Synergistic Neuroprotective Effect of Curcumin and Pioglitazone Against Intranigral LPS-Induced Sub-Acute Neurodegeneration in Rats

Neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis and frontotemporal lobar dementia impose a pressing burden in most developed countries.Parkinson's disease (PD) is clinically characterized as motor dysfunction disorder resulting from selective loss of substantia nigras dopaminergic neurons in the midbrain region.PD pathogenesis is multifactorial involving redox imbalance, glia-mediated inflammation and aggregated proteins accumulations that collectively lead to neuronal cell loss.Although traditional treatments relieve symptoms in early PD condition but they do not reverse the damage of dopaminergic neurons.Therefore, the present work was designed to investigate the neuroprotective efficacy of a novel combination of pioglitazone (PPAR- agonist) and curcumin in LPSinduced sub-acute dopaminergic neurodegeneration in rat model.We tested the effect of the combinations of pioglitazone (18 mg/ kg.bw once daily) and curcumin (100 mg/kg.bw), in comparison to each one alone for five consecutive days before intranigral injection with lipopolysaccharide (LPS; 10 g/2l sterile saline/injection) against LPS-mediated neurotoxicity.The experimental results indicated that pretreatment with combined curcumin and pioglitazone, rather than each one alone, have powerful and synergistic anti-inflammatory effects by inhibiting the production of the cytokines TNF-, IL-1 and IL-6 and inflammation-associated enzymes COX-2, iNOS through inhibition of NF-B activity.Furthermore, this combination improved the brain antioxidant capacity by markedly elevating reduced glutathione content and catalase activity while reducing malondialdehyde level that were imbalanced by LPS.Moreover, pretreatment with pioglitazone and curcumin combination induced significant restoration in two of the inflammatory master regulator miRNAs (miR-155 and miR-124) levels toward normal profile expression.This study sheds light on the possible mechanism by which curcumin and pioglitazone combination might exert synergistic neuroprotective effect and provide benefit for those afflicted by neurodegenerative disorders.Further studies are still required to highlight in depth the efficacy of this combination for therapeutic applications.