Abstract
Epipregnanolone (3β-hydroxy-5β-pregnan-20-one, Epi) is an endogenous steroid with important physiological effects and high affinity for GABAA receptors. The effect of Epi on GABA-induced chloride current (IGABA) in native neurons has hardly been studied. In this work, we studied the influence of Epi on the IGABA in the Purkinje cells of rat cerebellum and pyramidal neurons of rat hippocampus with the patch clamp technique. We showed that Epi is a positive modulator of the IGABA with EC50 of 5.7 µM in Purkinje cells and 9.3 µM in hippocampal neurons. Epi-induced potentiation of the IGABA was more potent at low vs. high GABA concentrations. Isopregnanolone (3β-hydroxy-5α-pregnan-20-one, Iso) counteracted Epi, reducing its potentiating effect by 2–2.3 times. Flumazenil, a nonsteroidal GABAA receptor antagonist, does not affect the Epi-induced potentiation. Comparison of the potentiating effects of Epi and allopregnanolone (3α-hydroxy-5α-pregnan-20-one, ALLO) showed that ALLO is, at least, a four times more potent positive modulator than Epi. The combined application of ALLO and Epi showed that the effects of these two steroids are not additive. We conclude that Epi has a dual effect on the IGABA increasing the current in the control solution and decreasing the stimulatory effect of ALLO.
Highlights
Steroids with pregnane skeleton were shown to be effective modulators of neuronal gamma-aminobutyric acid (GABAA ) receptors [1,2]
It has been shown that 3α-hydroxypregnanes potentiate the GABA-induced chloride current (IGABA ) in nanomolar concentrations, while the 3β-hydroxy-pregnanes, i.e., epipregnanolone (Epi) and isopregnanolone (Iso) exhibit antagonistic properties and reduce the stimulating effect of 3α-hydroxypregnanes on IGABA [4]
Co-application of 2 μM GABA (EC5 ) with a different concentration of Epi caused the potentiation of the IGABA (Figure 2)
Summary
Steroids with pregnane skeleton were shown to be effective modulators of neuronal gamma-aminobutyric acid (GABAA ) receptors [1,2]. It has been shown that 3α-hydroxypregnanes (for example, allopregnanolone, ALLO,) potentiate the GABA-induced chloride current (IGABA ) in nanomolar concentrations, while the 3β-hydroxy-pregnanes, i.e., epipregnanolone (Epi) and isopregnanolone (Iso) exhibit antagonistic properties and reduce the stimulating effect of 3α-hydroxypregnanes on IGABA [4]. Note that the literature describing the effect of 3β-hydroxypregnanes on IGABA is controversial. The majority of studied 3β-hydroxy compounds were described to be effectively inert [5,6,7]. Some 3beta-hydroxy compounds, including Epi, have been found to induce mild positive modulatory effects
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