Progesterone blocks multiple routes of ion flux

Abstract

The administration of progesterone as a neuroprotective agent following traumatic brain injury has recently entered phase III clinical trials. Previous work has demonstrated that therapeutic concentrations of progesterone decrease excitotoxicity through direct inhibition of voltage-gated calcium channels, an action independent of the nuclear progesterone receptor. Here we report using cultured rat striatal neurons that these same concentrations of progesterone also block voltage-gated potassium channels, sodium channels and GABAA currents. The actions of progesterone act at the surface membrane of neurons in a steroid specific, voltage-independent, concentration-dependent manner. Notably, these broad actions of progesterone on ion channel and neurotransmitter receptor function mirror those of dihydropyridines, and indicate potential shared mechanisms of action, the prospective of additional therapeutic applications, and possibly, untoward effects.

Aberrant gastrocnemius muscle innervation by tibial nerve afferents after implantation of chitosan tubes impregnated with progesterone favored locomotion recovery in rats with transected sciatic nerve

“…Progesterone could change ion influx by blocking voltage-gated calcium channels 32 and also voltage-gated potassium channels and sodium channels in rat striatal neurons. 27 Our data could also indicate a possible reduction in the flow of sodium across the membranes of the remyelinated fibers, due to a large progesterone concentration in the tube, which consequently induced a blocking effect on action potential propagation. 38 Nerve regeneration was deficient in chitosan tubes, as well as in silicone tubes; perhaps very few axons were well myelinated.…”

“…Sodium voltage-dependent currents are inactivated. 27,31 In this study, we analyzed gastrocnemius muscle electromyography responses produced by sciatic nerve electrical stimulation after implanting progesterone-impregnated chitosan tubes, unaltered chitosan tubes, or silicone tubes in the transected sciatic nerve of the rat. In addition, we analyzed the morphology of the contralateral (control) and ipsilateral sciatic nerve sections.…”

Eag1 K+ Channel: Endogenous Regulation and Functions in Nervous System

“…Like other steroids, the effects of estrogen and progesterone are thought to be dependent on their genomic effect via activation of their nuclear receptors [88, 89]. However, the nongenomic effect of both hormones has been appreciated and, at least in part, is dependent on their direct regulation of select ion channels.…”

Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection

“…Recent work from our laboratory suggests that this supplementary inhibition extends beyond voltage-gated calcium channels to voltage-gated potassium channels, voltage-gated sodium channels, and GABA A receptors [84]. While these additional effects may underlie the anesthetic properties of progesterone [85; 86], it is currently unclear how inhibition of these ion channels contributes to neuroprotection.…”

“…The ability of micromolar range concentrations of progesterone to inhibit multiple classes of ion channels parallel the effects of similarly high concentrations of nifedipine, a dihydropyridine sensitive L-type calcium channel blocker that also non-selectively inhibits voltage-gated sodium channels, potassium channels, and GABA A [84; 90; 91; 92]. The results from several other studies corroborate the finding that in addition to L-type calcium channels, dihydropyridines inhibit voltage-gated sodium channels, voltage-gated potassium channels, and GABA A receptors [90; 91; 92; 93].…”