Anti-inflammatory effects of pioglitazone on iron-induced oxidative injury in the nigrostriatal dopaminergic system

作者：Yu H C; Feng S F; Chao P L; Lin A M Y^*

来源：Neuropathology and Applied Neurobiology, 2010, 36(7): 612-622.

DOI：10.1111/j.1365-2990.2010.01107.x

• alpha-synuclein aggregation
• anti-inflammation
• ER stress
• iron
• pioglitazone
• PPAR-gamma

Aims: Transition metals, oxidative stress and neuroinflammation have been proposed as part of a vicious cycle in central nervous system neurodegeneration. Our aim was to study the anti-inflammatory effect of pioglitazone, a peroxisome proliferative activated receptor-gamma agonist, on iron-induced oxidative injury in rat brain. Methods: Intranigral infusion of ferrous citrate (iron) was performed on anaesthetized rats. Pioglitazone (20 mg/kg) was orally administered. Oxidative injury was investigated by measuring lipid peroxidation in the substantia nigra (SN) and dopamine content in the striatum. Western blot assay and DNA fragmentation were employed to study the involvement of alpha-synuclein aggregation, neuroinflammation as well as activation of endoplasmic reticulum (ER) and mitochondrial pathways in iron-induced apoptosis. Results: Intranigral infusion of iron time-dependently increased alpha-synuclein aggregation and haem oxygenase-1 levels. Furthermore, apoptosis was demonstrated by TUNEL-positive cells and DNA fragmentation in the iron-infused SN. Systemic pioglitazone was found to potentiate iron-induced elevation in nuclear peroxisome proliferative activated receptor-gamma levels. However, pioglitazone inhibited iron-induced alpha-synuclein aggregation, elevations in interleukin-1 beta and interleukin-6 mRNA levels as well as increases in oxygenase-1, cyclo-oxygenase II, nitric oxide synthase and ED-1 protein levels, an indicator of activated microglia. Moreover, iron-induced DNA laddering as well as activation of ER and mitochondrial pathways were attenuated by pioglitazone. In addition, pioglitazone decreased iron-induced elevation in lipid peroxidation in the infused SN and depletion in striatal dopamine level. Conclusions: Our results suggest that pioglitazone prevents iron-induced apoptosis via both ER and mitochondrial pathways. Furthermore, inhibition of alpha-synuclein aggregation and neuroinflammation may contribute to the pioglitazone-induced neuroprotection in central nervous system.

• 出版日期2010-12