Resveratrol natural product inspired compound as a potent neuroprotectant against acute oxidative stress.

Resveratrol as well as natural products biosynthetically derived from it, have been shown to have protective effects against oxidative stress. However, these compounds possess poor druglike properties. At sub-nanomolar concentrations, a novel compound (RVM-6) inspired by a resveratrol natural product prolongs synaptic viability in neuromuscular junctions in exposed to acute oxidative stress.

Bridged bicyclic compounds: Comprehending a novel compound class as potential anti-seizure agents.

Objective: In the present study, we describe a novel class of small-molecule synthetic compounds that ameliorate seizure-like behavior, using an electroshock assay to examine seizure duration in Caenorhabditis elegans. We also examine the hypothesis that these compounds, which we have called resveramorphs (RVMs), act by an irreversible binding mechanism.

Methods: Our electroshock assay examines seizure duration in C.

Atropine reduces aldicarb-induced sensitivity to electroshock model.

Atropine has been used as an established anticonvulsant treatment for nerve agent intoxication. Atropine reduces electroshock recovery time among aldicarb-exposed wild-type .

Roundup and glyphosate's impact on GABA to elicit extended proconvulsant behavior in Caenorhabditis elegans.

As 3 billion pounds of herbicides are sprayed over farmlands every year, it is essential to advance our understanding how pesticides may influence neurological health and physiology of both humans and other animals. Studies are often one-dimensional as the majority examine glyphosate by itself. Farmers and the public use commercial products, like Roundup, containing a myriad of chemicals in addition to glyphosate.

The Critical Role of Spreading Depolarizations in Early Brain Injury: Consensus and Contention.

Background: When a patient arrives in the emergency department following a stroke, a traumatic brain injury, or sudden cardiac arrest, there is no therapeutic drug available to help protect their jeopardized neurons. One crucial reason is that we have not identified the molecular mechanisms leading to electrical failure, neuronal swelling, and blood vessel constriction in newly injured gray matter. All three result from a process termed spreading depolarization (SD).

Questioning Glutamate Excitotoxicity in Acute Brain Damage: The Importance of Spreading Depolarization.

Background: Within 2 min of severe ischemia, spreading depolarization (SD) propagates like a wave through compromised gray matter of the higher brain. More SDs arise over hours in adjacent tissue, expanding the neuronal damage. This period represents a therapeutic window to inhibit SD and so reduce impending tissue injury.

O-GlcNAc transferase OGT-1 and the ubiquitin ligase EEL-1 modulate seizure susceptibility in C. elegans.

Neurodevelopmental disorders such as epilepsy and autism have been linked to an imbalance of excitation and inhibition (E/I) in the central nervous system. The simplicity and tractability of C. elegans allows our electroconvulsive seizure (ES) assay to be used as a behavioral readout of the locomotor circuit and neuronal function.

Characterization of a novel stimulus-induced glial calcium wave in larval peripheral segmental nerves and its role in PKG-modulated thermoprotection.

Insects, as poikilotherms, have adaptations to deal with wide ranges in temperature fluctuation. Allelic variations in the gene that encodes a cGMP dependent protein kinase, were discovered to have effects on behavior in by Dr. Marla Sokolowski in 1980.

Neural shutdown under stress: an evolutionary perspective on spreading depolarization.

Neural function depends on maintaining cellular membrane potentials as the basis for electrical signaling. Yet, in mammals and insects, neuronal and glial membrane potentials can reversibly depolarize to zero, shutting down neural function by the process of spreading depolarization (SD) that collapses the ion gradients across membranes. SD is not evident in all metazoan taxa with centralized nervous systems.

In vivo expression of peptidylarginine deiminase in Drosophila melanogaster.

Peptidylarginine deiminase (PAD) modifies peptidylarginine and converts it to peptidylcitrulline in the presence of elevated calcium. Protein modification can lead to severe changes in protein structure and function, and aberrant PAD activity is linked to human pathologies. While PAD homologs have been discovered in vertebrates-as well as in protozoa, fungi, and bacteria-none have been identified in Drosophila melanogaster, a simple and widely used animal model for human diseases.

NO/cGMP/PKG activation protects Drosophila cells subjected to hypoxic stress.

The anoxia-tolerant fruit fly, Drosophila melanogaster, has routinely been used to examine cellular mechanisms responsible for anoxic and oxidative stress resistance. Nitric oxide (NO), an important cellular signaling molecule, and its downstream activation of cGMP-dependent protein kinase G (PKG) has been implicated as a protective mechanism against ischemic injury in diverse animal models from insects to mammals. In Drosophila, increased PKG signaling results in increased survival of animals exposed to anoxic stress.

Natural polymorphism in protein kinase G modulates functional senescence in .

The common fruit fly, , is a well-characterized model for neurological disorders and is widely used to investigate the biology of aging, stress tolerance and pleiotropy. The () gene encodes a cGMP-dependent protein kinase (PKG), which has been implicated in several behavioral phenotypes including feeding, sleep, learning and memory, and environmental stress tolerance. We used the well-established activity monitor (DAM) to investigate the effects of the conserved NO/cGMP/PKG signaling pathway on functional senescence.

BK channels and a cGMP-dependent protein kinase (PKG) function through independent mechanisms to regulate the tolerance of synaptic transmission to acute oxidative stress at the Drosophila larval neuromuscular junction.

A cGMP-dependent protein kinase (PKG) has previously been shown to regulate synaptic transmission at the Drosophila neuromuscular junction (NMJ) during acute oxidative stress, potentially through modulation of downstream K channel kinetics; however, the specific K channels through which PKG functions remains unclear. In this study, we hypothesized that PKG may be acting on calcium-activated large-conductance Slo K channels, or BK channels. We found that genetic elimination and pharmacological inhibition of BK channel conductance increases synaptic transmission tolerance to acute HO-induced oxidative stress.

Resveratrol-Inspired Bridged Bicyclic Compounds: A New Compound Class for the Protection of Synaptic Function from Acute Oxidative Stress.

While resveratrol protects organisms from the deleterious effects of oxidative stress, its multifarious mechanism of action limits its potential as a selective medicinal agent. To address this shortcoming, we have designed a molecular scaffold that we have termed a resveramorph. The structure of this compound class possesses much of the functional group characteristics of resveratrol but in a nonplanar molecular arrangement, and, in the present work, we probe the neuroprotective activities of two resveramorph analogues.

egl-4 modulates electroconvulsive seizure duration in C. elegans.

Increased neuronal excitability causes seizures with debilitating symptoms. Effective and noninvasive treatments are limited for easing symptoms, partially due to the complexity of the disorder and lack of knowledge of specific molecular faults. An unexplored, novel target for seizure therapeutics is the cGMP/protein kinase G (PKG) pathway, which targets downstream K channels, a mechanism similar to Retigabine, a recently FDA-approved antiepileptic drug.

Contribution of a natural polymorphism in protein kinase G modulates electroconvulsive seizure recovery in .

is a well-characterized model for neurological disorders and is widely used for investigating causes of altered neuronal excitability leading to seizure-like behavior. One method used to analyze behavioral output of neuronal perturbance is recording the time to locomotor recovery from an electroconvulsive shock. Based on this behavior, we sought to quantify seizure susceptibility in larval with differences in the enzymatic activity levels of a major protein, cGMP-dependent protein kinase (PKG).

Electroshock Induced Seizures in Adult .

The nematode is a useful model organism for dissecting molecular mechanisms of neurological diseases. While hermaphrodite contains only 302 neurons, the conserved homologous neurotransmitters, simpler neuronal circuitry, and fully mapped connectome make it an appealing model system for neurological research. Here we developed an assay to induce an electroconvulsive seizure in which can be used as a behavioral method of analyzing potential anti-epileptic therapeutics and novel genes involved in seizure susceptibility.

The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development.

Genetic changes in the HECT ubiquitin ligase HUWE1 are associated with intellectual disability, but it remains unknown whether HUWE1 functions in post-mitotic neurons to affect circuit function. Using genetics, pharmacology, and electrophysiology, we show that EEL-1, the HUWE1 ortholog in C. elegans, preferentially regulates GABAergic presynaptic transmission.

Postprandial sleep mechanics in .

Food consumption is thought to induce sleepiness. However, little is known about how postprandial sleep is regulated. Here, we simultaneously measured sleep and food intake of individual flies and found a transient rise in sleep following meals.

cGMP-Dependent Protein Kinase Inhibition Extends the Upper Temperature Limit of Stimulus-Evoked Calcium Responses in Motoneuronal Boutons of Drosophila melanogaster Larvae.

While the mammalian brain functions within a very narrow range of oxygen concentrations and temperatures, the fruit fly, Drosophila melanogaster, has employed strategies to deal with a much wider range of acute environmental stressors. The foraging (for) gene encodes the cGMP-dependent protein kinase (PKG), has been shown to regulate thermotolerance in many stress-adapted species, including Drosophila, and could be a potential therapeutic target in the treatment of hyperthermia in mammals. Whereas previous thermotolerance studies have looked at the effects of PKG variation on Drosophila behavior or excitatory postsynaptic potentials at the neuromuscular junction (NMJ), little is known about PKG effects on presynaptic mechanisms.

Modulating Behavior in C. elegans Using Electroshock and Antiepileptic Drugs.

The microscopic nematode Caenorhabditis elegans has emerged as a valuable model for understanding the molecular and cellular basis of neurological disorders. The worm offers important physiological similarities to mammalian models such as conserved neuron morphology, ion channels, and neurotransmitters. While a wide-array of behavioral assays are available in C.

Pseudopterosin A: Protection of Synaptic Function and Potential as a Neuromodulatory Agent.

Natural products have provided an invaluable source of inspiration in the drug discovery pipeline. The oceans are a vast source of biological and chemical diversity. Recently, this untapped resource has been gaining attention in the search for novel structures and development of new classes of therapeutic agents.

Pushing the limit: examining factors that affect anoxia tolerance in a single genotype of adult D. melanogaster.

Drosophila melanogaster is a promiscuous species that inhabits a large range of harsh environments including flooded habitats and varying temperature changes. To survive these environments, fruit flies have adapted mechanisms of tolerance that allow them to thrive. During exposure to anoxic stress, fruit flies and other poikilotherms enter into a reversible, protective coma.

RanBP9 overexpression accelerates loss of dendritic spines in a mouse model of Alzheimer's disease.

We previously demonstrated that RanBP9 overexpression increased Aβ generation and amyloid plaque burden, subsequently leading to robust reductions in the levels of several synaptic proteins as well as deficits in the learning and memory skills in a mouse model of Alzheimer's disease (AD). In the present study, we found striking reduction of spinophilin-immunoreactive puncta (52%, p<0.001) and spinophilin area (62.

RanBP9 Plays a Critical Role in Neonatal Brain Development in Mice.

RanBP9 is known to act as a scaffolding protein bringing together a variety of cell surface receptors and intracellular targets thereby regulating functions as diverse as neurite and axonal outgrowth, cell morphology, cell proliferation, myelination, gonad development, myofibrillogenesis and migration of neuronal precursors. Though RanBP9 is ubiquitously expressed in all tissues, brain is one of the organs with the highest expression levels of RanBP9. In the neurons, RanBP9 is localized mostly in the cytoplasm but also in the neurites and dendritic processes.