Nonclinical Evidence of Progesterone's Neuroprotective Properties

Numerous nonclinical studies demonstrate the powerful neuroprotective properties of progesterone.1,2,3,4,5,6,7,8,9 Progesterone has been found to be beneficial as a neuroprotectant in a number of animal species and in several modes of neurological injury, suggesting wide-ranging neuroprotective properties.

Some of the characterized mechanisms of this neurosteroid action in acute treatment of TBI and stroke include:

  • Preventing inflammation by:
    • Inhibiting the production of inflammatory cytokines such as IL-1β, TNF-α and IL-6
    • Reducing levels of inflammation-related factors including complement factor C3 fragments, NF-κB (and increasing IκB) and Cox-2
    • Inhibiting activation of microglial cells, thus preventing NO and TNF-α production
  • Preventing excitotoxicity by up-regulating expression and stimulating the GABA-A receptor
  • Preventing apoptosis by:
    • Preventing the insults that induce apoptosis, such as calcium flux, nitric oxide production, lipid peroxidation and production of inflammatory cytokines
    • Preventing the cascade by up-regulating Bcl-2 and Bcl-XL, down-regulating Bad and Bax, and decreasing levels of caspase 3
  • Controlling:
    • Vasogenic edema by reconstituting the blood brain barrier and modulating expression of the aquaporin-4 water transporter
    • Cytotoxic edema by modulating expression of the aquaporin-4 water transporter and preventing Ca2+ flux caused by excitoxicity.10,11,12,13,14

In addition, progesterone up-regulates expression of the following neurotrophic factors, an effect which may last well beyond the acute treatment phase and may be relevant to structural and functional recovery from TBI:

  • Brain Derived Neurotrophic Factor (BDNF)
  • Na/K ATPase
  • Microtubule-Associated Protein 2 (MAP-2)
  • Choline Acetyltransferase (ChAT)
  • Glial-Derived Neurotrophic Factor (GDNF)

Progesterone has also been shown to promote remyelinization.15,16

Studies of progesterone administered to animals with various forms of brain injury have demonstrated that progesterone has clear and potent neuroprotective effects with the following promising therapeutic characteristics.17

  • Rapidly crossing the blood-brain barrier
  • Reducing cerebral edema and lesion size
  • Being active both in males and females
  • Enhancing survival of neurons known to be involved in higher-order processes
  • Having activity in models of ischemic stroke
  • Enhancing functional recovery
  • Having a broad therapeutic window
  1. De Nicola, A.F. et al. (2006). J. Mol. Neurosci., 28, 3-15.
  2. Gibson, C.L. and Murphy, S.P. (2004). J. Cereb. Blood Flow Metab. 24, 805-813.
  3. Pettus, E.H., Wright, D.W., Stein, D.G., and Hoffman, S.W. (2005). Brain Res., 1049, 112-9.
  4. Roof, R.L. and Stein, D.G. (1992). Restor. Neurol. Neurosci., 4, 425.
  5. Roof R.L., Duvdevani R., and Stein, D.G. (1993). Brain Research, 607, 333-336.
  6. Roof, R.L., Duvdevani, R., Braswell, L., and Stein, D.G. (1994). Exp. Neurol., 129, 64-69.
  7. Stein, D.G. (2001). Trends Neurosci., 24, 386-391.
  8. Stein, D.G. (2008). Brain Res. Rev., 57, 386-397.
  9. Stein, D.G., Wright. D.W., and Kellermann, A.L. (2008). Ann. Emerg. Med., 51, 164-172.
  10. He, J., Hoffman, S.W., and Stein, D.G. (2004). Restor. Neurol. Neurosci. 22, 19.
  11. Pettus, E.H., Wright, D.W., Stein, D.G., and Hoffman, S.W. (2005). Brain Res., 1049, 112-9.
  12. Drew, P.D. and Chaivs, J. (2000). J Neuroimmunol., 111(1-2), 77-85.
  13. Cutler, S.M., Vanlandingham, J.W., and Stein, D.G. (2006). Exp. Neurol. 200, 378-385.
  14. VanLandingham, J.W, et.al.. (2006). Neuropharmacology. 51, 1078-1085.
  15. DiNicola et al., (2009). Front Neuroendocrinol., Mar 24. [Epub].
  16. Lee et al., (2009). J Steroid Biochem Mol Biol, 115(1-2), 30-5.
  17. Stein, D.G., Wright. D.W., and Kellermann, A.L. (2008). Ann. Emerg. Med., 51, 164-172.