Bilobalide modulates serotonin-controlled behaviors in the nematode Caenorhabditis elegans.
BACKGROUND
Dysfunctions in the serotonergic system have been implicated in several neurological disorders such as depression. Elderly individuals who have been diagnosed with clinical depression show elevated cases of neurodegenerative diseases. This has led to suggestions that modulating the serotonin (5-HT) system could provide an alternative method to current therapies for alleviating these pathologies. The neuroprotective effects of bilobalide in vitro have been documented. We aim to determine whether bilobalide affects the 5-HT system in the nematode C. elegans. The wild type worms, as well as well-characterized 5-HT mutants, were fed with bilobalide in a range of concentrations, and several 5-HT controlled behaviors were tested.


RESULTS
We observed that bilobalide significantly inhibited 5-HT-controlled egg-laying behavior in a dose-dependent manner, which was blocked in the 5-HT receptor mutants (ser-4, mod-1), but not in the 5-HT transporter (mod-5) or synthesis (tph-1) mutants. Bilobalide also potentiated a 5-HT-controlled, experience-dependent locomotory behavior, termed the enhanced slowing response in the wild type animals. However, this effect was fully blocked in 5-HT receptor mod-1 and dopamine defective cat-2 mutants, but only partially blocked in ser-4 mutants. We also demonstrated that acetylcholine transmission was inhibited in a transgenic C. elegans strain that constitutively expresses Abeta, and bilobalide did not significantly affect this inhibition.


CONCLUSIONS
These results suggest that bilobalide may modulate specific 5-HT receptor subtypes, which involves interplay with dopamine transmission. Additional studies for the function of bilobalide in neurotransmitter systems could aid in our understanding of its neuroprotective properties.
Brown
Marishka K
MK
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA. mbrow004@umaryland.edu
Luo
Yuan
Y
D000367:Age Factors; D000448:Aldicarb / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D018118:Chloride Channels / Q000235:genetics; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003517:Cyclopentanes / Q000494:pharmacology*; D004298:Dopamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000494:pharmacology*; D046934:Ginkgolides / Q000494:pharmacology*; D006801:Humans; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000145:classification / Q000235:genetics; D012098:Reproduction / Q000187:drug effects / Q000235:genetics; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D029742:Caenorhabditis elegans Proteins; D018118:Chloride Channels; D002800:Cholinesterase Inhibitors; D003517:Cyclopentanes; D005663:Furans; D046934:Ginkgolides; C417030:MOD-1 protein, C elegans; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D000448:Aldicarb; C073710:bilobalide; D004298:Dopamine