Effects of Neomycin on Polyphosphoinositides in Inner Ear Tissues and Monomolecular Films

A PI3K Pathway Mediates Hair Cell Survival and Opposes Gentamicin Toxicity in Neonatal Rat Organ of Corti

“…Treatment with the PI3K inhibitor, LY294002, combined with gentamicin worsened hair cell loss. This indicates that PI3K plays a role in promoting hair cell survival, and supports the previous observations of Schacht et al (1977) that implicate PI metabolism in ototoxicity. In addition, especially the PKC inhibitor (calphostin C) and, to a lesser extent, the PKB/Akt inhibitor (SH-6) combined with gentamicin enhanced hair cell death more than gentamicin alone.…”

“…Our data, implicating PI3K in the hair cell response to gentamicin, support the observations of Schacht and his colleagues regarding the importance of PI metabolism in the process of aminoglycoside ototoxicity (e.g., Schacht et al 1977;Willams et al 1987). They also complement the many other recent studies that have documented signal transduction pathways leading to hair death due to a variety of stressors, including aminoglycosides (e.g., Pirvola et al 2000;Bodmer et al 2002a), cisplatin (e.g., Zhang et al 2003;Wang et al 2004), and noise exposure (e.g., Harris et al 2005;Lang et al 2006).…”

“…Protein kinase activity including protein kinase C has been demonstrated in normal organ of Corti (Coling and Schacht 1991). Also, aminoglycoside ototoxicity was shown to interact with PI metabolism (Schacht et al 1977). Schacht and colleagues observed PI cascade abnormalities in hair cells during gentamicin ototoxicity, and further observed that aminoglycosides bind preferentially to phosphatidylinositol 4,5-biphosphate (PIP2).…”

Stress and Survival Pathways in the Mammalian Cochlea

“…In a follow-up study using gene arrays and a biochemical assay, we were able to link the NF-B-induced HC loss to PI3k [Nagy et al, 2007]. Interestingly, the PI3k pathway has been previously linked to HC survival [Chung et al, 2006] and to aminoglycosides [Schacht et al, 1977;Jiang et al, 2006c]. Activated PI3k phosphorylates the membrane lipid PIP2 at the 3 -OH position to generate PIP3.…”

Neomycin Inhibits the Phosphatidylinositol Monophosphate and Phosphatidylinositol Bisphosphate Stimulation of Plasma Membrane ATPase Activity

“…Neomycin, a positively charged aminoglycoside, can form electroneutral complexes with PIP and PIP2 (4,9,18) and thereby block the binding of PIP and PIP2 to the solubilized enzyme (8). Ifthe effect ofthe inositol phospholipids is caused by interaction of the negatively charged, inositol phosphate head groups with the ATPase, then adding neomycin should decrease the effect of the lipids.…”