Two sponges of the genus Hyrtios have been found to contain new sesquiterpene/quinones identified by detailed spectroscopic analysis. Four new compounds with a 4,9-friedodrim-3-ene skeleton [hyrtiophenol (2), 5-epihyrtiophenol (3), 18-hydroxy-5-epihyrtiophenol (4), and 18-hydroxyhyrtiophenol (5)] were isolated from Hyrtios sp. (Seychelles Islands) along with isospongiaquinone (1). Moreover, the new compound 21-hydroxy-19-methoxyarenarone (8), which bears the 4, 9-friedodrim-4(15)-ene skeleton, was isolated from Hyrtios tubulatus (Curaçao) along with arenarol (6) and 5-epiilimaquinone (7). Assignment of the (13)C NMR signals of four types of 4, 9-friedodrimene skeletons found in sponges is presented.

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Neuroprotective actions of scatter factor/hepatocyte growth factor (SF/HGF) have not been described. We examined the effects of SF/HGF in comparison to acidic fibroblast growth factor-1 (FGF-1) on N-methyl-D-aspartate (NMDA) and quinolinic acid (QUIN)-induced excitotoxicity in primary cerebellar granule neurons. Exposure to NMDA or QUIN for 24 h resulted in concentration-dependent cell death (p < 0.001) that was completely attenuated (p < 0.001) by pre-treatment of cells with SF/HGF (50 ng/mL) or FGF-1 (40 ng/mL). SF/ HGF and FGF-1 activated both Akt and MAP-kinase > threefold (p < 0.001). Neither SF/HGF nor FGF-1 activated cyclic AMP-response element binding protein (CREB), a downstream target of MAP-kinase, whereas brain-derived neurotrophic factor (BDNF) activated both MAP-kinase and CREB in granule neurons. Neuroprotection against NMDA or QUIN by SF/HGF and FGF-1 was negated by the addition of LY294002 (10 lM) or wortmannin (100 nM), two distinct inhibitors of phosphatidylinositol 3-kinase (PI3-K), but not by the MAP-kinase kinase (MEK) inhibitor PD98059 (33 lM). Likewise, expression of a dominant-negative mutant of Akt (Akt-kd) completely prevented the neuroprotective actions of SF/HGF and FGF-1. Overexpression of a constitutively activated Akt (Akt-myr) or wild-type Akt (wtAkt) attenuated excitotoxic cell death. These data show that both SF/HGF and FGF-1 protect cerebellar granule neurons against excitotoxicity with similar potency in a PI3-K/Akt-dependent and MAPkinase/CREB-independent manner.

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