Cellular redox dysregulation produced by aldose reductase (AR) in the presence of high blood sugar is a mechanism involved in neurodegeneration commonly observed in diabetes mellitus (DM) and Parkinson's disease (PD); therefore, AR is a key target for treatment of both diseases. The substituted triazinoindole derivatives 2-(3-thioxo-2H-[1,2,4]triazino[5,6-b]indol-5(3H)-yl) acetic acid (cemtirestat or CMTI) and 2-(3-oxo-2H-[1,2,4]triazino[5,6-b]indol-5(3H)-yl) acetic acid (COTI) are well-known AR inhibitors (ARIs). The neuroprotective properties of CMTI, COTI, the clinically used epalrestat (EPA), and the pyridoindole antioxidants stobadine and SMe1EC2 were all tested in the neurotoxic models produced by hyperglycemic glucotoxicity (HG, 75 mM d-glucose, 72 h), 6-hydroxydopamine (6-OHDA), and HG+6-OHDA models in PC12 cells. Cell viability decreased in all toxic models, increased by 1-5 mu M EPA, and decreased by COTI at >= 2.5 mu M. In the HG model alone, where compounds were present in the medium for 24 h after a continuous 24-h exposure to HG, cell viability was improved by 100 nM-5 mu M EPA, 1-10 mu M ARIs, and the antioxidants studied, but decreased by EPA at >= 10 mu M. In the 6-OHDA model alone, where cells were treated with compounds for 24 h and further exposed to 100 mu M 6-OHDA (8 h), only the antioxidants protected cell viability. In the HG+6-OHDA model, where cells were treated with all compounds (1 nM to 50 mu M) for 48 h and exposed to 75 mM glucose for 24 h followed by incubation with 6-OHDA for 8 h, cell viability was protected by 100 nM-10 mu M ARIs and 100-500 nM EPA, but not by antioxidants. All ARIs inhibited the HG+6-OHDA-induced increase in iNOS, IL-1 beta, TNF-alpha, 3-NT, and total oxidant status at 1-50 mu M, while increased SOD, CAT, GPx, and total antioxidant status at 1-10 mu M. EPA and CMTI also reduced the HG+6-OHDA-induced increase in the cellular levels of nuclear factor kB (NF-KB). The neuroprotective potential of the novel ARIs and the pyridoindole antioxidants studied constitutes a promising tool for the development of therapeutic strategies against DM-induced and PD-related neurodegeneration.