Glucose Promotes Resistance In Lymphocytes Against Oxidative Stress-Induced Apoptosis Through Signaling And Metabolic Pathways. Implications For Parkinson'S Disease

Introduction: Parkinson's disease (PD) is a neurological disorder associated with the selective loss of dopaminergic (DAergic) neurons. Clinical data suggest that oxidative stress (OS) and dysregulation of glucose (G) metabolism are early events in PD. However, no data are available to explain the molecular connection between glucose metabolism, OS, and neuronal demise in PD. Human lymphocytes share a similar dopaminergic signaling mechanism with DAergic neurons. Further, rotenone (ROT) is a mitochondrial complex I inhibitor that selectively induces apoptosis through OS in dopaminergic neurons and lymphocytes. Thus, to test the hypothesis that G metabolism and OS are linked in dopaminergic system toxicity and PD, human lymphocytes were cultured with ROT in the presence or absence of various concentrations of glucose.Objective: This study examines the response of human lymphocytes to glucose (11, 55, 166, 277, 555 mM G) in the absence or presence of ROT (250 microM).Methods: Light and fluorescence microscopy and immunocytochemistry techniques were used to evaluate morphological and biochemical changes in human lymphocytes.Results: 55 mM G was effective in suppressing ROT-induced apoptosis in lymphocytes via 5 pathways: (i) pentose phosphate pathway (PPP), (ii) glutathione (GSH) pathway, (iii) superoxide dismutase (SOD) and catalase (CAT) antioxidant systems, and (iv) Phosphoinositide 3-kinase (PI3-K) signaling. Additionally, we report for the first time that G rescued lymphocytes from ROT-induced apoptosis by (v) activating NF-kB and down-regulating p53 and caspase-3. Signaling (e.g., LY294002) and metabolic inhibitors of these pathways (e.g., dehydroepiandrosterone (DHEA), L-buthionine-sulfoximine (BSO), 1,3-Bis (2-chloroethyl)-1-nitrosourea (BCNU), mercaptosuccinic acid (MS), 3-amino-1,2,4-triazole (AT), sodium diethyldithiocarbamate (DDC)) only partially reversed the protective effect of 55 mM G on lymphocytes exposed to ROT.Conclusion: These data suggest that high G simultaneously triggers cellular signaling and antioxidant systems to ensure global cell protection against stressful conditions in DAergic cells.