Effects of High Glucose Concentrations on PC12 Cells: Possible Implications on Neurodegeneration

Hyperglycemia, which arises in type 1 or 2 diabetes, leads to different complications, such as macrovascular disease, nephropathy, retinopathy, and neuropathy. In addition, different cognitive variations are associated with type 1 diabetes. Long-term changes in glucose metabolism might induce effects on the central nervous system (CNS) such as reduced mental performance and loss of consciousness, which could be implicated in neurotoxicity. The direct impact of hyperglycemia and elevated glucose concentrations on neuronal cells remains to be fully elucidated, primarily due to the multifaceted mechanisms underlying glucose neurotoxicity, including apoptosis, oxidative stress, and alterations in signaling cascades. The multifaceted mechanisms further complicate the study of the relationship between diabetes and neurodegeneration. Research in this field is continually advancing, with the aim of investigating these eventual connections and developing more effective preventive and therapeutic strategies. The present study aims to assess the damage induced by different glucose concentrations (from 25 to 150 mM) in a neuronal model, such as PC12 cells, rat pheochromocytoma cells. In glucose-exposed PC12 cells, we have tested oxidative stress, apoptosis, and cell migration by (a) viability screening, (b) intracellular levels of anion superoxide (O2-), (c) extracellular levels of MDA and nitrites, (d) apoptosis, and (e) the wound healing assay. By the cell viability assay, it has emerged that glucose (25-150 mM) showed a stronger effect at the highest concentrations (100 and 150 mM). The increase in MDA and O2- levels was determined in PC12 cells treated with high glucose concentrations (6.5-8.8 fold for MDA). High concentrations (100 and 150 mM) significantly reduced the expression of full-length caspase-3 (2.8-fold and 4.2-fold decrease at 24 and 72 h) and caspase-9 (3.4-fold and 2.8-fold decrease at 24 h and 5-fold decrease at 72 h) compared with control conditions. Finally, the wound healing assay showed different scenarios during the several time points. Indeed, the wound closure rate was reduced in a dose-dependent manner (24 h: control 18%, G 50 mM 9%, 100 and 150 mM 8%; 48 h: control 26%, G 50 mM 20%, G 100 mM 13%, 150 mM 11%), following the treatment with three concentrations considered (50, 100, 150 mM). The results obtained in these experimental conditions highlight that glucose, at high concentrations, induced cell damage and corroborate the hypothesis that it could be involved in neurodegenerative diseases.