Four pentacyclic guanidine derivatives (crambescidin 800 [5], crambescidin 816 [6], isocrambescidin 800 [9], and crambine [10]) related to ptilomycalin A [11] have been isolated from the Mediterranean sponge Crambe crambe. Isocrambescidin 800 and crambidine are new derivatives, the structures of which have been determined on the basis of their spectral properties. The absolute configuration of crambescidin 816 at the stereogenic center C-43 has been determined by applying Mosher's method. Pharmacological and biological activities of the Crambe crambe alkaloids are reported. In particular, crambescidin 816 was found to have a potent Ca++ antagonist effect and to inhibit the acetylcholine-induced contraction of guinea pig ileum at very low concentrations.

The regulation of neurotrophin (NT) secretion is critical for many aspects of NT-mediated neuronal plasticity. Neurons release NTs by activity-regulated secretion pathways, initiated either by neurotransmitters and͞or by existing NTs by a positive-feedback mechanism. This process depends on calcium release from intracellular stores. Little is known, however, about potential pathways that down-regulate NT secretion. Here we demonstrate that nitric oxide (NO) induces a rapid down-regulation of brain-derived neurotrophic factor (BDNF) secretion in cultured hippocampal neurons. Similar effects occur by activating a downstream target of intracellular NO, the soluble guanylyl cyclase, or by increasing the levels of its product, cGMP. Furthermore, down-regulation of BDNF secretion is mediated by cGMP-activated protein kinase G, which prevents calcium release from inositol 1,4,5-trisphosphate-sensitive stores. Our data indicate that the NO͞cGMP͞protein kinase G pathway represents a signaling mechanism by which neurons can rapidly down-regulate BDNF secretion and suggest that, in hippocampal neurons, NT secretion is finely tuned by both stimulatory and inhibitory signals.N eurotrophins (NTs), such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-4͞5 (NT-4͞5), and neurotrophin-3 (NT-3), regulate neuronal survival and differentiation during embryonic development (1, 2). In addition to their trophic role, NTs are thought to participate in certain brain functions such as modulation of synaptic transmission and memory formation (3-6). NTs have been shown to modulate synaptic transmission across a broad temporal spectrum ranging from short-term modulation, which occurs in the order of seconds to minutes (7-17), to a prolonged effect that persists for many hours, such as the long-term potentiation (LTP) (18-23) or long-term depression (24-27) response. In fact, NTs are required for the maintenance of LTP in hippocampal slices, because inhibition of BDNF signaling by using receptor bodies applied early after LTP induction restored potentiated synaptic transmission to baseline levels (22). In addition, pretreatment of hippocampal neuron slices with anti-NT receptor antiserum prevented the late phase of the LTP (22). It has been suggested that BDNF concentrations in CA3͞ CA1 hippocampal slices must reach a critical threshold level to initiate and maintain the LTP response (18). This phenomenon has been demonstrated in heterozygous BDNF-defective mice (18,20) that, having impaired endogenous NT production, require either the exogenous administration (20) or local reexpression (19) of BDNF to initiate the LTP response. These observations emphasize the important role played by NTs in modulating synaptic activity and the need to understand better the mechanisms that regulate NT secretion.Recent studies have investigated how neuronal activity can modulate NT secretion. NGF and BDNF secretion is induced in hippocampal slices and cultured hippocampal neurons in response to excitatory neurotransmitters ...

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