A Monoclonal Anti-HMGB1 Antibody Attenuates Neurodegeneration in an Experimental Animal Model of Glaucoma

Abstract

Neuroinflammation is a crucial process for the loss of retinal ganglion cells (RGC), a major characteristic of glaucoma. High expression of high-mobility group box protein 1 (HMGB1) plays a detrimental role in inflammatory processes and is elevated in the retinas of glaucoma patients. Therefore, this study aimed to investigate the effects of the intravitreal injection of an anti-HMGB1 monoclonal antibody (anti-HMGB1 Ab) in an experimental animal model of glaucoma. Two groups of Spraque Dawley rats received episcleral vein occlusion to chronically elevate intraocular pressure (IOP): (1) the IgG group, intravitreal injection of an unspecific IgG as a control, n = 5, and (2) the HMGB1 group, intravitreal injection of an anti-HMGB1 Ab, n = 6. IOP, retinal nerve fiber layer thickness (RNFLT), and the retinal flash response were monitored longitudinally. Post-mortem examinations included immunohistochemistry, microarray, and mass spectrometric analysis. RNFLT was significantly increased in the HMGB1 group compared with the IgG group (p < 0.001). RGC density showed improved neuronal cell survival in the retina in HMGB1 compared with the IgG group (p < 0.01). Mass spectrometric proteomic analysis of retinal tissue showed an increased abundance of RNA metabolism-associated heterogeneous nuclear ribonucleoproteins (hnRNPs), such as hnRNP U, D, and H2, in animals injected with the anti-HMGB1 Ab, indicating that the application of the antibody may cause increased gene expression. Microarray analysis showed a significantly decreased expression of C-X-C motif chemokine ligand 8 (CXCL8, p < 0.05) and connective tissue growth factor (CTGF, p < 0.01) in the HMGB1 group. Thus, these data suggest that intravitreal injection of anti-HMGB1 Ab reduced HMGB1-dependent inflammatory signaling and mediated RGC neuroprotection.

Intraocular Pressure-Induced Endothelial Dysfunction of Retinal Blood Vessels Is Persistent, but Does Not Trigger Retinal Ganglion Cell Loss

“…EVO has been widely used as a method in studies of glaucoma rodents [ 11 , 23 ], leading to significant RGC loss to imitate neurodegeneration in glaucoma [ 20 , 24 ]. In a previous study of our own [ 8 ], we found that IOP elevation also impairs vascular endothelial function and autoregulation.…”

“…Optic nerve degeneration was assessed by p-phenylenediamine (PPD)-stained optic nerve cross sections, as previously described [ 19 , 20 ]. The semi-thin cross sections of optic nerves were taken from 1.0 mm posterior to the eyeballs.…”

Secreted phosphoprotein 1 slows neurodegeneration and rescues visual function in mouse models of aging and glaucoma

“…Neuroinflammation is observed in human glaucomatous optic nerves and retinas, 54 and it is a common feature of animal models of the disease. 55 – 57 Aging, a major risk factor for glaucoma, leads to chronic low-grade inflammation of the CNS. 58 In Spp1 KO astrocytes, production of inflammatory mediators is chronically elevated, even at a young age, whereas the neurotrophic factors are down-regulated.…”

Synthetic antibody-derived immunopeptide provides neuroprotection in glaucoma through molecular interaction with retinal protein histone H3.1

“…Furthermore, newest findings demonstrate the great potential of caffeine for RGC neuroprotection with its anti-inflammatory and anti-oxidative properties (4) illustrating new perspectives for the medical management of retinal diseases in the future. In accordance with that, our research group focuses the application of antibody-based immunotherapeutics as promising starting point for the treatment of glaucoma, which specifically target pathogenic key molecules in the retina such as HMGB1 (5) or α-synuclein (6) and provide ocular neuroprotection by different modes of action. Since the pharmaceutical trend nowadays is toward the development of small drug compounds with enhanced bioactivity (7), the downsizing of large biomolecules and the restriction to only biologically active binding sites has become of great interest for clinical manufacturing.…”