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Low dose naltrexone treatment of established relapsing-remitting experimental autoimmune encephalomyelitis

Hammer, LA;Zagon, IS;McLaughlin, PJ;

More than 2.3 million individuals worldwide have multiple sclerosis [1], and a majority of the individuals experience the relapseremitting form. All forms of MS are characterized by progressive neurodegeneration in the spinal cord and brain, resulting in a reduction in the quality of life and increased medical expenditures [2]. Approved therapies often target symptoms of the disease rather than diseasebased mechanisms, and thus are not completely effective leading to reduced compliance [1-6]. A novel biological pathway has been identified that regulates homeostasis of replicating cells and tissues [7]. The pathway involves the endogenous opioid termed methionine enkephalin (opioid growth factor, OGF) and its nuclear-associated receptor, OGF receptor (OGFr) [7,8]. Modulation of the pathway can be direct by exogenous administration of OGF peptide or endogenously by stimulating production of peptides and receptors following short-term opioid receptor blockade by naltrexone. The use of low dosages of naltrexone (LDN) to invoke a short duration of opioid receptor blockade markedly inhibits cancer cell replication [9]. LDN treatment changes the course of progressive experimental autoimmune encephalomyelitis (EAE) [10,11]. Previous studies have reported that mice immunized with myelin oligodendrocytic glycoprotein 35-55 (MOG35-55) to establish progressive EAE and injected daily with 0.1 mg/kg NTX beginning at the time of disease induction had delayed onset of clinical disease, as well as reduced severity of behavioral deficits; in some cases the course of EAE was reversed within a few days [10-12]. Neuropathology of the lumbar spinal cord revealed significant reductions in the number of activated astrocytes and regions of demyelination [10,11]. Despite more than 85% of patients presenting initially with relapseremitting forms of MS [1,2], animal models for this form of MS are not widely used. For those models that have been routinely used in basic science research, review of the data reveal that depending on the source of mice, there are problems with penetrance and consistent expression of behavioral characteristics [13]. In general relapse-remitting experimental autoimmune encephalomyelitis (RR-EAE) is induced in mice by immunization with proteolipid protein 139-151 (PLP139-151) [14-17]. The animal response is manifested by proliferation and activation of T-lymphocytes, microglia, and astrocytes, resulting in inflammation, demyelination, and axonal damage, that characterizes a well-defined clinical behavior and neuropathology [13,17]. Some investigators have suggested that the RR-EAE mouse model is inconsistent with human scenarios because not all animals express remissions, and many appear to have a more chronic progressive disorder [13]. Our laboratory has established this model of RR-EAE and initiated treatment at the time of induction before behavioral changes were observed [18]. Daily treatment with exogenous OGF of mice immunized with PLP reduced clinical signs of disease within 9 days of treatment. Median cumulative disease scores of OGF-treated RR-EAE mice were decreased 66% from median behavioral scores of saline-treated RR-EAE mice [18]. Importantly, the number and severity of relapses were limited over the course of 55 days. In recent studies utilizing OGF treatment of established disease, OGF was shown to markedly reduce clinical disease in SJL mice that responded to OGF, reduce relapses, and render many mice in total remission [19]. A few clinical trials have utilized LDN for treatment of patients with progressive or relapse-remitting forms of MS [20,21]. Chart reviews of patients taking LDN therapy, alone or in combination with other immune modulating drugs such as Copaxone revealed that patients reported no side effects and some resolution to the nausea and fatigue associated with multiple sclerosis [22]. The present study examined the effects of daily LDN therapy on established RR-EAE disease beginning LDN treatment 2 days after initial clinical signs. The animals were observed daily for 40 days to evaluate relapses and remissions. Periodically, lumbar spinal cord tissue was collected examined histologically to assess the expression of microglia, macrophages, T lymphocytes, activated astrocytes and proliferating cells. Changes in pathology were correlated to behavioral differences.