TRPV4 channels promote vascular permeability in retinal vascular disease.

This study aimed to determine the role of transient receptor potential vanilloid 4 (TRPV4), a calcium (Ca2+)-permeable cation channel, in the pathophysiology of retinal vascular disease. The retinal vein occlusion (RVO) murine model was created by irradiating retinal veins using lasers. TRPV4 expression and localization were evaluated in RVO mice retinas. In addition, we examined the effects of TRPV4 antagonists (RQ-00317310, HC-067047, GSK2193874, and GSK2798745) on retinal edema, blood flow, and ischemic areas in RVO mice. Furthermore, changes in the retinal expression of tumor necrosis factor (TNF)-α and aquaporin4 (AQP4) by RQ-00317310 were analyzed using Western blot. We also assessed the barrier integrity of epithelial cell monolayers using trans-endothelial electrical resistance (TEER) in Human Retinal Microvascular Endothelial Cells (HRMECs). The expression of TRPV4 was significantly increased and co-localized with glutamine synthetase (GS), a Müller glial marker, in the ganglion cell layer (GCL) of the RVO mice. Moreover, RQ-00317310 administration ameliorated the development of retinal edema and ischemia in RVO mice. In addition, the up regulation of TNF-α and down-regulation of AQP4 were lessened by the treatment with RQ-00317310. Treatment with GSK1016790A, a TRPV4 agonist, increased vascular permeability, while RQ-00317310 treatment decreased vascular endothelial growth factor (VEGF)- or TRPV4-induced retinal vascular hyperpermeability in HRMECs. These findings suggest that TRPV4 plays a role in the development of retinal edema and ischemia. Thus, TRPV4 could be a new therapeutic target against the pathological symptoms of retinal vascular diseases.

Identification of a highly potent and selective CB2 agonist, RQ-00202730, for the treatment of irritable bowel syndrome.

Herein we report the identification of a highly potent and selective CB2 agonist, RQ-00202730 (40), obtained by lead optimization of the benzimidazole scaffold. Compound 40 showed strong agonistic activity with an EC50 of 19nM and excellent selectivity (>1300-fold) over the CB1 receptor. Compound 40 displayed a dose dependent analgesic effect on TNBS-induced visceral hypersensitivity in rats by oral administration (ED50 0.66mg/kg at 2.5h after oral administration). In addition, 40 did not show a significant effect on body temperature in rats after oral administration at 300mg/kg. These findings suggest that highly selective CB2 agonists will be effective agents for IBS therapy.

Characterization of primary sensory neurons mediating static and dynamic allodynia in rat chronic constriction injury model.

Mechanical allodynia, such as static and dynamic allodynia, is a prominent feature of neuropathic pain syndromes. The aim of this study is to characterize primary sensory neurons mediating the mechanical allodynia in a rat chronic constriction injury (CCI) model with a combination of pharmacological and histological investigations. N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carbox-amide (BCTC), a selective and competitive antagonist of the vanilloid receptor 1 (TRPV1), and resiniferatoxin, which causes desensitization of TRPV1-expressing fibres, suppressed static allodynia but not dynamic allodynia in CCI rats. Immunohistochemical studies of TRPV1 and NF200, an A-fibre marker 200 kDa neurofilament, in dorsal root ganglion neurons demonstrated that each 48% of the positive-stained neurons were immunoreactive only for TRPV1 or NF200. The other 4% of stained neurons were double-positive for TRPV1 and NF200. Of the TRPV1positive neurons, more than 99% were small-(diameter <25 microm) and medium-(25-45 microm) sized. In contrast, 97% of NF200 single-labelled neurons were medium-and large-(>45 microm) sized. These findings suggest that two types of mechanical allodynia are transmitted by different primary sensory neurons: static allodynia is mediated by TRPV1 positive small-and medium-sized neurons and dynamic allodynia might be signalled by TRPV1-negative medium- and large-sized neurons.

A novel antibiotic CJ-17,572 from a fungus, Pezicula sp.

A new antibiotic, CJ-17,572 (I) was isolated from the fermentation broth of a fungus Pezicula sp. CL11877. The structure of I was determined to be a new equisetin derivative by spectroscopic analyses. The compound inhibits the growth of multi-drug resistant Staphylococcus aureus and Enterococcusfaecalis with IC50s of 10 and 20 microg/ml, respectively.

CJ-15,696 and its analogs, new furopyridine antibiotics from the fungus Cladobotryum varium: fermentation, isolation, structural elucidation, biotransformation and antibacterial activities.

CJ-15,696 and 7 novel furopyridine antibiotics were isolated from the fungus Cladobotryum varium CL12284. Their structures were determined by X-ray crystallography and spectral analysis. Three biotransformed analogs were also prepared from CJ-15,696. CJ-15,696 showed moderate activity against various Gram-positive bacteria including some drug resistant strains such as methicillin resistant Staphylococcus aureus (MRSA).