Natural products have played pivotal roles in neuropharmacology due to their potent and selective targeting of specific biochemical pathways and receptors, and are highly useful as probe substances and therapeutic leads. Marine cyanobacteria are exceptionally rich in diverse natural product structures, many of which are toxic or have other biological properties. We propose to continue our productive collaboration between a natural products chemist (Gerwick) and a neuropharmacologist (Murray), expanding on our previous investigations of these life forms for their new and biologically-insightful neuroactive compounds. Thus, we have the long range goals of 1) developing new compounds to serve as novel tools for pharmacology and cell biology, 2) describing new putative environmental toxins so that appropriate actions can be taken should outbreaks occur, and 3) development of neuroactive substances as potential therapeutic lead compounds, especially in the treatment of stroke-induced brain injury. To accomplish these goals we have the following four specific aims: 1) to collect 250 samples of cyanobacteria and algae, and produce high quality focused fraction libraries for screening in assays designed to detect neuroactive natural products, 2) to evaluate the above diverse extracts using high throughput spontaneous Ca2+ oscillation and Na+ influx assays in cerebrocortical neurons, 3) to use innovative and accelerated methods to isolate and structurally characterize new neuroactive substances from marine cyanobacteria testing positively in the screening assays, featuring nanoscale NMR and MSn methods, 4) to further define the molecular pharmacology of several cyanobacterial toxins discovered during prior support. Additionally, to evaluate the influence of newly discovered cyanobacterial ligands on neurite outgrowth, spinogenesis and synaptogenesis in neocortical neurons. Select compounds active in these in vitro assays will be advanced into a mouse model for focal stroke. This will require the production of additional supplies or analogs of these newly discovered compounds, including radioisotope-labeled analogs to be used in radioligand binding and distribution assays. Completion of these aims will increase our knowledge of the unique and neuroactive natural products produced by marine cyanobacteria and algae. The past two cycles of support for this collaborative program have been highly productive, and we now have a mature, well functioning, and highly effective program. We continue to refine our approaches and thinking as applied to the discovery and utility of novel marine neuroactive substances, and this leads us in new research directions for the proposed coming grant period, such as the application of voltage-gated sodium channel activators that promote neurite outgrowth in neocortical neurons to the potential treatment of stroke-induced brain injury.

Public Health Relevance

This project focuses on describing the natural neuroactive compounds present in marine algae and cyanobacteria, and this impacts human health in three areas: 1) this research will find neuroactive compounds that work by new mechanisms, thus allowing a better description of how cells communicate and react to their environment, 2) some of these neuroactive compounds may lead to new therapies for diseases such as stroke, epilepsy, pain control, schizophrenia, and cognitive disorders, and 3) by fully describing the structures and pharmacology of some of these toxic natural products, this research can help reduce human exposures and suggest treatment options in case of exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS053398-12
Application #
8526577
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Jett, David A
Project Start
2001-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
12
Fiscal Year
2013
Total Cost
$479,079
Indirect Cost
$74,555
Name
University of California San Diego
Department
Zoology
Type
Schools of Earth Sciences/Natur
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Mevers, Emily; Matainaho, Teatulohi; Allara', Marco et al. (2014) Mooreamide A: a cannabinomimetic lipid from the marine cyanobacterium Moorea bouillonii. Lipids 49:1127-32
Cao, Zhengyu; Cui, Yanjun; Busse, Eric et al. (2014) Gambierol inhibition of voltage-gated potassium channels augments spontaneous Ca2+ oscillations in cerebrocortical neurons. J Pharmacol Exp Ther 350:615-23
Winnikoff, Jacob R; Glukhov, Evgenia; Watrous, Jeramie et al. (2014) Quantitative molecular networking to profile marine cyanobacterial metabolomes. J Antibiot (Tokyo) 67:105-12
Engene, Niclas; Gunasekera, Sarath P; Gerwick, William H et al. (2013) Phylogenetic inferences reveal a large extent of novel biodiversity in chemically rich tropical marine cyanobacteria. Appl Environ Microbiol 79:1882-8
Gerwick, William H; Fenner, Amanda M (2013) Drug discovery from marine microbes. Microb Ecol 65:800-6
Yang, Jane Y; Sanchez, Laura M; Rath, Christopher M et al. (2013) Molecular networking as a dereplication strategy. J Nat Prod 76:1686-99
Gerwick, William H; Moore, Bradley S (2012) Lessons from the past and charting the future of marine natural products drug discovery and chemical biology. Chem Biol 19:85-98
Choi, Hyukjae; Proteau, Philip J; Byrum, Tara et al. (2012) Cymatherelactone and cymatherols A-C, polycyclic oxylipins from the marine brown alga Cymathere triplicata. Phytochemistry 73:134-41
Malloy, Karla L; Suyama, Takashi L; Engene, Niclas et al. (2012) Credneramides A and B: neuromodulatory phenethylamine and isopentylamine derivatives of a vinyl chloride-containing fatty acid from cf. Trichodesmium sp. nov. J Nat Prod 75:60-6
Nunnery, Joshawna K; Engene, Niclas; Byrum, Tara et al. (2012) Biosynthetically intriguing chlorinated lipophilic metabolites from geographically distant tropical marine cyanobacteria. J Org Chem 77:4198-208

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