CNR - Institute of Neuroscience CNR
Institute of Neuroscience


Mechanisms of action of pharmacologically active compounds on GABAA or strychnine-sensitive glycine receptors

The rational development of new drugs requires an understanding, on a molecular level, of their targets and mechanism of action. The ligand gated ion channel receptors (LGICRs) are important sites of action for several pharmacologically active molecules. My interest centers on the modulation, mainly by novel synthesized molecules, of different receptors and ion channels. In particular, my interest focus on the inhibitory receptors: the γ-aminobutyric acid type A receptor (GABAAR) and the strychnine sensitive glycine receptor (GlyR). These receptors are ligand-gated ion channels that mediate fast inhibitory synaptic transmission in the central nervous system. Binding of the respective neurotransmitters to these pentameric membrane proteins triggers a conformational change that leads to opening of the central ion pore and allows chloride ions to pass mediating, therefore, an inhibiting signal. Several drugs modulate the action of GABA or glycine. Among them alcohol and general anesthetics promote the opening of the chloride channel at both GABA and GlyR, potentiating the action of these neurotransmitters. However, benzodiazepines, barbiturates and several neurosteroids act at the GABAA receptor only.

At the present time, we are looking at the mechanism of action of honokiol and its structural isomer magnolol, two biphenolic and active compounds present in the cones, bark, and leaves of Magnolia officinalis. These two molecules have been widely used in the traditional Chinese medicine as anxiolytic, anti-thrombotic, anti-depressant, anti-emetic, and anti-bacterial. We are focusing our attention to the anxiolytic properties of honokiol and magnolol. After expressing the GABAA and the GlyR receptors in Xenopus laevis oocytes, we studied the effects of honokiol and magnolol through electrophysiology (two-electrode voltage clamp). According to our results, honokiol and magnolol are positive modulators of both the GABAAR and the GlyR function. However, their anxyolitic properties are not due to interaction with the benzodiazepine binding site nor with the alcohol, the barbiturates or the neurosteroids binding site.

Role of lithium and thiocolchicoside on neuronal excitability in rat dentate gyrus

Thiocolchicoside is a potent antagonist of the GABAAR, in addition inhibits the function of the GlyR. Given that drugs that reduce or block the function of these two inhibitory receptors act as proconvulsant or convulsant agents, our data obtained in recombinant GABAA and strychnine-sensitive glycine receptors, provided evidence that thiocolchicoside induces seizures in animals and humans by down-regulating the function of the main inhibitory systems in brain and spinal cord (Mascia et al., 2007). A recent report indicate that the convulsant effects of thiocolchicoside are potentiated in lithium-pretreated rats. We are currently evaluating the effects of interaction between lithium and thiocolchicoside on neuronal excitability in the rat dentate gyrus.


  • Mascia MP, Bachis E, Obili N, Maciocco E, Cocco GA, Sechi GP, Biggio G (2007) Thiocolchicoside inhibits the activity of various subtypes of recombinant GABA(A) receptors expressed in Xenopus laevis oocytes. Eur. J. Pharmacol. 558:37-42.


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Maria Paola Mascia

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