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  • Author or Editor: Aij-Lie Kwan x
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Huei-Chuan Shih, Chih-Lung Lin, Shu-Chuan Wu, Aij-Lie Kwan, Yi-Ren Hong and Shen-Long Howng

Object

The authors previously demonstrated that 17β-estradiol benzoate (E2) treatment prevents subarachnoid hemorrhage (SAH)–induced cerebral vasospasm and preserves endothelial nitric oxide synthase (eNOS) in male rats. Changes in the expression of estrogen receptor (ER) subtypes ERα and -β and their roles in the E2-mediated preservation of eNOS in SAH remain unknown. In the present study the effects of SAH on the expression of ERα and -β in the cerebral arteries were clarified, and the receptor roles in the E2-mediated preservation of eNOS expression in SAH were differentiated.

Methods

A 2-hemorrhage SAH model was induced by 2 autologous blood injections into the cisterna magna of adult male rats. The effect of SAH on ERα and -β expression was evaluated. Other rats subcutaneously received implanted Silastic tubes containing corn oil with E2 and daily injections of various doses of an ERα- (methyl-piperidinopyrazole [MPP]) or ERβ-selective antagonist (R,R-tetrahydrochrysene) after the first hemorrhage. The protein levels of ERα, ERβ, eNOS, and inducible nitric oxide synthase (iNOS) from basilar arteries were examined using Western blot analysis, and their mRNAs were evaluated by reverse transcription–polymerase chain reaction.

Results

The ERα but not the ERβ was upregulated in the basilar artery after SAH. Treatment with MPP eliminated E2-mediated effects in SAH, relieved cerebral vasospasm, preserved eNOS expression, and suppressed iNOS expression.

Conclusions

Estrogen receptor α is upregulated in the basilar artery after SAH. Note that E2 exerts its protective effects through ERα-dependent pathways to relieve cerebral vasospasm and preserve eNOS expression. A selective ERα agonist may be the drug of choice for the treatment of patients with SAH.

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Chih-Lung Lin, Aij-Lie Kwan, Aaron S. Dumont, Yu-Feng Su, Neal F. Kassell, Chih-Jen Wang, Shu-Chuan Wu, Ching-Ling Kuo, Ching-Shan Huang, Arco Y. Jeng and Chin-San Liu

Object

Adhesion molecules, including intercellular adhesion molecule–1 (ICAM-1), vascular cell adhesion molecule–1 (VCAM-1), and E-selectin, are important mediators of inflammation, and their levels are elevated in the serum of patients following aneurysmal subarachnoid hemorrhage (SAH). The investigators previously found that CGS 26303 is effective in preventing and reversing arterial narrowing in a rabbit model of SAH. The purpose of the present study was to examine whether levels of adhesion molecules are altered after treatment with CGS 26303 in this animal model.

Methods

New Zealand White rabbits were each injected with 3 ml of autologous blood in the cisterna magna, and intravenous treatment with CGS 26303 (30 mg/kg) was initiated 1 hour later. The compound was subsequently administered at 12, 24, and 36 hours post-SAH. Blood samples were collected at 48 hours post-SAH to measure ICAM-1, VCAM-1, and E-selectin levels. After the rabbits had been killed by perfusion–fixation, the basilar arteries (BAs) were removed and sliced, and their cross-sectional areas were measured.

Treatment with CGS 26303 attenuated arterial narrowing after SAH. Morphologically, corrugation of the internal elastic lamina of BAs was prominently observed in the SAH only and vehicle-treated SAH groups, but not in the CGS 26303–treated SAH group or in healthy controls. There were no significant differences in the levels of VCAM-1 among the four groups. The levels of E-selectin were increased in all animals subjected to SAH (those in the SAH only, SAH plus vehicle, and SAH plus CGS 26303 groups) compared with healthy controls (no SAH); however, the levels of ICAM-1 in the SAH only and SAH plus vehicle groups were significantly elevated (p < 0.001), and treatment with CGS 26303 reduced ICAM-1 to control levels following SAH.

Conclusions

These results show that ICAM-1 may play a role in mediating SAH-induced vasospasm and that a reduction of ICAM-1 levels after SAH may partly contribute to the antispastic effect of CGS 26303.