Pioglitazone Attenuates Lipopolysaccharide-Induced Oxidative Stress, Dopaminergic Neuronal Loss and Neurobehavioral Impairment by Activating Nrf2/ARE/HO-1

• Published in: Neurochemical research Vol. 44; no. 12; pp. 2856 - 2868
• Main Authors: Zakaria, Aya, Rady, Mona, Mahran, Laila, Abou-Aisha, Khaled
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-12-2019; Springer Nature B.V
• Subjects: Antioxidants; Anxiety; Biochemistry; Biomedical and Life Sciences; Biomedicine; Carbonyl compounds; Carbonyls; Cell Biology; Dopamine receptors; Enzymatic activity; Enzyme activity; Enzymes; Gene expression; Inflammation; Lipopolysaccharides; Memory tasks; Neurochemistry; Neurodegeneration; Neurology; Neuroprotection; Neurosciences; NF-κB protein; Original Paper; Oxidative stress; Pioglitazone; Proteins; Protoporphyrin; Signal transduction; Spatial analysis; Spatial memory; Substantia nigra; Transcription activation; Zinc; Dopaminergic neurons; Oxidative stress; Nrf2/HO-1 signaling pathway; Transcriptional activation; Pioglitazone; Neurobehavioral impairment
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-019-02907-0

The aim of the present study was to examine the neuroprotective potential of pioglitazone via activation of Nrf2/ARE-dependent HO-1 signaling pathway in chronic neuroinflammation and progressive neurodegeneration mouse model induced by lipopolysaccharide (LPS). After assessing spatial memory, anxiety and motor-coordination, TH+ neurons in substantia nigra (SN) were counted. The oxidative stress marker carbonyl protein levels and HO-1 enzyme activity were also evaluated. RT-qPCR was conducted to detect HO-1, Nrf2 and NF-κp65 mRNA expression levels and Nrf2 transcriptional activation of antioxidant response element (ARE) of HO-1 was investigated. Pioglitazone ameliorated LPS-induced dopaminergic neuronal loss, as well as mitigated neurobehavioral impairments. It enhanced Nrf2 mRNA expression, and augmented Nrf2/ARE-dependent HO-1 pathway activation by amplifying HO-1 mRNA expression. Moreover, it induced a significant decrease in NF-κB p65 mRNA expression, while reducing carbonyl protein levels and restoring the HO-1 enzyme activity. Interestingly, LPS induced Nrf2/antioxidant response element (ARE) of HO-1 activation, ultimately resulting in slight enhanced HO-1 mRNA expression. However, LPS elicited decrease in HO-1 enzyme activity. Zinc protoporphyrin-IX (ZnPPIX) administrated with pioglitazone abolished its effects in the LPS mouse model. The study results demonstrate that coordinated activation of Nrf2/ARE-dependent HO-1 pathway defense mechanism by the PPARγ agonist pioglitazone mediated its neuroprotective effects.