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Astrocytes, the most abundant glial cell type in the brain, are considered to have physiological and pathological roles in neuronal activities. We found that reperfusion of cultured astrocytes after Ca2+ depletion causes Ca2+ overload followed by delayed cell death and the Na(+)-Ca2+ exchanger in the reverse mode is responsible for this Ca(2+)-mediated cell injury (Ca2+ paradox injury). The Ca2+ paradox injury of cultured astrocytes is considered to be an in vitro model of ischemia/reperfusion injury, since a similar paradoxical change in extracellular Ca2+ concentration is reported in ischemic brain tissue. This review summarizes the mechanisms underlying the Ca(2+)-mediated injury of astrocytes and the protective effects of drugs against Ca2+ reperfusion injury. This study shows that Ca2+ reperfusion injury of astrocytes is accompanied by apoptosis as evidenced by DNA fragmentation and nuclear condensation. Calpain, reactive oxygen species, calcineurin, caspase-3, and NF-kappa B are involved in Ca2+ reperfusion-induced delayed apoptosis of astrocytes. Several drugs including CV-2619, T-588 and ibudilast protect astrocytes against the delayed apoptosis. CV-2619 prevents astrocytes from the delayed apoptosis by production of nerve growth factor, resulting in an activation of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3 (PI3) kinase signal pathways. The protective effect of T-588 is mainly mediated by an activation of MAP/ERK signal cascade. Moreover, ibudilast prevents the Ca2+ reperfusion-induced delayed apoptosis of astrocytes via cyclic GMP signaling pathway. Further studies in this system will contribute to the development of new drugs that attenuate ischemia/reperfusion injury via modulation of astrocytes.

The artificially induced cough reflex in experimental animals should necessarily be similar to the cough which occurs naturally in humans. The curve demonstrated during a cough of each patient with respiratory disease was characteristic. Compared with the curve of a cough-like reflex (CLR) induced by DMPP, the curve of a cough induced by electrical stimulation of the tracheal mucosa was similar to that of a cough in humans. In dogs and cats anesthetized with alpha-chloralose (80 similar to 100 mg/kg i.p.), the number of CLR with DMPP was dose dependent. Tachphylaxis did not occur despite repeated administration of DMPP. DMPP (5 similar to 10 mug/kg i.v.) did not affect airway resistance. CLR with DMPP was depressed not only by morphine, codeine, oxymethebanol, picoperidamine, piclobetol and hexacol but also by hexamethonium. Thus, it appears that the mechanism of CLR with DMPP is different from that in the cough reflex. This CLR may be utilized for determining the physiology of cough reflex and the site of action of antitussives.