Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease associated with inflammation and neurodegeneration of the central nervous system. MS pathogenesis includes angiogenesis, the formation of new blood vessels from existing vasculature. Angiogenesis facilitates the migration of inflammatory immune cells across the blood-brain barrier in MS. The opioid growth factor (OGF)-opioid growth factor receptor (OGFr) axis is a potential target for limiting angiogenesis in MS. OGF is a ubiquitous endogenous opioid with inhibitory growth properties when bound to OGFr. Low dosages of naltrexone (LDN), an opioid receptor antagonist, transiently block OGFr and lead to upregulated OGF production when naltrexone is unbound. To investigate the role of the OGF-OGFr axis in angiogenesis in a preclinical model of MS, C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein (MOG35-55) to establish chronic progressive experimental autoimmune encephalomyelitis (EAE). Mice were treated with intraperitoneal OGF (10 mg/kg) or LDN (0.1 mg/kg) prophylactically for 10 days or therapeutically for 10 days or 3 weeks. Prophylactically treated EAE + OGF or EAE + LDN mice had markedly reduced spinal cord inflammation (OGF: p=0.03; LDN: p<0.01) and white matter blood vessel density (OGF: p<0.0001; LDN: p<0.0001) compared to vehicle treated EAE mice. Therapeutic EAE + OGF or EAE + LDN mice had improved clinical behavior and reduced white matter blood vessel density (OGF: p=0.05; LDN: p<0.05) with an insignificant decrease in spinal cord inflammation (OGF: p=0.15; LDN: p=0.53) after 3 weeks of treatment. This study is the first to demonstrate a role for LDN and the OGF-OGFr axis in reducing angiogenesis in EAE mice. Most current MS therapies have significant side-effects and high costs, while LDN has been shown to be safe and inexpensive. This study provides preclinical evidence for LDN as a promising therapy for limiting MS pathophysiology.
Keywords
Multiple sclerosis, Experimental autoimmune encephalomyelitis, Angiogenesis, Neuroinflammation, Opioid growth factor, Opioid growth factor receptor, Low-dose naltrexone