Editing Progesterone (section)

====Proposed mechanism====
The mechanism of progesterone protective effects may be the reduction of inflammation that follows brain trauma and hemorrhage.<ref name="pmid18188998">{{cite journal | vauthors = Pan DS, Liu WG, Yang XF, Cao F | title = Inhibitory effect of progesterone on inflammatory factors after experimental traumatic brain injury | journal = Biomedical and Environmental Sciences | volume = 20 | issue = 5 | pages = 432–438 | date = October 2007 | pmid = 18188998 }}</ref><ref name="pmid27143417">{{cite journal | vauthors = Jiang C, Zuo F, Wang Y, Wan J, Yang Z, Lu H, Chen W, Zang W, Yang Q, Wang J | display-authors = 6 | title = Progesterone exerts neuroprotective effects and improves long-term neurologic outcome after intracerebral hemorrhage in middle-aged mice | journal = Neurobiology of Aging | volume = 42 | pages = 13–24 | date = June 2016 | pmid = 27143417 | pmc = 4857017 | doi = 10.1016/j.neurobiolaging.2016.02.029 }}</ref>

Damage incurred by traumatic brain injury is believed to be caused in part by mass [[depolarization]] leading to [[excitotoxicity]]. One way in which progesterone helps to alleviate some of this excitotoxicity is by blocking the [[voltage-dependent calcium channel]]s that trigger [[neurotransmitter]] release.<ref name="pmid22101209">{{cite journal | vauthors = Luoma JI, Stern CM, Mermelstein PG | title = Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 131 | issue = 1–2 | pages = 30–36 | date = August 2012 | pmid = 22101209 | pmc = 3303940 | doi = 10.1016/j.jsbmb.2011.11.002 }}</ref> It does so by manipulating the signaling pathways of [[transcription factor]]s involved in this release. Another method for reducing the excitotoxicity is by up-regulating the [[GABAA receptor|GABA<sub>A</sub>]], a widespread inhibitory neurotransmitter receptor.<ref name="pmid17826842">{{cite journal | vauthors = Stein DG | title = Progesterone exerts neuroprotective effects after brain injury | journal = Brain Research Reviews | volume = 57 | issue = 2 | pages = 386–397 | date = March 2008 | pmid = 17826842 | pmc = 2699575 | doi = 10.1016/j.brainresrev.2007.06.012 }}</ref>

Progesterone has also been shown to prevent [[apoptosis]] in neurons, a common consequence of brain injury. It does so by inhibiting enzymes involved in the apoptosis pathway specifically concerning the mitochondria, such as activated [[caspase 3]] and [[cytochrome c]].<ref name="pmid22088981">{{cite journal | vauthors = Espinoza TR, Wright DW | title = The role of progesterone in traumatic brain injury | journal = The Journal of Head Trauma Rehabilitation | volume = 26 | issue = 6 | pages = 497–499 | year = 2011 | pmid = 22088981 | pmc = 6025750 | doi = 10.1097/HTR.0b013e31823088fa }}</ref>

Not only does progesterone help prevent further damage, it has also been shown to aid in [[neuroregeneration]].<ref name="pmid26746666">{{cite journal | vauthors = Jiang C, Zuo F, Wang Y, Lu H, Yang Q, Wang J | title = Progesterone Changes VEGF and BDNF Expression and Promotes Neurogenesis After Ischemic Stroke | journal = Molecular Neurobiology | volume = 54 | issue = 1 | pages = 571–581 | date = January 2016 | pmid = 26746666 | pmc = 4938789 | doi = 10.1007/s12035-015-9651-y }}</ref> One of the serious effects of traumatic brain injury includes edema. Animal studies show that progesterone treatment leads to a decrease in [[edema]] levels by increasing the concentration of [[macrophage]]s and [[microglia]] sent to the injured tissue.<ref name="pmid22101209"/><ref name="pmid19401954">{{cite journal | vauthors = Herson PS, Koerner IP, Hurn PD | title = Sex, sex steroids, and brain injury | journal = Seminars in Reproductive Medicine | volume = 27 | issue = 3 | pages = 229–239 | date = May 2009 | pmid = 19401954 | pmc = 2675922 | doi = 10.1055/s-0029-1216276 }}</ref> This was observed in the form of reduced leakage from the [[blood brain barrier]] in secondary recovery in progesterone treated rats. In addition, progesterone was observed to have [[antioxidant]] properties, reducing the concentration of [[reactive oxygen species|oxygen free radicals]] faster than without.<ref name="pmid17826842"/> There is also evidence that the addition of progesterone can also help re[[myelin]]ate damaged [[axons]] due to trauma, restoring some lost neural signal conduction.<ref name="pmid17826842"/> Another way progesterone aids in regeneration includes increasing the circulation of endothelial progenitor cells in the brain. This helps new [[vasculature]] to grow around scar tissue which helps repair the area of insult.<ref name="pmid21534727">{{cite journal | vauthors = Li Z, Wang B, Kan Z, Zhang B, Yang Z, Chen J, Wang D, Wei H, Zhang JN, Jiang R | display-authors = 6 | title = Progesterone increases circulating endothelial progenitor cells and induces neural regeneration after traumatic brain injury in aged rats | journal = Journal of Neurotrauma | volume = 29 | issue = 2 | pages = 343–353 | date = January 2012 | pmid = 21534727 | pmc = 3261789 | doi = 10.1089/neu.2011.1807 }}</ref>