The Temporal Dynamics of Pathological Profile and Functional Impairment in Neuromyelitis Optica Spectrum Disorders associated Optic Neuritis

Background Optic neuritis (ON) linked to Neuromyelitis Optica Spectrum Disorders (NMOSD), particularly in Asians, causes irreversible vision loss. The lack of comprehensive analysis that tracks the progression of changes over time hinders the identification of optimal timeframes for observation and intervention of the disease. Our aim is to map disease progression histologically and functionally in an optimized Neuromyelitis Optica Spectrum Disorders associated Optic Neuritis (NMOSD-ON) animal model. Materials and Methods The animals in the NMOSD-ON group involved the injections of aquaporin-4-immunoglobulin G (AQP4-IgG) and human complement into the posterior optic nerve, separated by 24 hours, repeated twice. The control group received injections of normal immunoglobulin G (normal IgG) and human complement. Histological analyses examined the immunoreactivity of aquaporin-4 (AQP4) protein, glial fibrillary acidic protein (GFAP) protein (maker of astrocytes), microglial activation, myelin oligodendrocyte glycoprotein (MOG) (maker of myelin sheath), and degeneration of retinal ganglion cells (RGCs), along with gene expression profiling of inflammatory cytokines at various time points (Baseline, Day 2, Week 1, Week 2, Week 4). In-vivo visual functional and retinal structural assessments were performed weekly up to Week 4 to track disease progression. Results Administration of AQP4-IgG and human complement triggered a series of events in mice with NMOSD-ON, leading to early changes in astrocyte pathology (loss of AQP4 and GFAP staining), upregulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), CXCL10, brain-derived neurotrophic factor (BDNF) and microglia activation in Week 1. This was followed by demyelination, culminating in damage to RGCs and nerve fibers in Week 2. Functionally, the delays of visual evoked potential N1 latency were detectable from Week 2, with reduced N1P1 amplitudes by Week 2. For the electroretinogram, the postive scotopic threshold response (pSTR) amplitude decreased at Week 2, while scotopic a- and b-wave amplitudes remained unchange, which corresponded to the retinal nerve fibre layer thinning in the in-vivo retinal structural scan commencing at Week 2. Conclusion This study outlines the progression timeline of NMOSD-ON disease and connects histological and molecular findings to retinal structural changes, in-vivo functional impariment following NMOSD-ON onset in an optimized animal model.