1 Eects of the cyclo-oxygenase (COX)-1 inhibitor SC-560 and the COX-2 inhibitors rofecoxib and DFU were investigated in the normal stomach and after acid challenge. 2 In healthy rats, neither SC-560 nor rofecoxib (20 mg kg 71 each) given alone damaged the mucosa. Co-treatment with SC-560 and rofecoxib, however, induced severe lesions comparable to indomethacin (20 mg kg 71) whereas co-administration of SC-560 and DFU (20 mg kg 71 each) had no comparable ulcerogenic eect 5 h after dosing. ) given alone were not ulcerogenic but aggravated SC-560-induced damage. DFU augmented SC-560 damage 1 but not 5 h after administration whereas rofecoxib increased injury after both treatment periods suggesting dierent time courses. 6 Gastric injurious eects of rofecoxib and DFU correlated with inhibition of in¯ammatory PGE 2 . 7 The ®ndings show that in the normal stomach lesions only develop when both COX-1 and COX-2 are inhibited. In contrast, during acid challenge inhibition of COX-1 renders the mucosa more vulnerable suggesting an important role of COX-1 in mucosal defence in the presence of a potentially noxious agent. In this function COX-1 is supported by COX-2. In the face of pending injury, however, COX-2 cannot maintain mucosal integrity when the activity of COX-1 is suppressed.

1 E ects of indomethacin, the selective cyclo-oxygenase (COX)-2 inhibitors NS-398 and DFU, and dexamethasone on gastric damage induced by 30 min ischaemia followed by 60 min reperfusion (I-R) were investigated in rats. Modulation of gastric levels of COX-1 and COX-2 mRNA by I-R was evaluated using Northern blot and reverse transcription-polymerase chain reaction. 2 I-R-induced gastric damage was dose-dependently aggravated by administration of indomethacin (1 ± 10 mg kg 71 ), NS-398 (0.4 ± 4 mg kg 71 ) or DFU (0.02 ± 2 mg kg 71 ) as assessed macroscopically and histologically. 3 Likewise, administration of dexamethasone (1 mg kg 71 ) signi®cantly increased I-R damage. 4 Low doses of 16,16-dimethyl-prostaglandin(PG)E 2 , that did not protect against ethanol-induced mucosal damage, reversed the e ects of the selective COX-2 inhibitors, indomethacin and dexamethasone. 5 I-R had no e ect on gastric COX-1 mRNA levels but increased COX-2 mRNA levels in a timedependent manner. Dexamethasone inhibited the I-R-induced expression of COX-2 mRNA. 6 I-R was not associated with a measurable increase in gastric mucosal formation of 6-keto-PGF 1a and PGE 2 . PG formation was substantially inhibited by indomethacin (10 mg kg 71 ) but was not signi®cantly reduced by NS-398 (4 mg kg 71 ), DFU (2 mg kg 71 ) or dexamethasone (1 mg kg 71 ). 7 The ®ndings indicate that selective COX-2 inhibitors and dexamethasone markedly enhance gastric damage induced by I-R. Thus, whereas COX-2 has no essential role in the maintenance of gastric mucosal integrity under basal conditions, COX-2 is rapidly induced in a pro-ulcerogenic setting and contributes to mucosal defence by minimizing injury. This suggests that in certain situations selective COX-2 inhibitors may have gastrotoxic e ects.

1 The eects of the non-selective cyclo-oxygenase (COX) inhibitor indomethacin and the selective COX-2 inhibitors, N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulphonamide (NS-398), 5-methanesulphonamido-6-(2,4-di¯uorothio-phenyl)-1-indanone (L-745,337) and 5,5-dimethyl-3-(3-¯uorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furanone (DFU), on the protection induced by the mild irritant 20% ethanol were investigated in the rat stomach. ). Likewise, the protective eect of these agents was not counteracted by NS-398 (1 mg kg 71 , p.o.). 9 Whereas indomethacin (20 mg kg 71 , p.o.) near-maximally inhibited gastric mucosal formation of PGE 2 , 6-keto-PGF 1a and thromboxane (TX) B 2 as well as platelet TXB 2 release, the selective COX-2 inhibitors were ineective. 10 The ®ndings show that selective COX-2 inhibitors, although lacking in ulcerogenic activity, prevent the protection conferred by a mild irritant. Prostaglandis generated by a constitutive COX-2 could thus contribute to physiological functions involved in gastric homeostasis, although at present a non-COX-2-related mechanism underlying the eect of the selective COX-2 inhibitors tested on mild irritant-induced protection cannot be completely excluded.

No abstract

Increase in the size of human neocortex-acquired in evolution-accounts for the unique cognitive capacity of humans. This expansion reflects the evolutionarily enhanced proliferative ability of basal progenitors (BPs), including the basal radial glia and basal intermediate progenitors (bIPs) in mammalian cortex, which may have been acquired through epigenetic alterations in BPs. However, how the epigenome in BPs differs across species is not known. Here, we report that histone H3 acetylation is a key epigenetic regulation in bIP amplification and cortical expansion. Through epigenetic profiling of sorted bIPs, we show that histone H3 lysine 9 acetylation (H3K9ac) is low in murine bIPs and high in human bIPs. Elevated H3K9ac preferentially increases bIP proliferation, increasing the size and folding of the normally smooth mouse neocortex. H3K9ac drives bIP amplification by increasing expression of the evolutionarily regulated gene, Trnp1, in developing cortex. Our findings demonstrate a previously unknown mechanism that controls cortical architecture.