Effects of the PPARγ activator pioglitazone on p38 MAP kinase and IκBα in the spinal cord of a transgenic mouse model of amyotrophic lateral sclerosis

Abstract

Emerging evidence suggests the involvement of programmed cell death and inflammation in amyotrophic lateral sclerosis (ALS). To assess molecular pathological effects of the anti-inflammatory peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist pioglitazone in ALS, we verified changes in the population of neurons, astrocytes, and microglia in the ventral horns of spinal cord lumbar segments from the pioglitazone-treated and non-treated groups of mice carrying a transgene for G93A mutant human superoxide dismutase-1 (SOD1) (ALS mice) and non-transgenic littermates (control mice), performed immunohistochemical and immunoblot analyses of PPARgamma, active form of phosphorylated p38 mitogen-activated protein kinase (p-p38) and inhibitor of nuclear factor-kappaB (NF-kappaB)-alpha (IkappaBalpha) in the spinal cords, and compared the results between the different groups. Image analysis revealed that optical density of NeuN-immunoreactive neurons was significantly lower in the non-treated groups of presymptomatic and advanced ALS mice than in the non-treated groups of age-matched control mice and was recovered with pioglitazone treatment, and that optical densities of GFAP-immunoreactive astrocytes and Iba1-immunoreactive microglia were significantly higher in the non-treated group of advanced ALS mice than in the non-treated group of control mice and were recovered with pioglitazone treatment. Immunohistochemical analysis demonstrated that immunoreactivities for PPARgamma and p-p38 were mainly localized in neurons, and that IkappaBalpha immunoreactivity was mainly localized in astrocytes and microglia. Immunoblot analysis showed that pioglitazone treatment resulted in no significant change in nuclear PPARgamma-immunoreactive density, a significant decrease in cytosolic p-p38-immunoreactive density, and a significant increase in cytosolic IkappaBalpha-immunoreactive density. Our results suggest that pioglitazone protects motor neurons against p38-mediated neuronal death and NF-kappaB-mediated glial inflammation via a PPARgamma-independent mechanism.

SOCS3 Transactivation by PPARγ Prevents IL-17–Driven Cancer Growth

“…Although activation of the transcription factor PPARg has been associated with reduced inflammation, the intracellular series of events consecutive to PPARg activation remain incompletely understood and the actual involvement of PPARg in the anti-inflammatory effects of PPARg ligands remains debated (34,35). In this study, we propose what we believe to be a novel molecular pathway by which PPARg contributes to limit the secretion of the proinflammatory cytokine IL-17.…”

Mitochondrial Dysfunction is a Converging Point of Multiple Pathological Pathways in Amyotrophic Lateral Sclerosis

“…The stress-responsive p38 MAP kinase pathway was reported to be activated in mutant SOD1 transgenic mice [91,120]. The activated kinases can phosphorylate KHC or KLC and affect anterograde transport [93,[121][122][123][124]. Alternatively, activated MAP kinase can also phosphorylate neurofilaments and lead to their accumulation in axons [91,92].…”

Amyotrophic Lateral Sclerosis: Role of the Canonical Wnt/Beta- Catenin Pathway and PPAR Gamma

“…The neuroprotective effect of pioglitazone has been demonstrated in G93A SOD1 transgenic mouse model of ALS and shows a significant increase in their survival. Pioglitazone protects motor neurons against p38-mediated neuronal death and NF-kappaB-mediated glial inflammation via a PPAR gamma-independent mechanism [50]. In ALS, PPAR gamma controls natural protective mechanisms against lipid peroxidation [51].…”