Aberrant Wnt signaling appears to play an important role in the onset of diabetes. Moreover, the insulin signaling pathway is defective in the nucleus tractus solitarii (NTS) of spontaneously hypertensive rats (SHRs) and fructosefed rats. Nevertheless, the relationships between Wnt signaling and the insulin pathway and the related modulation of blood pressure (BP) in the central nervous system have yet to be established. The aim of this study was to investigate the potential signaling pathways involved in Wnt-mediated BP regulation in the NTS. Pretreatment with the LDL receptor-related protein (LRP) antagonist Dickkopf-1 (DKK1) significantly attenuated the Wnt3a-induced depressor effect and nitric oxide production. Additionally, the inhibition of LRP6 activity using DKK1 significantly abolished Wnt3a-induced glycogen synthase kinase 3b (GSK-3b) S9 , extracellular signal-regulated kinases 1/2 T202/Y204 , ribosomal protein S6 kinase T359/S363 , and Akt S473 phosphorylation; and increased insulin receptor substrate 1 (IRS1) S332 phosphorylation. GSK-3b was also found to bind directly to IRS1 and to induce the phosphorylation of IRS1 at serine 332 in the NTS. By contrast, administration of the GSK-3b inhibitor TWS119 into the brain decreased the BP of hypertensive rats by enhancing IRS1 activity. Taken together, these results suggest that the GSK-3b-IRS1 pathway may play a significant role in Wnt-mediated central BP regulation.The nucleus tractus solitarii (NTS), which is located in the dorsal medulla of the brainstem, is the primary site of blood pressure (BP) and sympathetic nerve activity modulation. The NTS participates in cardiovascular, gastric, and gustatory regulation. Our previous studies revealed that several neuromodulators are involved in BP control of the NTS, including insulin (1,2) and nitric oxide (NO) (3).Insulin is primarily produced by pancreatic b-cells. Margolis and Altszuler (4) reported that insulin can cross the blood-brain barrier, as demonstrated by sensitive and specific radioimmunoassay results. However, insulin mRNA and immunoreactive insulin are present in the rat central nervous system (5,6). The insulin receptor (IR) is a tetrameric glycoprotein that belongs to the receptor tyrosine kinase superfamily. Insulin can bind to the IR, leading to the autophosphorylation of the b-subunit of the IR at tyrosine residues, which induces the tyrosine phosphorylation of IR substrates (IRSs) (7). IRs/IRSs can activate the following two major signaling pathways: the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, and the Ras-mitogenactivated protein kinase pathway. Insulin has also been implicated in the regulation of the baroreceptor reflex in the NTS (8,9). We previously found (1,2) that insulin is involved in the control of central BP via the PI3K-Akt-NO synthase (NOS) signaling pathway in the NTS.

BackgroundIn randomized, controlled trials of open-angle glaucoma (OAG) or ocular hypertension (OHT), bimatoprost 0.01 % improved tolerability while retaining the intraocular pressure (IOP)-lowering efficacy of bimatoprost 0.03 %. Given geographic/racial differences in glaucoma presentation, the APPEAL study assessed the occurrence and severity of hyperemia produced by bimatoprost 0.01 %, and its efficacy, in the Taiwanese clinical setting.MethodsIn this multicenter, open-label, observational study, treatment-naïve and previously treated patients with OHT or OAG received once-daily bimatoprost 0.01 % for 12 weeks. Hyperemia (primary endpoint) was graded at baseline, week 6, and week 12 using a photonumeric scale (0, +0.5, +1, +2, +3), grouped (≤ +1, none to mild; ≥ +2, moderate to severe), and reported as unchanged from baseline, improved, or worsened. IOP assessments followed the same schedule. Supplemental efficacy analyses were conducted based on previous therapies.ResultsThe intent-to-treat population (N = 312) included treatment-naïve (13.5 %) and previously treated (86.5 %) patients; mean age was 53.3 years. At baseline, 46.3 % of previously treated patients were receiving prostaglandin analog (PGA) monotherapy. At week 12, 91.2 %, 5.9 %, and 2.9 % of treatment-naïve patients exhibited unchanged, worsened, and improved hyperemia from baseline, respectively; 77.9 %, 12.9 %, and 9.2 % of previously treated patients showed no change, worsening, and improvement, respectively. There were no statistically significant shifts in hyperemia severity in either group, or in subgroups based on previous use of any PGA, any non-PGA, latanoprost, or travoprost monotherapies. In treatment-naïve patients, mean IOP reduction from baseline (18.0 ± 3.8 mm Hg) was 3.6 mm Hg at week 12 (P < 0.0001); 83.3 % had baseline IOP ≤ 21 mm Hg. In previously treated patients, mean additional IOP reduction from baseline (17.8 ± 3.9 mm Hg) was 2.6 mm Hg (P < 0.0001); similar results were observed in patient subgroups based on previous therapies.ConclusionsIn the Taiwanese clinical setting, bimatoprost 0.01 % provided significant IOP lowering in treatment-naïve patients (regardless of baseline IOP) and previously treated patients (even those with relatively low IOP on other therapies), while causing no significant changes in hyperemia from baseline.Trial registrationClinicaltrials.gov NCT01814761. Registered 18 March 2013.