An automated method by which effects of compounds on locomotor activity and spontaneous neuropathic pain-specific movements can be simultaneously evaluated in rats with chronic-constriction nerve injury.

Neuropathic pain patients are characterized by evoked pain (hyperalgesia and allodynia) and spontaneous pain, the latter of which is the predominant symptom. In animal models of neuropathic pain, effects of test compounds on spontaneous pain-related behaviors have been evaluated by direct visual observation. In addition, by performing another locomotor activity experiment in normal animals, it is also indispensable to examine whether test compounds cause motor impairment to avoid overestimation of their analgesic activities.

Inhibition of bone resorption in cultures of mouse calvariae by apicularen A.

Apicularens A and B were isolated from the myxobacterial genus Chondromyces apiculatus JW184. Apicularen A inhibited bafilomycin A1-sensitive ATP-dependent proton transport into microsome vesicles more potently than apicularen B. Bone resorption in cultures of mouse calvariae induced by human parathyroid hormone (PTH) or interleukin-1beta (IL-1beta) was inhibited by apicularen A at 10 and 100 nM, while apicularen B had no effect.

Effect of a V-ATPase inhibitor, FR202126, in syngeneic mouse model of experimental bone metastasis.

Purpose: It has been demonstrated that vacuolar ATPase (V-ATPase) is involved in various aspects of bone metastasis. The aim of this study is to investigate the effect of the anti-bone resorptive activity of the V-ATPase inhibitor FR202126 on bone metastases in mice with metastatic breast cancer.

Method: As a spontaneous model of breast cancer metastasis to bone, mouse breast cancer cells, 4T1, were injected into the mammary fat pad in immunocompetent syngeneic mice.

FR177995, a novel vacuolar ATPase inhibitor, exerts not only an inhibitory effect on bone destruction but also anti-immunoinflammatory effects in adjuvant-induced arthritic rats.

There is considerable evidence that osteoclasts are involved in the pathogenesis of juxta-articular bone destruction in rheumatoid arthritis. Vacuolar ATPases (V-ATPases), which are highly expressed in the ruffled border membrane of osteoclasts, play a central role in the process of bone resorption, and V-ATPase inhibitors are effective in preventing bone destruction in several animal models of lytic bone diseases. Here, we evaluated for the first time the effects of V-ATPase inhibition in rats with adjuvant-induced arthritis (AIA) using FR177995, a novel V-ATPase inhibitor.

Vacuolar ATPase as a drug discovery target.

Vacuolar ATPases (V-ATPases) are present not only in the plasma membranes of specialized cells but also in ubiquitous intracellular acidic compartments, which are essential for physiological cellular function. Consequently, although V-ATPases are important etiologically in several diseases, it seems that they might not be good molecular targets. In fact, bafilomycin A1, a potent and specific inhibitor of V-ATPase, exerts severe and acute toxic reaction when administered to animals.

Inhibition of vacuolar-type (H+)-ATPase by the cytostatic macrolide apicularen A and its role in apicularen A-induced apoptosis in RAW 264.7 cells.

Apicularen A and the known vacuolar-type (H(+))-ATPase (V-ATPase) inhibitor bafilomycin A(1) induced apoptosis of RAW 264.7 cells, while apicularen B, an N-acetyl-glucosamine glycoside of apicularen A, was far less effective. Apicularen A inhibited vital staining with acridine orange of the intracellular organelles of RAW 264.

A novel inhibitor of vacuolar ATPase, FR202126, prevents alveolar bone destruction in experimental periodontitis in rats.

An acidic microenvironment formed by vacuolar ATPase (V-ATPase) expressed in plasma membranes of osteoclasts is thought to be indispensable for bone resorption. This study examined the efficacy of a novel V-ATPase inhibitor, FR202126, in reducing alveolar bone loss caused by experimental periodontitis in rats. FR202126 inhibited H+ transport in plasma membrane vesicles of murine osteoclasts, whereas FR202126 exerted no effect on H+ transport of mitochondrial ATPase or gastric H+,K+-ATPase, indicating that FR202126 is a specific inhibitor of V-ATPase.

A vacuolar ATPase inhibitor, FR167356, prevents bone resorption in ovariectomized rats with high potency and specificity: potential for clinical application.

Unlabelled: FR167356, a novel inhibitor of vacuolar ATPase, has high potency against osteoclast V-ATPase and low potency against lysosomal V-ATPase. FR167356 is the first compound of this nature to be tested. It has the potential to be useful for clinical application.

A novel inhibitor of vacuolar ATPase, FR167356, which can discriminate between osteoclast vacuolar ATPase and lysosomal vacuolar ATPase.

1 Vacuolar ATPase (V-ATPase) has been proposed as a drug target in lytic bone diseases. Studies of bafilomycin derivatives suggest that the key issue regarding the therapeutic usefulness of V-ATPase inhibitors is selective inhibition of osteoclast V-ATPase. Previous efforts to develop therapeutic inhibitors of osteoclast V-ATPase have been frustrated by a lack of synthetically tractable and biologically selective leads.

Effect of Aminopterin and Deoxyribonucleosides on the Cleavage and Embryogenesis of the Sea Urchin, Hemicentrotus pulcherrimus: (aminopterin/thymidine/5-bromo-2'-deoxyuridine/cell division/sea urchin development).

In the embryos of the sea urchin, Hemicentrotus pulcherrimus, reared with 150 μM aminopterin from the time of fertilization, cessation of the development occurred at the blastula stage, at which the dTTP level became quite low. Another addition of thymidine to the embryo culture containing aminopterin resulted in an elevation of dTTP concentration in the embryos and allowed them to develop normally. Decrease in the dTTP level, resulting from the inhibition of thymidylate synthesis by aminopterin, probably causes a failure of egg cleavage and development.