Q-VD-OPH

Alzheimer's disease (AD) is a neurodegenerative disease with a significant impact on global public health. The primary hallmarks of the disease included amyloid-beta peptide (Aβ) deposition, neurofibrillary tangles (NFT), and synaptic loss. Sirtuins, a group of NAD⁺-dependent deacetylase enzymes, are key regulators of AD pathogenesis. SIRT1, a member of sirtuins, has been identified to possess neuroprotective properties. Thus, its promising enhancers are included. Further, SIRT2 promising inhibitors are reviewed for therapeutic efficacy. The extrinsic and intrinsic apoptotic pathways of caspases are mediated by CD95 and DNA damage. The promising inhibitors Q-VD-OPh and minocycline are found to be specific for caspase-7 and caspase-3, respectively. Primarily, glycogen synthase kinase-3β (GSK-3β) is found to be involved in the generation of phosphorylated tau. The promising GSK-3 inhibitor included the COB-187 (IC₅₀ = 370 nM) and maleimide-derivative (compound 33, IC₅₀ = 0.09 μM). This review highlights the molecular mechanisms of sirtuin, caspase, and GSK-3 in the pathophysiology of AD. Further, promising modulators specific to these targets are described.

Organophosphates cause hyperstimulation of the central nervous system, leading to extended seizures, convulsions, and brain damage. Sarin is a highly toxic organophosphate nerve agent that has been employed in several terrorist attacks. The prolonged toxicity of sarin may be enhanced by the neuroinflammatory response initiated by the inflammasome, caspase involvement, and generation/release of proinflammatory cytokines. Since neurodegeneration and neuroinflammation are prevalent in sarin-exposed animals, we were interested in evaluating the capacity of quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methyl ketone (Q-VD-OPh), a pan caspase inhibitor to attenuate neuroinflammation following sarin exposure. To test this hypothesis, sarin-exposed C57BL/6 mice were treated with Q-VD-OPh or negative control quinolyl-valyl-O-methylglutamyl-[-2,6-difluorophenoxy]-methyl ketone, sacrificed at 2- and 14-day time points, followed by removal of the amygdala and hippocampus. A Bio-Rad 23-Plex cytokine analysis was completed on each tissue. The results suggest that exposure to sarin induced a dramatic increase in interleukin-1β and 6 other cytokines and a decrease in 2 of the 23 cytokines at 2 days in the amygdala compared with controls. Q-VD-OPh attenuated these changes at the 2-day time point. At 14 days, six of these cytokines were still significantly different from controls. Hippocampus was less affected at both time points. Diazepam, a neuroprotective drug against nerve agents, caused an increase in several cytokines but did not have a synergistic effect with Q-VD-OPh. Treatment of sarin exposure with apoptosis inhibitors appears to be a worthwhile approach for further testing as a comprehensive counteragent against organophosphate exposure. SIGNIFICANCE STATEMENT: A pan inhibitor of caspases (Q-VD-OPh) was proposed as a potential antidote for sarin-induced neuroinflammation by reducing the level of inflammation via inflammasome caspase inhibition. Q-VD-OPh added at 30 minutes post-sarin exposure attenuated the inflammatory response of a number of cytokines and chemokines in the amygdala and hippocampus, two brain regions sensitive to organophosphate exposure. Apoptotic marker reduction at 2 and 14 days further supports further testing of inhibitors of apoptosis as a means to lessen extended organophosphate toxicity in the brain.