HMGB1 links neuroinflammation and mitochondrial dysfunction in an MPTP-induced zebrafish model of Parkinsonism

Introduction: Parkinson’s disease (PD) is the most prevalent movement disorder, with global prevalence increasing by 153% since 1990. It is characterized by dopaminergic neuronal loss in the substantia nigra, driven in part by mitochondrial dysfunction and neuroinflammation. High-mobility group box 1 (HMGB1), a nuclear protein that acts as a damage-associated molecular pattern (DAMP) upon extracellular release, has been implicated in both processes, yet its role in PD remains underexplored. Hence, this study aims to investigate the role of HMGB1 and the effects of its inhibition in a zebrafish model of parkinsonism. Materials and methods: Adult zebrafish were administered a single dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) via intraperitoneal (i/p) injection, followed by two doses of glycyrrhizin, an HMGB1 inhibitor, at day 1 and day 2 post-MPTP exposure. At day 3 post-injection, locomotor activity, gene expression, tissue morphology, and blood–brain barrier (BBB) permeability were assessed. Results: HMGB1 inhibition improved locomotor deficits, reduced gene expression of inflammatory mediators: toll-like receptor 4b duplicate a (tlr4ba), nuclear factor kappa light polypeptide gene enhancer in B-cells 1 (nfκb), tumor necrosis factor alpha (tnfα), interleukin-1β (il1β), normalized mitochondrial quality control markers: PTEN-induced kinase 1 (pink1), parkin RBR E3 ubiquitin protein ligase (prkn), fission mitochondrial 1 (fis1), and attenuated BBB disruption. However, morphological alterations in the posterior tuberculum and subpallium regions of the brain persisted. Additionally, in silico analyses showed strong molecular interactions between 1-methyl-4-phenylpyridinium (MPP+) and dopamine transporter, as well as glycyrrhizin to HMGB1 in zebrafish, supporting translational relevance. Conclusions: These findings suggest that HMGB1 is closely associated with the intersection of neuroinflammation and mitochondrial dysfunction in MPTP-induced parkinsonism. Modulating HMGB1 pathways helps mitigate these downstream functional and molecular impairments, highlighting its potential utility as an indirect biomarker and therapeutic target. Ultimately, this study supports the translational value of the zebrafish PD model for investigating complex neurodegenerative mechanisms.