Monkey Models

The first use of monkeys for the study of vasospasm was reported in 1965 (29). In this study, a transoral approach to the skull base was used to expose the basilar and vertebral arteries, vaso-spasm was induced through application of autologous blood, and measurements were taken by in situ photographic analyses of the vessel calibers.

Currently, the most popular technique is the one described in 1982 in cynomolgus monkeys (Macaca fascicularis) (30). In this model, a preoperative angiogram is obtained, a right frontotem-poral craniectomy is performed, and the arachnoid cisterns encasing the internal carotid artery (ICA), anterior cerebral artery (ACA), and middle cerebral artery (MCA) are dissected. Arterial blood is withdrawn and allowed to clot, and the resulting clot is sectioned into fragments that are placed adjacent to the exposed vessels (Fig. 1). A repeat angiogram is obtained 7 days after surgery, and vasospasm is determined by comparison with the preoperative angiogram (Fig. 2). Angiographic vessel narrowing ranges from 3l% to 100% and typically occurs in all animals (30 ) . Severe vasospasm, defined as a reduction >50% in arterial caliber, was present in only approximately 25% of the animals. The mortality reported by the authors was 10% (30). In our laboratory, however, we have had no mortality attributable to the model (32,33).

Advantages of this model include a well-defined course of angiographic vasospasm, development of distal vessel narrowing, histopathologic modifications in the exposed vessels, loss of autoregulatory mechanisms, disruption of cerebral blood flow (CBF), presence of a contralateral control, and absence of pharmacologic responses to standard vasodilators. Disadvantages of the model include high costs and risk of contamination with simian herpes virus. This model has been extensively used as described, or with minor modifications, to test several experimental therapies (34-43) and to analyze proposed pathogenetic mechanisms (11,42,44-52).

Figure 1 Monkey model of subarachnoid hemorrhage (SAH). (A) An artist's illustration of the surgical technique for induction of SAH in monkey. (B) Cerebral angiograms of a cynomolgus monkey before (top) and after (bottom) SAH.

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Figure 1 Monkey model of subarachnoid hemorrhage (SAH). (A) An artist's illustration of the surgical technique for induction of SAH in monkey. (B) Cerebral angiograms of a cynomolgus monkey before (top) and after (bottom) SAH.

Other popular techniques used to induce vasospasm in monkeys are based on blood injection into intracranial cisterns, a technique first described in 1968 that involves injection of 2 to 3 ml of blood into the cisterna magna (53) of African green monkeys. Modifications of this technique include injections into the subfrontal subarachnoid space (53) and prepontine cistern (via cervical laminectomy) (54). Standardization of blood volumes is critical to induce reproducible vasospasm with these methods. Disadvantages of this model, compared to clot placement techniques, include the lack of a contralateral control vessel and the high variability in the severity and course of the induced vasospasm. Models using rupture, puncture, or avulsion of the intracranial vessels were used in the past (55-58), but the high mortality rates and the limited reproducibility of vasospasm have been discouraging.

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