Tomihisa Yokoyama

Role of Angiotensin II Type 1 Receptor on Retinal Vascular Leakage in a Rat Oxygen-Induced Retinopathy Model

Aim: To investigate the role of angiotensin type 1 (AT1) and type 2 (AT2) receptors in hypoxia-induced retinal vascular hyperpermeability. Methods: Brown-Norway rat pups were exposed to hyperoxic conditions from postnatal day 7 (P7) to P12, and to subsequent normal air for 5 days [oxygen-induced retinopathy (OIR) model]. Olmesartan medoxomil (AT1 receptor antagonist; administered orally), PD123319 (AT2 receptor antagonist; administered subcutaneously) or a vehicle was administered once daily during the last 5 days. At P16, the retinal permeability was determined by measuring the leaked fluorescein-conjugated dextran concentration in the retina. The vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF-1) α proteins in the retina were assessed by an ELISA and western blotting, respectively. Results: Olmesartan medoxomil partially, but significantly, inhibited the retinal vascular hyperpermeability induced by hypoxia. In contrast, PD123319 did not show a significant effect. The VEGF and HIF-1α protein levels were significantly elevated in the OIR retina; however, there was no significant effect of olmesartan medoxomil on the expression of either protein. Conclusions: These results suggest that the AT1 receptor is, at least partly, responsible for hyperpermeability in the OIR rat retina via a mechanism independent of HIF-1 and VEGF expression.

Olmesartan medoxomil ameliorates sciatic nerve regeneration in diabetic rats.

To evaluate the effect of angiotensin II type1 receptor blocker on nerve regeneration delay in diabetic rats, nerve regeneration was monitored by a pinch test on the crushed sciatic nerves of streptozotocin-induced diabetic rats. Nerve regeneration was significantly delayed in diabetic rats and was partly ameliorated by treatment with olmesartan medoxomil (3 mg/kg/day, orally). In the ipsilateral dorsal root ganglia, the mRNA level of insulin-like growth factor-1 and ciliary neurotrophic factor (CNTF) was downregulated, whereas the mRNA level of neurotrophin-3 and CNTF receptor was upregulated. Olmesartan medoxomil significantly enhanced the CNTF expression. These results showed that angiotensin II type1 receptor blocker treatment is effective on nerve regeneration delay in diabetic animals and may provide an effective therapy for clinical diabetic neuropathy.

Pharmacological, pharmacokinetics and safety profiles of DS-5565, a novel α2δ ligand

OBJECTIVE: To clarify the characteristics of DS-5565 as a novel α 2 δ ligand , we conducted the experiments using pregabalin (PGB) as a reference. BACKGROUND: DS-5565 is an analgesic drug that binds to the α 2 δ subunit (α 2 δ-1 and α 2 δ-2) of voltage-dependent Ca 2+ channels. The α 2 δ-1 is the main target for the analgesic effect of α 2 δ ligands. The contribution of the α 2 δ-2 to the CNS side effects of α 2 δ ligands still remains to be elucidated. DESIGN/METHODS: The binding affinity and dissociation rate were investigated with rat α 2 δ-1 and α 2 δ-2 transfected cells. The analgesic effect was investigated with von Frey test in streptozotocin (STZ)-induced diabetic rats. The CNS side effects were investigated with rota-rod performance (RR) and locomotor activity (LA) in rats.The plasma drug concentration was measured by LC-MS/MS. RESULTS: The binding affinities of DS-5565 for α 2 δ-1 and α 2 δ-2 were comparable to those of PGB. Interestingly DS-5565 showed a slower dissociation rate from α 2 δ-1 than α 2 δ-2, in particular α 2 δ-1 compared to PGB. DS-5565 showed potent and sustained analgesic effects and the ED 50 was ca 2.5 mg/kg (ED 50 for PGB: 29.3 mg/kg). The plasma concentration of DS-5565 in the STZ rats was about 65-fold less than PGB. DS-5565 inhibited RR (ID 50 : 9.4 mg/kg) and LA (ID 50 : 43.9 mg/kg) and the ratios ID 50 /ED 50 (CNS safety margin) were ca 3.8 in RR and ca 18 in LA. The ratios for PGB were 0.4 and 3.9, respectively. CONCLUSIONS: DS-5565 has superior analgesic effects with a wider CNS safety margin relative to PGB. These profiles of DS-5565 are possibly due to its unique binding characteristics to α 2 δ-1 and α 2 δ-2. Disclosure: Dr. Yokoyama has received personal compensation for activities with Daiichi Pharmaceutical Corp. as an employee. Dr. Arakawa has received personal compensation for activities with Daiichi Pharmaceutical Corporation as an employee. Dr. Domon has received personal compensation for activities with Daiichi Pharmaceutical Corp. as an employee. Dr. Matsuda has received personal compensation for activities with Daiichi Pharmaceutical Corp. Dr. Inoue has received personal compensation for activities with Daiichi Pharmaceutical Corp. as an employee. Dr. Kitano has received personal compensation for activities with Daiichi Pharmaceutical Corp. Dr. Takahashi has received personal compensation for activities with Daiichi Pharmaceutical Corp. as an employee. Dr. Yamamura has received personal compensation for activities with Daiichi Sankyo. Dr. has received personal compensation for activities with Daiichi Pharmaceutical Corp. as an employee.

Discovery of (phenoxy-2-hydroxypropyl)piperidines as a novel class of voltage-gated sodium channel 1.7 inhibitors

A novel class of NaV1.7 inhibitors has been identified by high-throughput screening followed by structure activity relationship studies. Among this series of compounds, piperidine 9o showed potent human and mouse NaV1.7 inhibitory activities with fair subtype selectivity over NaV1.5. Compound 9o successfully demonstrated analgesic efficacy in mice comparable to that of the currently used drug, mexiletine, but with an expanded central nervous system safety margin.

Contents Vol. 41, 2009

Anatomy, Pathology and Cell Biology A. Prescott, Dundee Biochemistry, Molecular Biology and Molecular Genetics J. Graw, Neuherberg Clinical and Epidemiological Research M. Kojima, Kahoku Clinical Retina P. Wiedemann, Leipzig Cornea and Ocular Surface C. Marfurt, Gary, Ind. Glaucoma C. Erb, Berlin Immunology and Microbiology U. Pleyer, Berlin Lens and Cataract S. Varma, Baltimore, Md. Miscellaneous U. Pleyer, Berlin Neuro-Ophthalmology and Vision Sciences P. Aydin, Ankara Ocular Oncology M. Jager, Leiden Physiology, Pharmacology and Toxicology A. Wegener, Bonn Retina and Retinal Cell Biology M. Boulton, Gainesville, Fla. P. Wiedemann, Leipzig Editorial Board