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Chih-Lung Lin, Huei-Chuan Shih, Ann-Shung Lieu, Kung-Shing Lee, Aaron S. Dumont, Neal F. Kassell, Shen-Long Howng, and Aij-Lie Kwan

Object

Impaired endothelium-dependent relaxation is present in vasospastic cerebral vessels after subarachnoid hemorrhage (SAH) and may result from deficient production of endothelial nitric oxide synthase (eNOS) or increased production and/or activity of inducible NOS (iNOS). Accumulating evidence demonstrates that adenosine A2A receptors increase the production of NO by human and porcine arterial endothelial cells, which in turn leads to vasodilation. This study was designed to examine the effects of an adenosine A2A receptor agonist, (2(4-[2-carboxyethyl]phenyl)ethylamino)-5′-N-ethylcarboxamidoadenosine (CGS 21680), in the prevention of SAH-induced vasospasm.

Methods

Experimental SAH was induced in Sprague–Dawley rats by injecting 0.3 ml of autologous blood into the cisterna magna of each animal. Intraperitoneal injections of CGS 21680 or vehicle were administered 5 minutes and 24 hours after induction of SAH. The degree of vasospasm was determined by averaging measurements of cross-sectional areas of the basilar artery (BA) 48 hours after SAH. Expression of eNOS and iNOS in the BA was also evaluated.

Prior to perfusion–fixation, there were no significant differences among animals in the control and treated groups in any physiological parameter that was recorded. The CGS 21680 treatment significantly attenuated SAH-induced vasospasm. Induction of iNOS mRNA and protein in the BA by the SAH was significantly diminished by administration of CGS 21680. The SAH-induced suppression of eNOS mRNA and protein was also relieved by the CGS 21680 treatment.

Conclusions

This is the first evidence that adenosine A2A receptor agonism is effective in preventing SAH-induced vasospasm without significant complications. The beneficial effect of adenosine A2A receptor 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. Adenosine A2A receptor agonism holds promise in the treatment of cerebral vasospasm following SAH and merits further investigation.

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Chih-Lung Lin, Huei-Chuan Shih, Aaron S. Dumont, Neal F. Kassell, Ann-Shung Lieu, Yu-Feng Su, Shen-Long Hwong, and Chin Hsu

Object

Sex differences in the outcome of aneurysmal subarachnoid hemorrhage (SAH) are controversial, and the potential influence of estradiol on vasodilation is unclear. In the present study the authors evaluate the effect and possible mechanism of 17β-estradiol (E2) on SAH-induced vasospasm in a two-hemorrhage rodent model of SAH.

Methods

A 30-mm Silastic tube filled with E2 in corn oil (0.3 mg/ml) was subcutaneously implanted in male rats. Serum levels of E2 were measured on Days 0, 1, 2, 3, 4, and 7 postimplantation. The degree of vasospasm was determined by averaging the cross-sectional areas of the basilar artery (BA) 7 days after the first SAH. Expressions of endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) in the BA were also evaluated.

Serum levels of E2 in the E2-treated rats were at physiological levels (56–92 pg/ml) and were significantly higher than those in the control and vehicle-treated groups. Treatment with E2 significantly (p < 0.01) attenuated SAH-induced vasospasm. Induction of iNOS messenger (m)RNA and protein in the BA by SAH was significantly diminished by the E2 treatment but not by vehicle treatment. The SAH-induced suppression of eNOS mRNA and protein was relieved by E2 treatment.

Conclusions

These results suggest 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 iNOS expression and the preservation of normal eNOS expression after SAH. Treatment with E2 holds therapeutic promise in the treatment of cerebral vasospasm following SAH and merits further investigation.

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Chih-Lung Lin, Aaron S. Dumont, Ann-Shung Lieu, Chen-Po Yen, Shiuh-Lin Hwang, Aij-Lie Kwan, Neal F. Kassell, and Shen-Long Howng

Object. The reported incidence, timing, and predictive factors of perioperative seizures and epilepsy after subarachnoid hemorrhage (SAH) have differed considerably because of a lack of uniform definitions and variable follow-up periods. In this study the authors evaluate the incidence, temporal course, and predictive factors of perioperative seizures and epilepsy during long-term follow up of patients with SAH who underwent surgical treatment.

Methods. Two hundred seventeen patients who survived more than 2 years after surgery for ruptured intracranial aneurysms were enrolled and retrospectively studied. Episodes were categorized into onset seizures (≤ 12 hours of initial hemorrhage), preoperative seizures, postoperative seizures, and late epilepsy, according to their timing.

The mean follow-up time was 78.7 months (range 24–157 months). Forty-six patients (21.2%) had at least one seizure post-SAH. Seventeen patients (7.8%) had onset seizures, five (2.3%) had preoperative seizures, four (1.8%) had postoperative seizures, 21 (9.7%) had at least one seizure episode after the 1st week postoperatively, and late epilepsy developed in 15 (6.9%). One (3.8%) of 26 patients with perioperative seizures (onset, preoperative, or postoperative seizure) had late epilepsy at follow up. The mean latency between the operation and the onset of late epilepsy was 8.3 months (range 0.3–19 months). Younger age (< 40 years old), loss of consciousness of more than 1 hour at ictus, and Fisher Grade 3 or greater on computerized tomography scans proved to be significantly related to onset seizures. Onset seizure was also a significant predictor of persistent neurological deficits (Glasgow Outcome Scale Scores 2–4) at follow up. Factors associated with the development of late epilepsy were loss of consciousness of more than 1 hour at ictus and persistent postoperative neurological deficit.

Conclusions. Although up to one fifth of patients experienced seizure(s) after SAH, more than half had seizure(s) during the perioperative period. The frequency of late epilepsy in patients with perioperative seizures (7.8%) was not significantly higher than those without such seizures (6.8%). Perioperative seizures did not recur frequently and were not a significant predictor for late epilepsy.