title: Improved clinical behavior of established relapsing-remitting experimental autoimmune encephalomyelitis following treatment with endogenous opioids: implications for the treatment of multiple sclerosis.
abstract: Relapse-remitting multiple sclerosis is a chronic disease of the CNS that affects 350,000 individuals in the U.S., reducing the quality of life and often resulting in paralysis. Most current therapies do not target the underlying pathophysiology of multiple sclerosis (MS). This study examined the therapeutic efficacy of an endogenous peptide (opioid growth factor, OGF) known to inhibit cell replication in a receptor-mediated manner, utilizing a mouse model of relapse-remitting experimental autoimmune encephalomyelitis (RR-EAE). RR-EAE was induced by immunization of SJL/J mice with proteolipid protein. Two days following establishment of clinical disease, treatment with OGF (10mg/kg) or saline was initiated and mice were observed on a daily basis. OGF treated mice had markedly reduced clinical signs of disease over the course of 40 days. OGF treatment increased the incidence and lengthened the time of remissions relative to saline-treated mice with RR-EAE. OGF therapy also reduced relapses, and facilitated extended periods of mild disease. Neuropathological examination of lumbar spinal cord after 40 days of treatment revealed decreased numbers of Iba-1 and CD3+ reactive cells, suggesting that OGF inhibited proliferation of microglia/macrophages and T lymphocytes, as well as decreasing the number of proliferating activated astrocytes (Ki-67 and GFAP dual labeled sections). Peptide treatment for 40 days diminished levels of demyelination in comparison to saline-treated mice with RR-EAE. These data are the first to demonstrate that exposure to OGF initiated at the time of established disease can reverse the course of RR-EAE and reduce neuropathological deficits.
authors: Department of Neural & Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA, United States.
authors: Leslie A
authors: LA
authors: Hammer
authors: Department of Neural & Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA, United States.
authors: Ian S
authors: IS
authors: Zagon
authors: Department of Neural & Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA, United States. Electronic address: pxm9@psu.edu.
authors: Patricia J
authors: PJ
authors: McLaughlin
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D017252:CD3 Complex / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005904:Glial Fibrillary Acidic Protein; D007155:Immunologic Factors / Q000008:administration & dosage*; D019394:Ki-67 Antigen / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018991:Myelin Proteolipid Protein; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018847:Opioid Peptides / Q000008:administration & dosage*; D010446:Peptide Fragments; D011897:Random Allocation; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D016896:Treatment Outcome
chemical_list: C491049:Aif1 protein, mouse; D017252:CD3 Complex; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D007155:Immunologic Factors; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; D018847:Opioid Peptides; D010446:Peptide Fragments; C528900:glial fibrillary astrocytic protein, mouse; C435023:myelin proteolipid protein (139-151)
keywords: Astrocyte activation; Microglial proliferation; Opioid growth factor (OGF); Relapse-remitting EAE; Spinal cord demyelination