Marine cyanobacteria represent a unique source in the field of drug discovery due to the secondary metabolites they produce and the structural similarity these compounds have to endogenous mammalian receptor ligands. A series of cyanobacteria were subjected to extraction, fractionation by column chromatography and screened for affinity against CNS targets with a focus on serotonin receptors (5-HTRs). Out of 276 fractions screened, 21% had activity at 5-HTRs and/or the 5-HT transporter (SERT). One sample, a cyanobacterium identified by 16S rRNA sequencing as Leptolyngbya from Las Perlas archipelago in Panama, contained a fraction with noted affinity for the 5-HT7 receptor (5-HT7 R). This fraction (DUQ0002I) was screened via intracerebroventricular (ICV) injections in mice using depression and anxiety assays including the forced swim, tail suspension, elevated zero maze, and light-dark preference tests. DUQ0002I decreased depression and anxiety-like behaviors in males and did not have effects in 5-HT7 R knockout or female mice. Administration of DUQ0002I to the CA1 of the hippocampus induced antidepression-like, but not anxiolytic-like behaviors. Testing of further purified materials showed no behavioral effects, leading us to hypothesize that the behavioral effects are likely caused by a synergistic effect between multiple compounds in the fraction. Finally, DUQ0002I was used in a model of neuropathic pain with comorbid depression (spared nerve injury-SNI). DUQ0002I had a similar antidepressant effect in animals with SNI, suggesting a role for the 5-HT7 R in the development of comorbid pain and depression. These results demonstrate the potential that cyanobacterial metabolites have in the field of neuropharmacognosy.
Anti-Anxiety Agents/pharmacology , Antidepressive Agents/pharmacology , Biological Products/pharmacology , Cyanobacteria , Serotonin Antagonists/pharmacology , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/isolation & purification , Antidepressive Agents/chemistry , Antidepressive Agents/isolation & purification , Anxiety Disorders/drug therapy , Behavior, Animal/drug effects , Biological Products/chemistry , Biological Products/isolation & purification , Cyanobacteria/chemistry , Cyanobacteria/genetics , Depressive Disorder/drug therapy , Disease Models, Animal , Drug Discovery , Female , Hippocampus/drug effects , Male , Mice, Inbred C57BL , Mice, Knockout , Pain/drug therapy , Phylogeny , Receptors, Serotonin/genetics , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Antagonists/isolation & purification
