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.

TracMouse: A computer aided movement analysis script for the mouse inverted horizontal grid test

“…Only a small cohort of mice was tested for feasibility and sensitivity of method, but more routine studies will follow in the future. Clearly, our histopathological analysis confirmed the significant lowering of striatal dopamine and loss of substantia nigra neurons as pertinent for Parkinsonian models242526. This resulted in a heightened number and distance covered by forepaw movements relative to controls.…”

The Role of HMGB1 in Pial Arteriole Dilating Reactivity following Subarachnoid Hemorrhage in Rats

“…HMGB1 is a central player in the inflammatory network because it can be induced by a number of cytokines, and itself induces a series of inflammatory reactions [3]. The activation of both RAGE and TLR4 can induce neuroinflammation, contributing to the development of neurodegenerative diseases [4,5,6]. Neuroinflammation has also been associated with the induction of cerebral vasoconstriction following subarachnoid hemorrhage (SAH) [7,8,9].…”

High‐mobility group box 1 in Parkinson's disease: from pathogenesis to therapeutic approaches

“…Additionally, HMGB1 can elicit pro‐inflammatory responses via its interaction with multi‐ligand receptors including the receptor for advanced glycation end products (RAGE) and toll‐like receptor (TLR) 2 and 4 (Santoro et al . ). In the nucleus, HMGB1 acts as a non‐histone chromatin‐binding protein, regulating several interactions of transcription factors with DNA as well as contributing to genome stability and DNA repair (Balliano et al .…”