Achieving regeneration in the central nervous system represents one of the greatest intellectual and practical challenges in neurobiology, and yet it is an absolute requirement if spinal cord injury patients are to have any hope of recovery. The mission of the International Spinal Research Trust (ISRT), established in 1980, is to raise money speci®cally for spinal research, with a view to ending the permanence of paralysis caused by spinal cord injury. This review summarises some of the major steps forward made in recent years in understanding the mechanisms involved in spinal cord injury and where these discoveries ®t in with the ISRT's overall objectives. We review approaches aimed at (1) preventing immediate adverse reactions to injury such as neuronal death and scar formation; (2) minimising inhibitory properties of the CNS environment and maximising the growth potential of damaged neurons; (3) understanding axonal guidance systems that will be required for directed outgrowth and functional reconnection; and (4) optimising the function of surviving systems. We also discuss infrastructural' prerequisites for applying knowledge gained through spinal research to the clinical condition, including basic scienti®c issues such as developing representative animal models of spinal cord injury and sensitive quantitative methods for assessing growth and functional restoration. In addition, we point out the importance of communication. The need to share knowledge between research groups is vital for advancing our understanding of injury and repair mechanisms. Equally important is the need for communication between basic scientists and clinicians which will be essential for what is the ultimate goal of the ISRT, the development of relevant treatment strategies that will prove bene®cial to the spinal injured patient. Spinal Cord (2000) 38, 449 ± 472

We have found that mouse ear oedema induced by the topical application of arachidonic acid is not a specific screen for compounds inhibiting the lipoxygenase or cyclo-oxygenase pathways of arachidonic acid metabolism. Although such compounds are able to reduce the oedema substantially, pharmacological agents such as histamine antagonists, phosphodiesterase inhibitors, free radical scavengers, and also various compounds not normally considered to have anti-inflammatory properties, can equally effectively reduce the oedema. A mutual potentiation of the effects of prostaglandins, leukotrienes and mast cell-derived histamine would allow many, but not all, of the active agents to be rationalised. The ability of compounds not influencing these three types of inflammatory mediators to reduce the oedematous response means the model is of limited value for directed screening.

The synthesis of a series of N-phosphonalkyl dipeptides 6 is described. Syntheses were devised that allowed the preparation of single diastereoisomers and the assignment of stereochemistry. The compounds were evaluated in vitro for their ability to inhibit the degradation of radiolabeled collagen by purified human lung fibroblast collagenase. Several of the compounds were potent collagenase inhibitors and were at least 10-fold more potent than their corresponding N-carboxyalkyl analogues. Activity was lost when the phosphonic acid group P(O)(OH)2 was replaced by the phosphinic acid groups P(O)(H)(OH) and P(O)(Me)(OH). At the P1 position, (R)- or (S)-alkyl groups, especially ethyl and methyl (e.g., 12a,b, 52a,b, and 53a,b), or an (R)-phenethyl moiety (55a) conferred high potency (IC50 values in the range 0.23-0.47 microM). (S)-Stereochemistry was preferred for the P1' isobutyl side chain. Structure-activity relationships were also investigated at the P2' site, and interestingly, compounds with basic side chains, such as the guanidine 57a, were equipotent with more lipophilic compounds, such as 52a. As with other series of collagenase inhibitors, potency was enhanced by introducing bicyclic aromatic P2' substituents. The most potent phosphonic acid of the series was the bicyclic aromatic P2' tryptophan analogue 59a (IC50 0.05 microM).

CD23, the low-affinity IgE receptor, is up-regulated on interleukin (IL)-4-stimulated B cells and monocytes, with a concomitant increase in the release of soluble fragments of CD23 (sCD23) into the medium by proteolytic processing of the surface-bound intact CD23. The effect of inhibition of the processing of CD23 on IgE production in human and mouse cells and in a mouse model in vivo was evaluated. CD23 processing to sCD23 from RPMI 8866 (a human Epstein-Barr virus-transformed B cell line) cell membranes was inhibited by a broad-spectrum matrix-metalloprotease inhibitor, batimastat, with an IC50 of 0.15 microM. Batimastat also inhibited CD23 processing in whole RPMI 8866 cells as well as in IL-4-stimulated purified human monocytes with similar IC50. Batimastat inhibited IgE production from IL-4/anti-CD40-stimulated human tonsil B cells as well as mouse splenic B cells in a manner consistent with inhibition of CD23 processing. Release of soluble fragments of CD23 in the cell supernatants of tonsil B cells was inhibited over the concentration range of 1-10 microM batimastat and intact cell surface CD23 was increased on mouse splenic B cells in the presence of these concentrations of batimastat. IgE production of IL-4-stimulated human peripheral blood mononuclear cells was also blocked by 1-10 microM batimastat, again with comparable inhibition of sCD23 release over the same concentration range. Finally, in a mouse model of IgE production, batimastat inhibited IgE production in response to ovalbumin challenge as determined by serum IgE levels. Taken together, the data support a role of CD23 in IgE production and point to CD23 processing to sCD23 as a therapeutically relevant control point in the regulation of IgE synthesis.

IL1-stimulated pig articular cartilage fragments were cultured in the and absence of various metalloproteinase inhibitors. Tissue inhibitor of metalloproteinases (TIMP) was unable to stop the release of proteoglycan from the cartilage. Incubation of cartilage with a potent synthetic metalloproteinase inhibitor inhibited the release of proteoglycan in a dose-dependent fashion. The results suggest that low-M(r) metalloproteinase inhibitors may have therapeutic potential in limiting connective tissue breakdown in conditions such as rheumatoid arthritis.