Brugia Malayi - Clark Science Center - Smith College

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The Effects of Flavonoids on GABA A Receptor Modulation via Patch-Clamping Electrophysiology and Tadpole Assays Salma Bargach γ-Aminobutyric acid, or GABA, is an amino acid neurotransmitter in the central nervous system. Known as the most prominent inhibitory neurotransmitter, its effects counteract those of excitatory pathways preventing seizures or death by excitotoxicity. GABA A receptors, a type of GABA receptor, are ligand-gated ion channels that consist of five subunits. When GABA binds to one of the GABA A receptor subunits, a chloride ion channel opens creating an influx of chloride ions, making the cell more negative. Each subunit has a unique composition that corresponds to certain pharmacological properties. One of the subunits, the γ-subunit, has a benzodiazepine-binding site. Benzodiazepines are allosteric modulators of GABA A receptors, which increase the frequency at which the chloride channel opens. The effects produced by benzodiazepines are counteracted by flumazenil, benzodiazepines’ competitive antagonist. Flavonoids are a polyphenolic compound found in plants, fruits, and vegetables. They are compounds categorized by their chemical structure, for instance, flavones, flavonoids, flavonols, and others. Some flavonoids can either act as flumazenil sensitive benzodiazepines or flumazenil insensitive benzodiazepines, resulting in negative or positive modulatoration of GABA receptor currents. Also their lipophilic characteristic gives them the ability to cross the blood brain barrier and reduce both oxidative stress and damage from free radicals, an action that has been suggested to reduce and prevent neurodegenerative diseases. Patch clamp electrophysiology is an electrophysiology technique that allows for the recording from a single ion channel or whole cell currents. The specific patch clamp technique used was the whole-cell patch clamp. In this technique, a recording electrode forms a gigaOhm seal on the cell’s membrane. Negative pressure is then used to break through the membrane allowing for the recording of all the receptors on the cell (hence ‘whole cell’). The cell is held at -50 mV and, when superfused with GABA, this opens the chloride ion channel and chloride ions flow out of the cell. This net flow of chloride ions is recorded as a current in picoamps. Different drugs can either positively or negatively modulate this current. Recordings showing a positive modulation are identified by increased chloride current via GABA A receptors expressed in HEK (human embryonic kidney) cells. In the following study, flavinoid-induced modulation of GABA currents was investigated in human embryonic kidney (HEK) cells that have been stably transfected with α 1 β 3 γ 2 GABA A receptors. Using patch clamp electrophysiology, this project focused on flavonoids that have been suggested to be positive modulators of GABA currents. The flavonoids used were baicalien, catechin hydrate, and naringenin. Each compound was co-applied with a constant GABA concentration, which also acted as a control, to see if any of the compounds would positively enhance the GABA currents (suggesting a possible anesthetic/sedative effect of the flavinoid). Alongside the electrophysiology, tadpole sedation/anesthesia assays were run for all three flavonoids and compared to propofol, a known anesthetic. Tadpoles were used as the animal model because the concentrations used to anesthetise tadpoles has been shown to be similar to mammalian levels. In the tadpole assay, both baicalien and naringenin acted as an anesthetic at very high concentrations. (>300µM) Catechin hydrate had no anesthetic effects. The electrophysiology data confirmed that none of the compounds tested were positive modulators of GABA A receptors. Although these three compounds did not enhance the GABA response, natural compounds are still of interest in neuropharmacology. As a result, in future experiments I hope to pursue natural compounds that have a higher probability of binding to the benzodiazepine site on the GABA A receptor in the search for new sedative or anesthetic compounds. (Supported by the Howard Hughes Medical Institute) Advisor: Adam Hall 2012 147
Patch-Clamp Investigation of the Modulation of GABA A Receptor Currents with Isomers of the Potential Anesthetic 2, 6-dimethylcyclohexanol Luvana Chowdhury Anesthetic compounds are used clinically to produce a loss of sensation, including pain, during invasive procedures. Anesthetic compounds bind to ligand-gated, GABA A receptors and increase inhibitory transmission, or positively modulate the GABA A receptor. Many anesthetic compounds consist of isomers. Although commonly used surgical anesthetic such as isoflurane is not separated for clinical use, understanding stereoselectivity and chirality are critical to achieving a desired anesthetic effect in patients. 2 A recent study showed positive modulation of the GABA A receptor using 2, 6 dimethylcyclohexanol. 1 However, the anesthetic potential of individual isomers of 2, 6 dimethylcyclohexanol has not been fully studied previously. In this patchclamp investigation, modulation of GABA A receptor currents with isomers of the potential anesthetic 2, 6-dimethylcyclohexanol were measured. With increasing 2,6-dimethycyclohexanol racemic mixture concentrations (1-300uM) co-applied with 3uM GABA, positive modulation of GABA A receptor currents was observed at higher doses (30, 100, 300uM) compared to currents evoked by 3uM GABA alone. The application of 3uM GABA co-applied with trans,trans 2,6-dimethylcyclohexanol resulted in an enhancement in the receptor currents compared to the 3uM GABA control, while cis,trans 2,6-dimethylcyclohexanol isomer co-applied with 3uM GABA had no effect on the receptor modulation. Lastly, 30uM of trans,trans isomer positively modulated the GABA dose response. The overall positive modulation of trans,trans demonstrated the highest anesthetic potency and effectiveness compared to the racemic mixture and the other isomers. (Supported by the National <strong>Science</strong> Foundation) Advisor: Adam Hall References: 1 Hall, A. C., Griffith, T. N., Tsikolia, M., Kotey, F. O., Gill, N., Humbert, D. J., Watt, E. E., Yermolina, Y. A., Goel, S., El-Ghendy, B., & Hall, C. D. 2011. Cyclohexanol analogues are positive modulators of GABA A receptor currents and act as general anaesthetics in vivo. European Journal of Pharmacology, 667(1-3), 175-81. 2 Burke, D. and D.J. Henderson. 2002. Chirality: a blueprint for the future, British Journal of Anaesthesia 88: 563-576. 2012 148
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