Investigating the Effects of the Kappa Opioid Receptor Agonist Nalfurafine, in a Mouse Model of Optic Nerve Demyelination

Optic neuritis is an inflammatory demyelinating disease of the optic nerve (ON) which is often associated with autoimmune diseases such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder. Its relationship with MS is closely interwoven, as optic neuritis is commonly the first clinical sign of MS and is experienced by 60-70% of MS patients in the course of their disease. Disease occurs when white matter lesions appear on the ON, leading to axonal loss and atrophy of the retinal nerve fibre layer, potentially leading to permanent vision loss despite the individual recovering from the acute immune attack. There is no cure for MS-associated optic neuritis, and current immunomodulatory treatments for MS and optic neuritis focus only on preventing attacks and slowing disease progression, not repairing the damage that has already been done.

Treatments targeting the oligodendrocyte lineage - responsible for myelination of the central nervous system - are promising due to their potential to drive remyelination. Recent preclinical studies using models of demyelination have presented the kappa opioid receptor (KOPr) as a target for remyelination, with KOPr receptor agonists having been shown to promote oligodendrocyte precursor cell differentiation into oligodendrocytes and increase myelination. The current research investigated the ON features in the experimental autoimmune encephalomyelitis (EAE) model of demyelination and the effect of the clinically available KOPr agonist, nalfurafine, on myelination, immune infiltration, oligodendrocyte lineage cells, microglia, and astrocytes in the model. Techniques used were Black-Gold II and haematoxylin and eosin staining, and immunolabelling with anti-SOX10, -GST-pi, -IBA1, and -GFAP antibodies. It was shown that demyelination and immune infiltration occur, mature oligodendrocytes are fewer, while microglia and astrocyte numbers increase in ONs of EAE mice. Additionally, nalfurafine suppressed astrocyte GFAP expression in the EAE model.