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Oxidative stress plays an important role in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The oxindole compound GIF-2165X-G1 is a hybrid molecule composed of the oxindole skeleton of the neuroprotective compound GIF-0726-r and the polyphenolic skeleton of the antioxidant curcumin. We previously reported that novel oxindole derivatives such as GIF-0726-r and GIF-2165X-G1 prevent endogenous oxidative stress-induced cell death in mouse hippocampal HT22 cells. In this study, we present a detailed investigation of the effect of GIF-2165X-G1 on endogenous oxidative stress in HT22 cells in comparison with GIF-0726-r and curcumin. GIF-2165X-G1 exhibited more potent neuroprotective activity than GIF-0726-r or curcumin and had less cytotoxicity than that observed with curcumin. Both GIF-0726-r and GIF-2165X-G1 were found to have ferrous ion chelating activity similar to that exhibited by curcumin. GIF-2165 X-G1 and curcumin induced comparable antioxidant response element transcriptional activity. Although the induction of heme oxygenase-1, an antioxidant response element-regulated gene product, was much stronger in curcumintreated cells than in GIF-2165X-G1-treated cells, it turned out that the induction of heme oxygenase-1 is dispensable for neuroprotection. These results demonstrate that the introduction of the polyphenol skeleton of curcumin to the oxindole GIF-0726-r improves neuroprotective features. Furthermore, intrastriatal injection of GIF-2165X-G1 alleviated apomorphineinduced rotation and prevented dopaminergic neuronal loss in a 6-hydroxydopamine mouse model of Parkinson's diseases. Collectively, our novel findings indicate that the novel oxindole compound GIF-2165X-G1 serves to delay the progression of Parkinson's disease by suppressing oxidative stress.

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Taste receptor cells (type II cells) transmit taste information to taste nerve fibres via ATP-permeable channels, including calcium homeostasis modulator (CALHM), connexin and/or pannexin1 channels, via the paracrine release of adenosine triphosphate (ATP) as a predominant transmitter. In the present study, we demonstrate that extracellular Ca 2+ -dependent biocytin-permeable channels are present in a subset of type II cells in mouse fungiform taste buds using biocytin uptake, immunohistochemistry and in situ whole-cell recordings. Type II cells were labelled with biocytin in an extracellular Ca 2+ concentration ([Ca 2+ ] out )-sensitive manner. We found that the ratio of biocytin-labelled type II cells to type II cells per taste bud was approximately 20% in 2 mM Ca 2+ saline, and this ratio increased to approximately 50% in nominally Ca 2+ -free saline. The addition of 300 µM GdCl 3 , which inhibits various channels including CALHM1 channels, significantly inhibited biocytin labelling in nominally Ca 2+ -free saline, whereas the addition of 20 µM ruthenium red did not.Moreover, Cs + -insensitive currents increased in nominally Ca 2+ -free saline in approximately 40% of type II cells. These increased currents appeared at a potential of above −35 mV, reversed at approximately +10 mV and increased with depolarization. These results suggest that biocytin labels type II cells via ion channels activated by [Ca 2+ ] out reduction, probably "CALHM-like" channels, on the basolateral membrane and that taste receptor cells can be categorized into two groups based on differences in the expression levels of [Ca 2+ ] out -dependent biocytin-permeable channels. These data indicate electrophysiological and pharmacologically relevant properties of biocytin-permeable channels and suggest their contributions to taste signal transduction. K E Y W O R D Sbiocytin uptake, fungiform papillae, immunohistochemical staining, outwardly rectifying currents, patchclamping 1606 | IWAMOTO eT Al.

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Organophosphorous compounds with such a wide variety in structure, application, and biochemical activities include pesticides, herbicides, nerve agents, medicines, reagents in organic chemistry, and additives for polymers. Binaphthyl phosphono-, phosphorothioates, and their derivatives, are useful chiral catalysts for various asymmetric reactions and are expected to act as heavy metal scavengers. In this study, we aimed to evaluate the neurotoxicity and biochemical properties of a new series of binaphthyl phosphonothioates called KK compounds using the mouse hippocampal HT22 cells. Despite negligible structural difference, the compounds exhibited differential general cytotoxic activity which was independent of acetylcholine esterase inhibition; on the other hand, all compounds tested prevented endogenous oxidative stress by suppressing generation of reactive oxygen species. Among them, KK397, KK387, KK410, and KK421 showed hormesis, i.e., biphasic dose responses to endogenous oxidative stress, characterized by beneficial effect at low dose and toxic effect at high dose. At cytotoxic concentrations, these compounds were potent radical generators and activated intracellular signaling molecules such as the p38 mitogen-activated protein kinase, c-Jun NH 2terminal kinase, growth arrest-and DNA damage-inducible gene 153, X-box binding protein 1, and heme oxygenase 1, which are preferentially activated by cell stress-inducing signals, including oxidative and endoplasmic reticulum stress. These findings indicated that novel binaphthyl phosphonothioates can exhibit multiple biochemical properties, functioning as antioxidants and/or prooxidants, depending on the concentration, and chemical modification of binaphthyl organophosphorus compounds endowed them with unique characteristics and multiple beneficial functions.

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