Glutathione, both reduced (GSH) and oxidized (GSSG), was effective in displacing binding of l‐[3H]‐glutamic acid (l‐[3H]Glu) and dl‐(E)‐2‐[3H]amino‐4‐propyl‐5‐phosphono‐3‐pentenoic acid ([3H]CGP‐39653) in rat brain synaptic membranes, with less potent displacement of binding of dl‐α‐amino‐3‐hydroxy‐5‐[3H]‐methylisoxazole‐4‐propionic and [3H]kainic acids. Liquid chromatographic analysis revealed that both GSH and GSSG were contaminated with l‐Glu by <1%. Both GSH and GSSG potentiated (+)‐5‐[3H]methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclohepten‐5,10‐imine ([3H]MK‐801) binding in a manner similar to that found with l‐Glu. Pre‐treatment with glutamate dehydrogenase (GDH) induced a marked rightward shift of the concentration‐response curve for l‐Glu in the presence of NAD without affecting that in its absence, whereas GDH was ineffective in affecting the potentiation by both GSH and GSSG even in the presence of NAD. In the presence of GSH at a maximally effective concentration, both glycine (Gly) and spermidine potentiated [3H]MK‐801 binding to a somewhat smaller extent than that found in the presence of l‐Glu at a maximally effective concentration. The potentiation of [3H]MK‐801 binding by GSH was invariably attenuated by addition of CGP‐39653, d‐2‐amino‐5‐phosphonovaleric acid (d‐AP5), and 5,7‐dichlorokynurenic acid (DCKA), whereas GSH was effective in diminishing potencies of CGP‐39653, d‐AP5, DCKA, and 6,7‐dichloroquinoxaline‐2,3‐dione to inhibit [3H]MK‐801 binding when determined in the presence of both l‐Glu and Gly. These results suggest that glutathione may be an endogenous agonist selective for the N‐methyl‐d‐aspartate (NMDA) recognition domain on the NMDA receptor ionophore complex.

Etoposide induces apoptotic cell death in normal and cancer cells. This apoptosis plays a role not only in anticancer effects but also in adverse reactions, such as myelosuppression. Because we had previously found that wogonin, a flavone found in a plant, suppresses thymocyte apoptosis induced by etoposide, we examined the effect of this flavone in cancer cells. Wogonin significantly potentiated etoposide-induced apoptosis in HL-60 cells. This flavone impaired the function of P-glycoprotein and then increased cellular content of etoposide in the cells. Thus, this flavone is likely to act as an inhibitor of P-glycoprotein and potentiate the apoptotic action of etoposide. On the other hand, wogonin inhibited etoposide-induced apoptosis in thymocytes, one of the normal cells. The potentiation by wogonin is likely to be a specific action for cancer cells but not normal cells. Therefore, this flavone may be used to reduce the excretion of the anticancer agents via P-glycoprotein and increase the pharmacological action of it in cancer cells. These results suggest that wogonin may play a role in overcoming multidrug resistance.

Cationic surfactants, such as benzalkonium chloride and benzethonium chloride, possess quaternary ammonium salt. These surfactants have antimicrobial action and are used as a preservative and an antiseptic. The positively charged polar head of cationic surfactants seems to play a role in the antimicrobial action of these compounds. Recently, benzalkonium chloride in eye drops has been reported to induce apoptosis in conjunctival cells. Here, we examined whether various types of surfactants including anionic and amphoteric surfactants induce apoptosis or not in mammalian cells. Antimicrobial cationic surfactants induced apoptosis at lower concentration than its critical micelle concentration (CMC) in rat thymocytes. Other quaternary ammonium surfactants, such as cetyltrimethylammonium bromide, similarly increased biochemical and morphological features of apoptosis, whereas both anionic and amphoteric surfactants had no significant effect on these apoptotic features. These results suggest that the positive charge of quaternary ammonium surfactants is involved with onset of the apoptotic process. The treatment of benzethonium chloride also led to apoptotic cell death in Jurkat cells. These results indicate that cationic surfactants induce apoptosis in the normal and cancer cells.

1 We examined the eect of 3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine (ibudilast), which has been clinically used for bronchial asthma and cerebrovascular disorders, on cell viability induced in a model of reperfusion injury. 2 Ibudilast at 10 ± 100 mM signi®cantly attenuated the H 2 O 2 -induced decrease in cell viability. 3 Ibudilast inhibited the H 2 O 2 -induced cytochrome c release, caspase-3 activation, DNA ladder formation and nuclear condensation, suggesting its anti-apoptotic eect. 4 Phosphodiesterase inhibitors such as theophylline, pentoxyfylline, vinpocetine, dipyridamole and zaprinast, which increased the guanosine-3',5'-cyclic monophosphate (cyclic GMP) level, and dibutyryl cyclic GMP attenuated the H 2 O 2 -induced injury in astrocytes. 5 Ibudilast increased the cyclic GMP level in astrocytes. 6 The cyclic GMP-dependent protein kinase inhibitor KT5823 blocked the protective eects of ibudilast and dipyridamole on the H 2 O 2 -induced decrease in cell viability, while the cyclic AMPdependent protein kinase inhibitor KT5720, the cyclic AMP antagonist Rp-cyclic AMPS, the mitogen-activated protein/extracellular signal-regulated kinase inhibitor PD98059 and the leukotriene D 4 antagonist LY 171883 did not. 7 KT5823 also blocked the eect of ibudilast on the H 2 O 2 -induced cytochrome c release and caspase-3-like protease activation. 8 These ®ndings suggest that ibudilast prevents the H 2 O 2 -induced delayed apoptosis of astrocytes via a cyclic GMP, but not cyclic AMP, signalling pathway.