The estrogen receptor is not essential for all estrogen neuroprotection: new evidence from a new analog.

Abstract

We synthesized an estrogen analog, ZYC-5, lacking activity at the classical estrogen receptor and examined its neuroprotective potential against necrosis induced by N-methyl-d-aspartate (NMDA) and apoptosis/necrosis induced by the NMDA receptor antagonist (+)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP). ZYC-5 protected cortical neurons in a dose-dependent manner, and the neuroprotection was more robust than with 17beta-estradiol. The effect of ZYC-5 was not mediated by the classical estrogen receptor, because it was unaffected by the antagonists 4-hydroxytamoxifen and ICI 182,780. The ZYC-5 protection against excitotoxicity was not directly mediated through the NMDA receptor, because there was no effect of ZYC-5 on NMDA current or the intracellular calcium increase induced by NMDA. Results obtained with the free-radical-sensitive dye, dihydroethidium, suggested that the neuroprotection of ZYC-5 was partly related to its radical scavenging properties. Although some of estrogen's neuroprotective effects may depend upon the estrogen receptor, our results suggest the possibility of neuroprotection without hormonal side effects.

• Authors: Shuli Xia, Zu Yun Cai, Liu Lin Thio, Jeong Sook Kim-Han, Laura L Dugan, Douglas F Covey, Steven M Rothman
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 9 Issue 3 Pg. 282-93 (Apr 2002) ISSN: 0969-9961 [Print] United States
• PMID: 11950274 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: (c) 2002 Elsevier Science (USA).

Chemical References

• Estrogen Antagonists
• Excitatory Amino Acid Agonists
• Excitatory Amino Acid Antagonists
• Neuroprotective Agents
• Reactive Oxygen Species
• Receptors, Estrogen
• ZYC 5
• Estradiol
• Adamantane

Topics

• Adamantane (analogs & derivatives, chemical synthesis, pharmacology)
• Animals
• Cell Death (drug effects, physiology)
• Cells, Cultured
• Cerebral Cortex (cytology, drug effects, pathology, physiology)
• Dose-Response Relationship, Drug
• Estradiol (analogs & derivatives, chemical synthesis, pharmacology)
• Estrogen Antagonists (pharmacology)
• Excitatory Amino Acid Agonists (toxicity)
• Excitatory Amino Acid Antagonists (toxicity)
• Mice
• Neurons (drug effects, pathology, physiology)
• Neuroprotective Agents (chemistry, pharmacology)
• Reactive Oxygen Species (metabolism)
• Receptors, Estrogen (antagonists & inhibitors, physiology)