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To investigate the changes of gene expression on the cerebral vasospasm after subarachnoid hemorrhage, we used genome-wide microarray for a canine double-hemorrhage model and analyzed the data by using a network-based analysis. Six dogs were assigned to two groups of three animals: control and hemorrhage. The effects were assessed by the changes in gene expressions in the artery 7 days after the first blood injection. Among 23,914 genes, 447 and 66 genes were up-regulated more than two- and fivefold, respectively, and 332 and 25 genes were down-regulated more than two- and fivefold, respectively. According to gene ontology, genes related to cell communication (P = 5.28E-10), host-pathogen interaction (7.65E-8), and defense-immunity protein activity (0.000183) were significantly overrepresented. The top high-level function for the merged network derived from the network-based analysis was cell signaling, revealing that the subgroup that regulates the quantity of Ca(2+) to have the strongest association significance (P = 4.75E-16). Canine microarray analysis followed by gene ontology profiling and connectivity analysis identified several functional groups and individual genes responding to cerebral vasospasm. Ca(2+) regulation may play a key role in these gene expression changes and may be involved in the pathogenesis of cerebral vasospasm.

Vasospasm following subarachnoid hemorrhage (SAH) remains difficult to prevent despite extensive investigative efforts. Nicardipine prolonged-release implants (NPRIs) have been used to prevent vasospasm in patients with SAH since October 1999. The present study analyzed the efficacy and safety of NPRIs in 100 patients with SAH and thick subarachnoid clot (mainly Fisher group 3) treated with NPRIs (diameter 2 mm, length 10 mm, containing 4 mg of nicardipine) during surgery after clipping of the aneurysm. The number and location of pellets depended on the amount and site of the subarachnoid clot on preoperative computed tomography and on the type of craniotomy. Two to 12 pellets were implanted in the cisterns of the internal carotid artery, middle cerebral artery, and/or anterior cerebral artery, where thick clots were present and vasospasm related to delayed ischemic neurological deficit (DIND) was highly likely. Only seven patients developed DIND and five patients suffered cerebral infarction. Angiography performed on days 7-12 revealed no vasospasm in any of the arteries close to the site of NPRI placement. NPRI placement can completely prevent vasospasm in arteries within the cisterns containing thick clots, but is less effective in remote locations.

Background and Purpose: Inflammatory cytokines are involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was conducted to examine the role of p38 mitogen-activated protein kinase (MAPK) in the development of vasospasm and cytokine production., Methods: We measured the expression levels of genes and proteins related to inflammation in human vascular smooth muscle cells (hVSMCs) treated with hemolysate and FR167653 (FR) (1 micromol/L), a selective p38MAPK inhibitor, for 48 hours by TaqMan real-time reverse transcription-polymerase chain reaction (RT-PCR) and ELISA. Twenty-one dogs were assigned to 3 groups of 7 animals: control, placebo, and FR-treated (1 mg/kg/d) groups in a double-hemorrhage model. The effects were assessed through the caliber of the basilar artery, and the changes in gene expressions and the activation of p38MAPK were assessed by Western blot analysis., Results: Treatment of hVSMCs with hemolysate induced significant upregulation of interleukin (IL)-1alpha, IL-1beta, and IL-8 gene and protein expressions, which was suppressed significantly with FR. The mean vessel caliber on day 7, as a percentage of that of day 0, was 49% in the placebo, and 74% in the FR group (P=0.0001). The gene expression levels of IL-1alpha, IL-1beta, and IL-8 in the arterial wall were extremely elevated in the placebo, and significantly suppressed in the FR group (P=0.0027, 0.0002, and 0.0073). p38MAPK phosphorylation was stimulated in the placebo and hemolysate in vitro, and suppressed in the FR group., Conclusions: These results suggest that p38MAPK is activated in the arterial wall after SAH, leading to the development of vasospasm, possibly through the upregulation of inflammatory cytokines.

Background and Purpose: Despite extensive investigative efforts, there are few treatments that can prevent vasospasm after subarachnoid hemorrhage. This study was conducted to examine the efficacy and safety of nicardipine prolonged-release implants (NPRI) for humans, which have already been proven in dogs., Methods: Twenty consecutive subarachnoid hemorrhage patients with thick subarachnoid clot were treated with NPRI (a pellet of diameter 2 mm, length 10 mm, containing 4 mg of nicardipine) during surgery after clipping of their aneurysm. The number and location of pellets depended on the amount and site of subarachnoid clot on preoperative CT and on craniotomy., Results: Two to 10 pellets were implanted in the cistern of the internal carotid, middle cerebral, and/or anterior cerebral artery, where thick clots existed and therefore vasospasm related to delayed ischemic neurological deficits was highly likely. Delayed ischemic neurological deficits and cerebral infarctions were seen in 1 patient. Angiography performed on days 7 to 12 revealed no vasospasm in any arteries near which NPRI were placed. No complications were experienced., Conclusions: Vasospasm was completely prevented for the arteries in thick clot cisterns, when NPRI were placed adjacent to the arteries during surgery. This drug-delivery system offers a promising approach for preventing vasospasm.