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

Abstract

Progesterone is being utilized as a therapeutic means to ameliorate neuron loss and cognitive dysfunction following traumatic brain injury Although there have been numerous attempts to determine the means by which progesterone exerts neuroprotective effects, studies describing the underlying molecular mechanisms are lacking What has become clear, however, is the notion that progesterone can thwart several physiological processes that are detrimental to neuron function and survival, including inflammation, edema, demyelination and excitotoxicity One clue regarding the means by which progesterone has restorative value comes from the notion that these aforementioned biological processes all share the common theme of eliciting pronounced increases in intracellular calcium. Thus, we propose the hypothesis that progesterone regulation of calcium signaling underlies its ability to mitigate these cellular insults, ultimately leading to neuroprotection. Further, we describe recent findings that indicate neuroprotection is achieved via progesterone block of voltage-gated calcium channels, although additional outcomes may arise from blockade of various other ion channels and neurotransmitter receptors.

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

“…19 Perhaps in the present experiments progesterone facilitated the release of trophic factors from nearby Schwann cells. 31,32,[45][46][47] Nerve sectioning plays a fundamental role in aberrant innervation, since it occurred even in animals implanted with silicone tubes. In our study, the synaptic connectivity between the nerve supply to the gastrocnemius muscle and the muscle itself seemed to be functional.…”

“…When the nerve was stimulated in the proximal or in the intratubular nerve segment, no EMG responses were produced 90 days after sciatic nerve sectioning. 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.…”

Neuron Based Surgery: Are We There Yet? Technical Developments in the Surgical Treatment of Brain Injury and Disease

“…Premenopausal women have better survival than men after intracerebral hemorrhage, a phenomenon postulated to be associated with the ability of estrogen to inhibit iron-induced autophagy of injured cells [ 22 ], leading researchers to look at estrogen as a potential drug for inhibiting autophagy in patients suffering TBI. Similarly, progesterone is being utilized as a therapeutic means to ward off neuron death and cognitive dysfunction following brain injury [ 23 ]. Evidence suggests that progesterone inhibits "several physiological processes that are detrimental to neuron function and survival including infl ammation, edema, demyelination and excitotoxicity," the mechanism of which is thought to be related to the blockage of voltage-gated calcium channels [ 23 ].…”

“…Similarly, progesterone is being utilized as a therapeutic means to ward off neuron death and cognitive dysfunction following brain injury [ 23 ]. Evidence suggests that progesterone inhibits "several physiological processes that are detrimental to neuron function and survival including infl ammation, edema, demyelination and excitotoxicity," the mechanism of which is thought to be related to the blockage of voltage-gated calcium channels [ 23 ].…”

PET and SPECT Imaging of Steroid Hormone Receptors

“…The neuroprotective mechanisms and anti-infl ammatory effects of progestins have been reviewed by several authors (Giatti et al 2012 ;Luoma et al 2012 ;De Nicola et al 2009 ;Sayeed and Stein 2009 ;Singh and Su 2012 ;Stein et al 2008 ). Progestins may prevent brain damage by controlling edema formation (vasogenic or cytogenic) via modulation of the expression of the aquaporin-4 water transporter, moderating Ca 2+ fl ux caused by excitotoxicity, and reconstitution of the blood-brain barrier.…”