Abstract
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. Pseudopterosins are group of marine diterpene glycosides that possess an array of potent biological activities in several therapeutic areas. Few studies have examined pseudopterosin effects during cellular stress and, to our knowledge, no studies have explored their ability to protect synaptic function. The present study probes pseudopterosin A (PsA) for its neuromodulatory properties during oxidative stress using the fruit fly, Drosophila melanogaster. We demonstrate that oxidative stress rapidly reduces neuronal activity, resulting in the loss of neurotransmission at a well-characterized invertebrate synapse. PsA mitigates this effect and promotes functional tolerance during oxidative stress by prolonging synaptic transmission in a mechanism that differs from scavenging activity. Furthermore, the distribution of PsA within mammalian biological tissues following single intravenous injection was investigated using a validated bioanalytical method. Comparable exposure of PsA in the mouse brain and plasma indicated good distribution of PsA in the brain, suggesting its potential as a novel neuromodulatory agent.
Highlights
Oxygen is essential for the survival of most organisms
Amplitude ofAmplitude evoked EJPsofreduced reduced over time at different rates in control preparations and those exposed to NaN3 reduced over time at different rates in control preparations and those exposed to time at different rates in control preparations and those exposed to NaN (75 μM)
These data demonstrate that pseudopterosin A (PsA) alters synaptic activity by promoting function during oxidative stress and readily crosses the blood-brain barrier (BBB), indicating its potential as a novel neuromodulatory agent
Summary
Oxygen is essential for the survival of most organisms. A natural byproduct of cellular respiration is the generation of toxic partially reduced forms of oxygen, known as reactive oxygen species (ROS) [1]. 22of production of ROS and cellular antioxidant defense mechanisms and DNA repair mechanisms that defense mechanisms and DNA repairbecomes mechanisms that fix the Structural among pseudopterosins, such as theof position of glycosylation on theskeleton terpene differencesdifferences among pseudopterosins, such as the position glycosylation on the terpene skeleton and the type of sugar moiety, affect their biological and cytotoxic activities and the type of sugar moiety, affect their biological and cytotoxic activities [18,19].
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