二氫基女性素與腺苷酸A2A接受器促效劑治療蜘蛛膜下腔出血引發的腦血管痙攣與腦損傷之病理機轉與治療探討

Pathogenic and therapeutic perspectives of 17beta-estradiol and adenosine AR2AR receptor agonist in the treatment of subarachnoid hemorrhage-induced vasospasm and brain injury

林志隆(Chih-Lung Lin)

指導教授 ： 洪純隆 ； 關皚麗

高雄醫學大學/醫學院/醫學研究所/博士(2008年)

https://doi.org/10.6832/KMU.2008.00022

摘要

雖然蜘蛛膜下腔出血後之腦血管痙攣已被認定超過半世紀，它仍舊是顱內動脈瘤破裂蜘蛛膜下腔出血後病人一個常見且極可能造成殘疾的併發症。雖然極力的研究，造成蜘蛛膜下腔出血後腦血管痙攣的機轉仍未明，以致於要發展出有效的治療方法有所困難。目前臨床上仍無確定治療與預防的有效對策。雖然一般認為血液代謝物尤其是氧化血紅素(oxyhemoglobin)導致蜘蛛膜下腔出血後之腦血管痙攣(蜘蛛膜下腔出血後1-3天的急性腦血管痙攣與接著的延遲性腦血管痙攣)，但真正的原因仍不確定。引發腦血管痙攣的病理原因與多種病理變化有關包括內皮的損傷、平滑肌因蜘蛛膜下腔血塊溶解所釋放出的收縮物質而收縮、血管的反應改變及血管壁對發炎或免疫的反應。
近十年來致力於以二氫基女性素（17beta-estradiol）減緩蜘蛛膜下腔出血後腦血管痙攣與續發性腦損傷機轉與治療之研究。不像其他的腦血管疾病，顱內動脈瘤的蜘蛛膜下腔出血較多發生於女性。性別不同是否對蜘蛛膜下腔出血的預設不同仍未有定論，女性賀爾蒙對蜘蛛膜下腔出血的影響也不清楚。研究的結果發現持續性全身給予二氫基女性素可以減緩蜘蛛膜下腔出血後的腦血管痙攣於大鼠的兩次蜘蛛膜下腔出血模式，二氫基女性素之保護作用可能為回復蜘蛛膜下腔出血引發的eNOS表現下降及減低蜘蛛膜下腔出血引發的iNOS表現增加。而後者之機轉是經由增加p65/ER的結合，接著抑制p65結合至iNOS DNA。接著我們證實二氫基女性素可經由調控apoptotic signals包括 tumor necrosis factor-a (TNF-a), caspase-3, Bcl-2, 與 Bax to prevent來減緩蜘蛛膜下腔出血後引發的續發性腦損傷。因此，二氫基女性素可視為治療蜘蛛膜下腔出血後苦無治療良方的腦血管痙攣一個未來發展的方向。
研究的另一方面著手於以腺苷酸A2A接受器促效劑在治療蜘蛛膜下腔出血引發腦血管痙攣與續發性腦損傷的效果。腺苷酸在所有哺乳類組織裡參與調節生理反應也在許多的病理情況下扮演一個重要的角色。腺苷酸活化血管可產生血管擴張或收縮的反應，至於何種腺苷酸接受器的亞型負責調控特別血管床的反應仍未有定論。本研究就針對腺苷酸之接受器A2A促效劑，來探討其對蜘蛛膜下腔出血後腦血管痙攣的作用，我們的結果發現第一個證據顯示腺苷酸A2A接受器促效劑可以減緩蜘蛛膜下腔出血後的腦血管痙攣，腺苷酸A2A接受器促效劑不只可回復eNOS且可抑制iNOS的過度表現，因此其抗腦血管痙攣是完全的，此結果更顯示出iNOS及eNOS在蜘蛛膜下腔出血後腦血管痙攣所扮演的重要角色，腺苷酸A2A接受器促效劑是將來研究治療蜘蛛膜下腔出血後腦血管痙攣的一個新方向，值得更進一步探討。
接著研究發現二氫基女性素可以經由求偶素接受器依賴機轉在蜘蛛膜下腔出血後增加腺苷酸A2A接受器與ERK的表現，來減緩蜘蛛膜下腔出血後腦血管痙攣與續發性腦損傷。腺苷酸A2A接受器與ERK的表現下降可能在蜘蛛膜下腔出血後引發之腦血管痙攣與續發性腦損傷上扮演重要的角色。也更進一步證明二氫基女性素可視為治療蜘蛛膜下腔出血後腦血管痙攣與續發性腦損傷的一個新治療法。

結論
將持續從藥理學、生物化學及分子生物學探討療蜘蛛膜下腔出血後腦血管痙攣的機轉，二氫基女性素擁有近十多年來治療蜘蛛膜下腔出血後腦血管痙攣藥物的綜合優點，有可能真正成為未來治療顱內動脈瘤破裂蜘蛛膜下腔出血後腦血管痙攣的一個好方法。唯有把以上機轉完全釐清，及更進一步研究治療蜘蛛膜下腔出血後腦血管痙攣的效果與安全性，才可運用到臨床，我希望在既有的基礎上，加快腳步，早日找到治療此一困擾許久，苦無良方的蜘蛛膜下腔出血後腦血管痙攣的良策，達到轉譯醫學的目地。

關鍵字

二氫基女性素 ； 腺苷酸AR2AR接受器 ； 蜘蛛膜下腔出血 ； 細胞凋亡

並列摘要

Although cerebral vasospasm associated subarachnoid hemorrhage (SAH) has been recognized for more than half a century, SAH-induced vasospasm is still a major cause of mortality and neurological morbidity in patients with rupture of intracranial aneurysm. Despite intensive research efforts, cerebral vasospasm remains incompletely understood from both the pathogenic and therapeutic perspectives. At present, no consistently efficacious and ubiquitously applied preventive and therapeutic measures are available in clinical practice. Though it is now widely accepted that blood products, especially oxyhemoglobin, contribute to cerebral vasospasm and that the arterial narrowing appears to be biphasic, with an initial acute phase of 1 to 3 days after SAH and a subsequent delayed phase, however, the agents responsible for the acute and the delayed phases of SAH-induced vasospasm have not been clearly identified. Many pathological processes have been proposed to explain the pathogenesis of delayed cerebral vasospasm after SAH, including endothelial damage, smooth muscle contraction, changes in vascular responsiveness, and inflammatory and/or immunological response of the vascular wall.
The role and mechanisms of 17beta-estradiol (E2) in the treatment of SAH-induced vasospasm and secondary brain injury have been evaluated for more than 10 years. Sex differences in the outcome of aneurysmal SAH are controversial, and the potential influence of estradiol on vasodilation is unclear. These study results demonstrated that continuous treatment with E2 at physiological levels prevents cerebral vasospasm following SAH. The beneficial effect of E2 may be in part related to the prevention of augmentation of inducible nitric oxide synthase (iNOS) expression and the preservation of normal endothelial nitric oxide synthase (eNOS) expression after SAH. The other possible mechanisms responsible for E2-induced vasodilation after SAH is the inhibition of the SAH-induced increase of iNOS by increasing the association of p65/ER, which in turn inhibits the binding of p65 to iNOS DNA. The next study showed that E2 acts at the apoptotic signals including tumor necrosis factor-a (TNF-a), caspase-3, Bcl-2, and Bax to prevent SAH-induced apoptotic death. E2 has an anti-apoptotic effect against brain injury of SAH via ER-dependent mechanisms. These data suggest potential applications of E2 in the treatment of SAH patients. However, the mechanism for E2 in the treatment of SAH-induced vasospasm and/or secondary brain injury is still controversial.
On the other hand, the effect of an adenosine A2A receptor (AR-A2A) agonist in the treatment of SAH-induced cerebrovasospasm was found. Impaired endothelium-dependent relaxation is present in vasospastic cerebral vessels after SAH and may result from deficient production of eNOS or increased production and/or activity of iNOS. Adenosine is a potent vasodilator and an important modulator of cardiovascular function. This was the first evidence that AR-A2A agonist is effective in preventing SAH-induced vasospasm without significant complications. The beneficial effect of AR-A2A agonists may be, at least in part, related to the prevention of augmented expression of iNOS and the preservation of normal eNOS expression following SAH. AR-A2A agonist holds promise in the treatment of cerebral vasospasm following SAH and merits further investigation.
Finally, the effect of E2 on the expression of AR-A2A in the treatment of SAH-induced vasospasm and secondary brain injury was evaluated. E2 was effective in attenuating SAH-induced cerebral vasospasm, decreasing apoptosis and increasing the expression of AR-A2A and ERK in the dentate gyrus after SAH. The down-regulated AR-A2A and ERK may play a role in vasospasm and apoptosis after SAH. The beneficial effect of E2 in attenuating SAH-induced vasospasm and apoptosis may be due to raised expression of AR-A2A and ERK via ER-dependent mechanisms. These data support further investigation of E2 in the treatment of SAH in humans.

Conclusions
In order to develop a safe and effective treatment in managing this devastating complication after aneurysmal rupture, continued investigation of the underlying mechanism of SAH-induced vasospasm from pharmacological, biochemical, and molecular biological studies is needed. The final goal is to translate the basic results to the clinical trial (from bench to bedside) to solve SAH-induced vasospasm; the most troublesome complication after aneurysmal rupture.

並列關鍵字

17b-estradiol(E2) ； adenosine AR2AR receptor ； subarachnoid hemorrhage(SAH) ； apoptosis

參考文獻

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