quil-a and Multiple-Sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that causes debilitating central neuropathic pain in many patients. Although mouse models of experimental autoimmune encephalomyelitis (EAE) have provided insight on the pathobiology of MS-induced neuropathic pain, concurrent severe motor impairments confound quantitative assessment of pain behaviors over the disease course. To address this issue, we have established and characterized an optimized EAE-mouse model of MS-induced neuropathic pain. Briefly, C57BL/6 mice were immunized with MOG35-55 (200μg) and adjuvants comprising Quil A (45μg) and pertussis toxin (2×250ng). The traditionally used Freund's Complete Adjuvant (FCA) was replaced with Quil A, as FCA itself induces CNS neuroinflammation. Herein, EAE-mice exhibited a mild relapsing-remitting clinical disease course with temporal development of mechanical allodynia in the bilateral hindpaws. Mechanical allodynia was fully developed by 28-30days post-immunization (p.i.) and was maintained until study completion (52-60days p.i.), in the absence of confounding motor deficits. Single bolus doses of amitriptyline (1-7mg/kg), gabapentin (10-50mg/kg) and morphine (0.1-2mg/kg) evoked dose-dependent analgesia in the bilateral hindpaws of EAE-mice; the corresponding ED50s were 1.5, 20 and 1mg/kg respectively. At day 39 p.i. in EAE-mice exhibiting mechanical allodynia in the hindpaws, there was marked demyelination and gliosis in the brain and lumbar spinal cord, mirroring these pathobiologic hallmark features of MS in humans. Our optimized EAE-mouse model of MS-associated neuropathic pain will be invaluable for future investigation of the pathobiology of MS-induced neuropathic pain and for efficacy profiling of novel molecules as potential new analgesics for improved relief of this condition.

Topics: Amines; Amitriptyline; Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain; Cyclohexanecarboxylic Acids; Demyelinating Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Female; Gabapentin; Gait; gamma-Aminobutyric Acid; Gliosis; Hyperalgesia; Mice; Morphine; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Neuralgia; Peptide Fragments; Pertussis Toxin; Quillaja Saponins

Multiple sclerosis (MS) and its different forms are studied in the animal model experimental autoimmune encephalomyelitis (EAE). Relapsing-remitting MS, the most common form of the disease can be induced in mice where clinical symptoms fluctuate in severity over time. However, the animal model does not experience periods of recovery where clinical signs are absent, unlike the human disease. We have developed a novel model of relapsing-remitting EAE in C57BL/6 mice immunised with myelin oligodendrocyte glycoprotein (MOG) peptide and Quil A as adjuvant. These animals have relapses that are followed by periods of recovery, during which time the animals do not exhibit illness. Furthermore, administration of the PPARgamma agonist pioglitazone prior to a predicted relapse prevents the expected development of symptoms in a dose-dependent fashion. Immune cell infiltration into white matter of the CNS and decreased production of inflammatory cytokine IFN-gamma in treated animals were also observed. Our model will be a valuable tool in assessing intervention therapies for RR-MS sufferers.

Topics: Adjuvants, Immunologic; Animals; Central Nervous System; Chemotaxis, Leukocyte; Disability Evaluation; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Female; Hypoglycemic Agents; Interferon-gamma; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Pioglitazone; PPAR gamma; Quillaja Saponins; Saponins; Secondary Prevention; Thiazolidinediones; Treatment Outcome; Vaccination