Estrogen activates classical and alternative mechanisms to orchestrate neuroprotection

Curr Neurovasc Res. 2005 Oct;2(4):287-301. doi: 10.2174/156720205774322629.


Evidence for a protective role of estradiol in neurodegenerative diseases has steadily increased over the past decade, though the mechanisms of action and the participation of true estrogen receptors (ERs) have proven a complex score. The protective effects of estrogens take place partly through pathways involving canonical ER activation, which is constitutively expressed in many brain regions and is able to initiate gene transcription after specifically binding to estradiol. In addition, non-genomic (or alternative) signalling pathways, involving extranuclear ERs, respond to physiological concentration of estrogens to elicit neuroprotection. Often, rapid activation of intracellular signallers such as mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K) underlie alternative estrogen-induced neuroprotection upon activation of specific binding sites at the plasma membrane. Although the molecular characteristics of these unconventional ERs are still largely unknown, the generally held view maintains that plasma membrane ER (mER) originates from, or is related to, classical nuclear ERs. The present article will review some of the most recent evidence revealing the relevance of alternative mechanisms in estrogen-dependent neuroprotection. Special emphasis will be paid to cellular models of amyloid-beta toxicity where classical and alternative pathways activated by estrogens seem to coexist to orchestrate neuroprotection.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain / physiopathology
  • Cytoprotection / drug effects
  • Cytoprotection / physiology*
  • Estrogens / metabolism*
  • Estrogens / pharmacology
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / physiopathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / metabolism*
  • Neuroprotective Agents / pharmacology
  • Receptors, Estrogen / drug effects
  • Receptors, Estrogen / metabolism


  • Amyloid beta-Peptides
  • Estrogens
  • Neuroprotective Agents
  • Receptors, Estrogen