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A series of cyclopropane-based conformationally restricted gamma-aminobutyric acid (GABA) analogs with stereochemical diversity, that is, the trans- and cis-2,3-methano analogs Ia and Ib and their enantiomers ent-Ia and ent-Ib, and also the trans- and cis-3,4-methano analogs IIa and IIb and their enantiomers ent-IIa and ent-Iib, were synthesized from the chiral cyclopropane units Type-a and Type-b that we developed. These analogs were systematically evaluated with four GABA transporter (GAT) subtypes. The trans-3,4-methano analog IIa had inhibitory effects on GAT3 (IC50 = 23.9 mu M) and betaine-GABA transporter1 (5.48 mu M), indicating its potential as an effective lead compound for the development of potent GAT inhibitors due to its hydrophilic and low molecular weight properties and excellent ligand efficiency. (C) 2013 Elsevier Ltd. All rights reserved.

Nitric oxide (NO) physiologically regulates numerous cellular responses through S -nitrosylation of protein cysteine residues. We performed antibody-array screening in conjunction with biotin-switch assays to look for S -nitrosylated proteins. Using this combination of techniques, we found that phosphatase with sequence homology to tensin (PTEN) is selectively S -nitrosylated by low concentrations of NO at a specific cysteine residue (Cys-83). S -nitrosylation of PTEN (forming SNO-PTEN) inhibits enzymatic activity and consequently stimulates the downstream Akt cascade, indicating that Cys-83 is a critical site for redox regulation of PTEN function. In ischemic mouse brain, we observed SNO-PTEN in the core and penumbra regions but found SNO-Akt, which is known to inhibit Akt activity, only in the ischemic core. These findings suggest that low concentrations of NO, as found in the penumbra, preferentially S -nitrosylate PTEN, whereas higher concentrations of NO, known to exist in the ischemic core, also S -nitrosylate Akt. In the penumbra, inhibition of PTEN (but not Akt) activity by S -nitrosylation would be expected to contribute to cell survival by means of enhanced Akt signaling. In contrast, in the ischemic core, SNO-Akt formation would inhibit this neuroprotective pathway. In vitro model systems support this notion. Thus, we identify unique sites of PTEN and Akt regulation by means of S -nitrosylation, resulting in an “on–off” pattern of control of Akt signaling.

The complement fixing (C-F) antibody titers to varicella-zoster and herpes simplex virus in 80 cases of peripheral facial nerve paralysis were determined in association with the inflammatory findings in the increased antibody group. Of 22 patients with Ramsay-Hunt's syndrome, 18 (81%) showed more than eightfold increases in complement fixing antibody titer to the varicella-zoster virus. Significant differences between this group and the normal control group were recognized. On the other hand, 11 (25%) of 44 cases initially diagnosed as idiopathic Bell's Palsy in the acute stage showed increased antibody titer. It was found that serological testing of paired sera was necessary to differentiate idiopathic Bell's palsy from Ramsay-Hunt's syndrome. The clinical findings in these cases were analyzed for relative symptoms and signs of viral infections.