Propofol hemisuccinate protects neuronal cells from oxidative injury

Oxidative stress contributes to the neuronal death observed in neurodegener ative disorders and neurotrauma. Some antioxidants for CNS injuries, howeve r, have yet to show mitigating effects in clinical trials, possibly due to the impermeability of antioxidants across the blood-brain barrier (BBB). Pr opofol (2,6-diisopropylphenol), the active ingredient of a commonly used an esthetic, acts as an antioxidant, but it is insoluble in water. Therefore, we synthesized its water-soluble prodrug, propofol hemisuccinate sodium sal t (PHS), and tested for its protective efficacy in neuronal death caused by non-receptor-mediated, oxidative glutamate toxicity. Glutamate induces apo ptotic death in rat cortical neurons and the mouse hippocampal cell line HT -22 by blocking cystine uptake and causing the depletion of intracellular g lutathione, resulting in the accumulation of reactive oxygen species (ROS). PHS has minimal toxicity and protects both cortical neurons and MT-22 cell s from glutamate. The mechanism of protection is attributable to the antiox idative property of PHS because PHS decreases the ROS accumulation caused b y glutamate. Furthermore, PHS protects MT-22 cells from oxidative injury in duced by homocysteic acid, buthionine sulfoximine, and hydrogen peroxide. F or comparison, we also tested alpha-tocopherol succinate (TS) and methylpre dnisolone succinate (MPS) in the glutamate assay. Although TS is protective against glutamate at lower concentrations than PHS, TS is toxic to HT-22 c ells. In contrast, MPS is nontoxic but also nonprotective against glutamate . Taken together, PHS, a water-soluble prodrug of propofol, is a candidate drug to treat CNS injuries owing to its antioxidative properties, low toxic ity, and permeability across the BBB.