Therapeutic implications of estrogen for cerebral vasospasm and delayed cerebral ischemia induced by aneurysmal subarachnoid hemorrhage.
Cerebral vasospasm (CV) remains the leading cause of delayed morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH). However, increasing evidence supports etiologies of delayed cerebral ischemia (DCI) other than CV. Estrogen, specifically 17 β -estradiol (E2), has potential therapeutic implications for ameliorating the delayed neurological deterioration which follows aneurysmal SAH. We review the causes of CV and DCI and examine the evidence for E2-mediated vasodilation and neuroprotection. E2 potentiates vasodilation by activating endothelial nitric oxide synthase (eNOS), preventing increased inducible NOS (iNOS) activity caused by SAH, and decreasing endothelin-1 production. E2 provides neuroprotection by increasing thioredoxin expression, decreasing c-Jun N-terminal kinase activity, increasing neuroglobin levels, preventing SAH-induced suppression of the Akt signaling pathway, and upregulating the expression of adenosine A2a receptor. The net effect of E2 modulation of these various effectors is the promotion of neuronal survival, inhibition of apoptosis, and decreased oxidative damage and inflammation. E2 is a potentially potent therapeutic tool for improving outcomes related to post-SAH CV and DCI. However, clinical evidence supporting its benefits remains lacking. Given the promising preclinical data available, further studies utilizing E2 for the treatment of patients with ruptured intracranial aneurysms appear warranted.
Department of Neurosurgery, University of Virginia, Charlottesville, VA 22908, USA.
Dale
0000-0002-2627-446X
D
Ding
Department of Neurosurgery, University of Virginia, Charlottesville, VA 22908, USA.
Robert M
RM
Starke
Department of Neurosurgery, Tulane University, New Orleans, LA 70112, USA.
Aaron S
AS
Dumont
Department of Molecular Physiology and Biophysics, Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
Gary K
GK
Owens
Department of Neurosurgery, University of Iowa, Iowa City, IA 52242, USA.
David M
DM
Hasan
Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA 19106, USA.
Nohra
0000-0002-2422-4346
N
Chalouhi
Department of Neurosurgery, Tulane University, New Orleans, LA 70112, USA.
Ricky
0000-0003-3188-7823
R
Medel
Department of Neurosurgery, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung, Taiwan ; Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Chih-Lung
0000-0002-6716-2771
CL
Lin
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000627:therapeutic use*; D004967:Estrogens / Q000627:therapeutic use*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014664:Vasodilation; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D004967:Estrogens; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D004958:Estradiol