Investigating the Role of a Novel Kappa Opioid Receptor Agonist in Functional Recovery in the Augmented Cuprizone Model of Demyelination and Its Side Effects
Multiple sclerosis (MS) is a debilitating neuroinflammatory disease that affects 2.8 million people worldwide. Myelin-specific peripheral lymphocytes infiltrate the central nervous system (CNS) and destroy the myelin sheath, causing further inflammatory damage and demyelination, closely followed by axonal injury and death. These events lead to lesion formation, which accumulates in number over time and results in symptoms that severely impact quality of life. There is no cure for MS and immunomodulatory therapies are used to help manage the disease. However, these are unable to promote recovery, are limited to slowing disease progression, and are ineffective for progressive forms of MS. Due to the lack of treatment options that promote recovery, researchers look towards therapeutic targets that promote remyelination.
Recent preclinical studies have presented the kappa opioid receptor (KOPr) as a promising target for the promotion of remyelination and potential treatment of multiple sclerosis. Most remyelination studies have used the KOPr agonist, U50,488, to demonstrate the promotion of remyelination through KOPr activation. This has been done through in vitro cell cultures as well as in vivo preclinical models of demyelination that mimic aspects of MS, by promoting oligodendrocyte precursor cell (OPC) differentiation to mature oligodendrocytes. However, the clinical use of KOPr agonists is limited due to the associated unpleasant side effects, such as dysphoria, anxiety, and sedation.
In this thesis, we used the novel KOPr agonist LDK-276, an analogue of U50,488, alongside the only clinically available KOPr agonist, nalfurafine, to preliminarily test its efficacy in promoting functional recovery in an improved augmented cuprizone model of extensive demyelination, using cuprizone and rapamycin (cupR) intoxication. To quantify and evaluate the efficacy of KOPr activation in functional recovery, we used the mouse motor skill sequence (MOSS) longitudinal to the augmented cuprizone model to quantify non evoked measures of home-age activity. No functional recovery was observed in cupR mice that were treated with LDK-276.
To evaluate whether LDK-276 causes some of the unpleasant side effects associated with KOPr agonists, we used behavioural side effect assays, alongside U50,488, to assess sedative effects, motor coordination, and locomotor deficit side effects. No undesirable side effects were identified in LDK-276 with these behavioural tests. LDK-276 has previously shown potential in promoting remyelination through an in vitro assay, so further investigation of its efficacy in remyelination and functional recovery may be beneficial.