Neuroprotective agents

The communication in the nervous system is a pharmacological balance between excitatory and inhibitory signals, and seizure behavior is one of the most common manifestations of when an imbalance occurs. Environmental toxins can cause significant disruption of excitation-inhibition balance, but while some toxins, like nerve agents, have known targets and require novel antidotes, some have unknown neurobiological mechanisms and require exploration. Of particular concern, there is little knowledge on how herbicides may affect neurological signaling. Glyphosate, the world’s most popular herbicide, was found to be in 80% of people’s urine, and since it is so prevalent, it is critical to understand its impact on both excitatory and inhibitory signaling. We used an electroshock assay developed for C. elegans to uncover evidence that glyphosate, and the commercial formula Roundup, disrupted the excitation-inhibition balance by blocking GABA-A receptors. This presented a novel hypothesis of an inhibitory neurobiological target for glyphosate. As glutamate is the major excitatory neurotransmitter in the human central nervous system, an electrophysiology assay using Drosophila was used and found that Roundup, but not glyphosate, reduced synaptic viability. This result directs attention to the undisclosed adjuvant component which may have a significant effect on synaptic transmission, though the exact mechanism requires further investigation.

Synaptic transmission is a mechanism that makes life possible for many organisms. Damaging this crucial process, such as with a buildup of Reactive Oxygen Species (ROS), is extremely detrimental for the entire organism. Previously, the Dawson-Scully lab has determined that exposure of the Drosophila melanogaster neuromuscular junction (NMJ) to ROS accumulation can result in synaptic failure at a faster rate than saline controls (Caplan et al., 2013). To combat such effects, novel three-dimensional Resveramorph compounds were created to act as a neuroprotective agent against the harmful effects of acute oxidative stress (Bollinger et al., 2019; Sial et al., 2019). With the initial Resveramorph compounds demonstrating neuroprotective effects, additional analysis of other Resveramorph compounds were of interest to better understand their role in neuroprotection. Further testing of these compounds allows for the investigation of how chemical structure affects a compound’s neuroprotective activity.

Cone snails are carnivorous marine mollusks, utilizing their neuropeptide-rich venom for prey capture. The venom of Conus brunneus, a wide-spread Eastern Pacific vermivore, has not been extensively studied. In the current work, peptides from the dissected venom were characterized and tested using preliminary bioassays. Six peptides (A-F) were isolated and tested. Three peptide identities were determined by comparison with previously reported data: bru9a (A), bru3a (F), and an a-conotoxin (E). Preliminary screening in a stroke-related model of induced glutamate excitotoxicity in primary neuronal cells and PC12 cell cultures indicated potential neuroprotective activity of peptide fractions A, D, and F. Further testing is necessary to determine and verify structure, activity, target, and mechanism of action of the promising peptides from C. brunneus, which may prove effective neuropharmacological agents to treat stroke.