Therapeutic Implications of Estrogen for Cerebral Vasospasm and Delayed Cerebral Ischemia Induced by Aneurysmal Subarachnoid Hemorrhage

Table 1

Summary of vasodilatory and neuroprotective mechanisms regulated by 17β-estradiol (E2).

Mediator	Physiology
Vasodilatory mechanisms regulated by E2
Endothelial nitric oxide synthase (eNOS)	Constitutively expressed isoform of NOS which generates the vasodilatory mediator NO. E2 activates eNOS and prevents the SAH-induced decrease of eNOS function via MAPK-dependent pathways.
Inducible nitric oxide synthase (iNOS)	Inducible isoform of NOS expressed in stress responses (e.g., SAH) which contributes to the generation of reactive oxygen species. E2 abrogates SAH-induced iNOS expression by sequestering NFκB, a transcriptional activator of iNOS.
Endothelin-1 (ET-1)	The most potent endogenous mediator of vasoconstriction. E2 decreases ET-1 production.
Neuroprotective mechanisms regulated by E2
Thioredoxin (Trx)	Antioxidant enzyme which reduces oxidized proteins and diminishes stress-induced proapoptotic signaling. E2 increases Trx expression.
c-Jun N-terminal kinase (JNK)	JNK phosphorylates downstream proteins which heterodimerize to form AP-1, a transcriptional activator of TNFα. E2 decreases JNK activity.
Neuroglobin (Ngb)	Globin protein which binds to oxygen with a greater affinity than hemoglobin thereby regulating oxygen homeostasis in neurons. Ngb provides protection against ROS-induced oxidative damage and prevents apoptosis by stabilizing the transcription factors HIF-1α and Nrf2 and by inhibiting cytochrome c release from the mitochondria. E2 increases Ngb expression.
Protein kinase B (Akt)	Akt activates mTOR which promotes cell survival and inactivates GSK3β which promotes apoptosis. E2 prevents SAH-induced suppression of Akt.
Adenosine A2a receptor (A2aAR)	G-protein couple receptor which inhibits proapoptotic signaling pathways partially through activation of ERK 1/2. E2 increases expression of A2aAR and ERK 1/2.