Background and purpose: Natural compounds obtained from marine organisms have received considerable attention as potential sources of novel drugs for treatment of human inflammatory diseases. Capnellene, isolated from the marine soft coral Capnella imbricate, 4,4,6a-trimethyl-3-methylene-decahydro-cyclopenta[ə]pentalene-2,3a-diol (GB9) exhibited antiinflammatory actions on activated macrophages in vitro. Here we have assessed the anti-neuroinflammatory properties of GB9 and its acetylated derivative, acetic acid 3a-hydroxy-4,4,6a-trimethyl-3-methylene-decahydro-cyclopenta[ə]pentalen-2-yl ester (GB10). Experimental approach: Effects of GB9 or GB10 on the expression of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in interferon-g (IFN-g)-stimulated mouse microglial BV2 cells were measured by Western blot. The in vivo effects of these compounds were examined in the chronic constriction injury (CCI) rat model of neuropathic pain, measuring thermal hyperalgesia, and microglial activation and COX-2 protein in lumbar spinal cord, by immunohistochemistry. Key results: In BV2 cells, GB9 and GB10 inhibited the expression of iNOS and COX-2, stimulated by IFN-g. Intrathecal administration of GB9 and GB10 inhibited CCI-induced nociceptive sensitization and thermal hyperalgesia in a dose-dependent manner. Intraperitoneal injection of GB9 inhibited CCI-induced thermal hyperalgesia and also inhibited CCI-induced activation of microglial cells and up-regulation of COX-2 in the dorsal horn of the lumbar spinal cord ipsilateral to the injury. Conclusion and implications: Taken together, these data indicate that the marine-derived capnellenes, GB9 and GB10, had anti-neuroinflammatory and anti-nociceptive properties in IFN-g-stimulated microglial cells and in neuropathic rats respectively. Therefore, capnellene may serve as a useful lead compound in the search for new therapeutic agents for treatment of neuroinflammatory diseases.

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The central nervous system (CNS) exhibits remarkable plasticity in early life and can be altered significantly by various prenatal influences. We previously showed that prenatal exposure to morphine altered kinetic properties of N-methyl-D-aspartate (NMDA) receptor-mediated synaptic currents in the hippocampus of young rat offspring at the age of 14 days (P14). The present study further investigates whether NMDA receptor-mediated synaptic plasticity and/or cyclic adenosine monophosphate-responsive element-binding protein (CREBSerine-133), an important transcription factor underlying learning and memory, can be altered by prenatal morphine exposure in these offspring. Subsequently, the Morris water maze task was performed at the older ages (P28-P31). The magnitude of long-term depression (LTD) generated by a low-frequency stimulation (LFS, 1 Hz for 15 min) in hippocampal slices from the vehicle-control offspring (P14) was significantly larger than that in slices from the morphine-treated offspring, although there was no such difference in the magnitude of long-term potentiation (LTP) elicited by a high-frequency stimulation (100 Hz for 1 s) between the two groups. Comparison of the expression range of glutamatergic synaptic plasticity in slices from the vehicle-control and morphine-treated offspring, calculated as the difference in the maximal magnitude between LTP and LTD, demonstrated a remarkably smaller range in the slices from the morphine-treated offspring. In addition, the decreased phosphorylation of CREBSerine-133 and the impaired ability of spatial learning were also seen in the morphine-treated offspring, as compared with the vehicle-control offspring. Collectively, the study suggests that maternal exposure to morphine reduces the range of synaptic plasticity by decreasing the expression of LTD, but not of LTP, in CA1 pyramidal neurons of the hippocampus from rat offspring. More importantly, decreased phosphorylation of CREBSerine-133 may play a role for the impaired spatial learning and memory in rat offspring exposure to prenatal morphine. Thus, the findings here may provide important insights into cellular/molecular mechanisms underlying pathophysiological changes in the CNS of young offspring from morphine-addicted mothers and serve as a basis for possible therapeutic intervention.