Assessment of drugs that may attenuate CIHL can therefore be performed quickly and easily using simple audiometric tests.The high incidence of CIHL in children and recent identication of genetic markers associated with this adverse side effect in younger patients increase the likelihood that drugs that reduce CIHL will be discovered by clinical trials in this population. To appreciate the mechanisms by which such drugs may also be useful in the treatment of neurodegenerative disorders, it is necessary to explore the central role of mitochondrial dysfunction in both CIHL and CNS disorders.This process is efcient, but a small percentage of electrons escape the electron transport chain and react with molecular oxygen, buy YK11 generating superoxide.Superoxide damages cells by reacting with DNA, proteins, and lipids.Superoxide also gives rise to highly reactive hydroxyl free radicals that further impair cellular function.These series of events have dire consequences for aging and neurodegenerative disorders in which iron concentrations in the brain and mitochondria are elevated. NADPH oxidases NADPH oxidases are membranebound, multisubunit enzyme complexes that transfer electrons across the plasma membrane from NADPH to molecular oxygen, generating superoxide. By producing ROS, activated NADPH oxidases participate in host defense, cellular signaling, regulation of gene expression, cell differentiation, metabolism, posttranslational processing of proteins, stress responses, and tissue homeostasis.Elevated NADPH oxidase activity has been observed in several chronic neurodegenerative disorders and is thought to drive destructive neuroinammatory events mediated by microglial activation. In terms of neurodegeneration associated with stroke and epilepsy, NADPH oxidase is the primary source of injurious ROS produced by overactivation of the NMDA receptor. NADPH oxidase activity is markedly enhanced by mitochondriaderived ROS, resulting in further mitochondrial injury that creates a vicious cycle of lethal ROS production.For these reasons, NADPH oxidases are attractive targets for clinical intervention; however, global NADPH oxidase inhibition compromises immune defense, thereby increasing the risk of severe bacterial and fungal infections. Preservation of NADPH oxidase activity in cells of the innate immune system is therefore an essential requirement for the effective targeting of this enzyme system in the treatment of chronic neurodegenerative disorders.XO activity is potently elevated by ROS derived from mitochondria and NADPH oxidases. In primary rat cortical neuron cultures subjected to anoxia followed by reoxygenation, XO represents a major source of ROS that contribute to hypoxic injury. Depletion of intracellular ATP resulting from impaired mitochondrial respiration leads to conversion of adenine nucleotides to hypoxanthine and xanthine, substrates for XO. As a consequence, XO is considered to be a signicant source of ROS that contributes to the cellular damage associated with mitochondrial dysfunction and NADPH oxidase activation, particularly in the case of cerebral ischemia. Cisplatin is concentrated in these sensory hair cells by organic cation transporters and the copper transporter CTR. On entering the lowchloride intracellular environment, cisplatin is hydrated to form positively charged species that can react with DNA and other nucleophilic species within the cell. The high afnity of cisplatin for nucleophilic proteins that comprise the mitochondrial ETC promotes the formation of destructive ROS. This ROS overload leads to the depletion of the cochlear antioxidant enzyme system that scavenges and neutralizes ROS.

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