Recent evidence suggests that clozapine and quetiapine (atypical antipsychotics), tamoxifen (selective-estrogen receptor modulator) and pioglitazone (PPARγ agonist) may improve functional recovery in multiple sclerosis (MS). We have compared the effectiveness of oral administration of these drugs, beginning at peak disease, at reducing ascending paralysis, motor deficits and demyelination in mice subjected to experimental autoimmune encephalomyelitis (EAE). Mice were immunized with an immunogenic peptide corresponding to amino acids 35-55 of the myelin oligodendrocyte glycoprotein (MOG35-55) in complete Freund's adjuvant and injected with pertussis toxin to induce EAE. Unlike clozapine, quetiapine and tamoxifen, administration of pioglitazone beginning at peak disease decreased both clinical scores and lumbar white matter loss in EAE mice. Using kinematic gait analysis, we found that pioglitazone also maintained normal movement of the hip, knee and ankle joints for at least 44 days after MOG35-55 immunization. This long-lasting preservation of hindleg joint movements was accompanied by reduced white matter loss, microglial and macrophage activation and the expression of pro-inflammatory genes in the lumbar spinal cords of EAE mice. These results support clinical findings that suggest pioglitazone may reduce the progressive loss of motor function in MS by decreasing inflammation and myelin damage.
Keywords: Clozapine; Demyelination; Inflammation; Kinematic gait analysis; Multiple sclerosis; Pioglitazone; Quetiapine; Spinal cord; Tamoxifen.
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