge, the first study (i) showing in vivo evidence that HMGB1 protein levels are altered in patients with PD and that blocking HMGB1 in an animal model of PD is neuroprotective, (ii) providing evidence of how HMGB1 contributes to the progression of the disease by causing activation of microglia and increased gliosis in the substantia nigra pars compacta (SNpc), and (iii) demonstrating that the damaging effects of HMGB1 can be reduced by administration of the naturally occurring HMGB1-binding compound glycyrrhizin
macrophage antigen complex 1 (Mac1) expressed on the surface of microglia is a promising candidate for additional HMGB1-mediated dopaminergic toxicity, as HMGB1 has recently been shown to induce the production of multiple inflammatory and neurotoxic factors via microglial Mac1 (Gao et al, 2011), and neutralization of HMGB1 as performed in this study dramatically reduced MPTP-induced gliosis
Summary
HMGB1 can be secreted actively from inflammatory cells but is released in greater amounts passively from dying cells during tissue damage and inflammatory disease and can act as a damage associated molecular pattern (DAMP) to initiate inflammatory responses (Andersson and Tracey, 2011). This mechanism may be relevant for PD as a recent study elegantly demonstrated that: by use of cell models reflecting PD pathophysiology HMGB1 signalling triggered progressive dopaminergic neurodegeneration by uncontrolled chronic inflammation (Gao et al, 2011).
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