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 (PPARγ) 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 PPARγ, active form of phosphorylated p38 mitogen-activated protein kinase (p-p38) and inhibitor of nuclear factor-kappaB (NF-κB)-alpha (IκBα) 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 PPARγ and p-p38 were mainly localized in neurons, and that IκBα immunoreactivity was mainly localized in astrocytes and microglia. Immunoblot analysis showed that pioglitazone treatment resulted in no significant change in nuclear PPARγ-immunoreactive density, a significant decrease in cytosolic p-p38-immunoreactive density, and a significant increase in cytosolic IκBα-immunoreactive density. Our results suggest that pioglitazone protects motor neurons against p38-mediated neuronal death and NF-κB-mediated glial inflammation via a PPARγ-independent mechanism.
- Amyotrophic lateral sclerosis
- Inhibitor of nuclear factor-kappaB-alpha
- Peroxisome proliferator-activated receptor-gamma
- p8 mitogen-activated protein kinase
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Clinical Neurology