Peroxisome proliferator‐activated receptor‐γ agonists prevent experimental autoimmune encephalomyelitis

Abstract

The development of clinical symptoms in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) involves T-cell activation and migration into the central nervous system, production of glial-derived inflammatory molecules, and demyelination and axonal damage. Ligands of the peroxisome proliferator-activated receptor (PPAR) exert anti-inflammatory effects on glial cells, reduce proliferation and activation of T cells, and induce myelin gene expression. We demonstrate in two models of EAE that orally administered PPARgamma ligand pioglitazone reduced the incidence and severity of monophasic, chronic disease in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide and of relapsing disease in B10.Pl mice immunized with myelin basic protein. Pioglitazone also reduced clinical signs when it was provided after disease onset. Clinical symptoms were reduced by two other PPARgamma agonists, suggesting a role for PPARgamma activation in protective effects. The suppression of clinical signs was paralleled by decreased lymphocyte infiltration, lessened demyelination, reduced chemokine and cytokine expression, and increased inhibitor of kappa B (IkB) expression in the brain. Pioglitazone also reduced the antigen-dependent interferon-gamma production from EAE-derived T cells. These results suggest that orally administered PPARgamma agonists could provide therapeutic benefit in demyelinating disease.

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

“…Administration of 15d-PGJ 2 at the onset of clinical disease significantly reduced EAE severity, supporting the potential clinical relevance of this treatment paradigm [12]. Feinstein et al [16] demonstrated that oral administration of thiazolidinediones including pioglitazone reduced the clinical severity of monophasic EAE, but it did not delay disease onset. In a relapsing EAE model, pioglitazone had no effect on the onset or severity of the initial disease attack, but rather reduced the severity of subsequent relapses and resulted in an overall decrease in mortality.…”

Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease

“…28 ApoE4 is more susceptible to degradation owing to protein folding differences between the isoforms. 18,30,31 At a mechanistic level, the relationship between APOE, RSG and cognition has not been elucidated. Several lines of evidence support a direct role of PPARg agonists, including RSG, on mitochondrial metabolism and remodeling.…”

“…15 Rosiglitazone (RSG), a PPARg agonist and an approved antidiabetic pharmacotherapy, is an insulinsensitizing agent that allows the body to use endogenous insulin more efficiently, maintain normal physiological feedback mechanisms 16,17 and produce anti-inflammatory actions. 18 A positive cognitive effect has been observed in a small pilot study of RSG in AD patients. 19 A strong biological rationale exists to test RSG's efficacy in AD.…”

The Synthetic Peroxisome Proliferator-Activated Receptor-γ Agonist Ciglitazone Attenuates Neuroinflammation and Accelerates Encapsulation in Bacterial Brain Abscesses

“…However, because brain abscess is one of the few CNS insults that resolve by fibrosis rather than gliosis, it is likely that the pro-fibrotic effects of ciglitazone demonstrated in this study are specific to infection. This tenant is supported by a lack of evidence for pro-fibrotic responses in other CNS disorders in which PPAR-␥ treatment has been used (15,(23)(24)(25). Another distinction between the regulated fibrosis that occurs during brain abscess development and pathological fibrosis is that the latter is typically associated with a Th2 cytokine environment (59,60), which is not the case during brain abscess development where a Th1 response predominates (T. Kielian, unpublished observations).…”

“…Animals receiving ciglitazone alone did not demonstrate any overt adverse effects to the drug (i.e., no significant alterations in body weight). The doses of ciglitazone tested are representative of PPAR-␥ agonist concentrations used in previously published reports of disparate CNS neurodegenerative models (23)(24)(25).…”