Animal Models Of Subarachnoid Hemorrhage Research Articles

Levetiracetam is Neuroprotective in Murine Models of Closed Head Injury and Subarachnoid Hemorrhage

Prophylactic treatment with antiepileptic drugs is common practice following subarachnoid hemorrhage (SAH) and traumatic brain injury. However, commonly used antiepileptic drugs have multiple drug interactions, require frequent monitoring of serum levels, and are associated with adverse effects that may prompt discontinuation. In the current study, we test the hypothesis that levetiracetam, an anticonvulsant with favorable interaction and adverse event profiles, is neuroprotective in clinically relevant models of SAH and closed head injury (CHI). A single intravenous dose of vehicle, low-dose (18 mg/kg), or high-dose (54 mg/kg) levetiracetam was administered intravenously followed CHI. Functional assessments were performed on a daily basis, and histological assessments performed at 24 hours. In a separate series of experiments, mice were randomized to receive intravenous administration of vehicle, low-dose, or high-dose levetiracetam every 12 hours for 3 days following SAH. Functional endpoints were assessed daily, followed by measurement of MCA luminal diameter on day 3. A single dose of levetiracetam improved functional and histological outcomes after CHI. This effect appeared specific for levetiracetam and was not associated with fosphenytoin treatment. Treatment with levetiracetam also improved functional outcomes and reduced vasospasm following SAH. Levetiracetam is neuroprotective in clinically relevant animal models of SAH and CHI. Levetiracetam may be a therapeutic alternative to phenytoin following acute brain injury in the clinical setting when seizure prophylaxis is indicated.

Hypertonic fluid resuscitation from subarachnoid hemorrhage in rats: A comparison between small volume resuscitation and mannitol

Objective Death and severe morbidity after subarachnoid hemorrhage (SAH) are mainly caused by global cerebral ischemia through increased intracranial pressure (ICP) and decreased cerebral blood flow (CBF). We have recently demonstrated neuroprotective effects of small volume resuscitation (7.5% saline in combination with 6% dextran 70) in an animal model of SAH, leading to normalization of increased ICP, reduced morphological damage and improved neurological recovery. In the present study, we compared the concept of small volume resuscitation represented by two clinically licenced hypertonic–hyperoncotic saline solutions with the routinely used hyperosmotic agent–mannitol–and investigated their effects on ICP, CBF, neurological recovery and morphological damage after SAH in rats. Methods 60 dextran-resistant Wistar rats were subjected to SAH by an endovascular filament. ICP, MABP (mean arterial blood pressure) and bilateral local CBF were continuously recorded. All animals were randomly assigned to four groups: (I) NaCl 0.9% (4 ml/kg bw), (II) 7.5% NaCl + 6% dextran 70 (4 ml/kg bw), (III) 7.2% NaCl + HES 200,000 (4 ml/kg bw) and (IV) 20% mannitol (9.33 ml/kg bw) given 30 min after SAH. Neurological deficits were assessed on days 1, 3 and 7 after SAH. The morphological damage was evaluated on day 7 after SAH. Results The induction of SAH resulted in an immediate ICP increase to 46.6 ± 3.2 mm Hg (mean ± S.E.M.) and 29.6 ± 1.3 (mean ± S.E.M.) mm Hg 90 min post-SAH. While a treatment with both hypertonic saline solutions (II, III) decreased ICP as well as the 20% mannitol solution, only the group treated with hypertonic saline and dextran 70 (II) showed an increase of ipsilateral CBF for 20 min after the infusion and significantly more surviving neurons in the motorcortex and caudoputamen. Mortality was reduced from 60% (I) and 73% (III and IV), respectively, to 40% in group II. Conclusion Of all hypertonic solutions investigated, small volume resuscitation with NaCl 7.5% in combination with 6% dextran 70 evolved to be most effective in terms of reducing the initial harmful sequelae of SAH, leading to lowered ICP and less morphological damage after SAH in the rat.

Local Delivery of Ibuprofen via Controlled-release Polymers Prevents Angiographic Vasospasm in a Monkey Model of Subarachnoid Hemorrhage

Adhesion and migration of leukocytes into the periadventitial space play a role in the pathophysiology of vasospasm after subarachnoid hemorrhage (SAH). Intercellular adhesion molecule-1 is a determinant cell adhesion molecule involved in this process. Ibuprofen has been shown to inhibit intercellular adhesion molecule-1 upregulation and prevent vasospasm in animal models of SAH. In this study, we report the toxicity and efficacy of locally delivered ibuprofen incorporated into controlled-release polymers to prevent vasospasm in a monkey model of SAH. Ibuprofen was incorporated into ethylene-vinyl acetate (EVAc) polymers at 45% loading (wt:wt). For the toxicity study, cynomolgus monkeys (n = 5) underwent surgical implantation of either blank/EVAc polymers (n = 3) or 45% ibuprofen/EVAc polymers (n = 2) in the subarachnoid space, were followed up for 13 weeks, and were killed for histopathological analysis. For the efficacy study, cynomolgus monkeys (n = 14) underwent cerebral angiography 7 days before and 7 days after surgery and SAH and were randomized to receive either a 45% ibuprofen/EVAc polymer (n = 7; mean dose of ibuprofen, 6 mg/kg) or blank EVAc polymers (n = 7) in the subarachnoid space. Angiographic vasospasm was determined by digital image analysis. Student's t test was used for analysis. Animals implanted with ibuprofen polymers showed no signs of local or systemic toxicity. Animals treated with ibuprofen polymers had 91 +/- 9% lumen patency of the middle cerebral artery, compared with 53 +/- 11% of animals treated with blank/EVAc polymers (P < 0.001). Ibuprofen polymers are safe and prevent angiographic vasospasm after SAH in the monkey model. These findings support the role of cell adhesion molecules and inflammation in the pathophysiology of vasospasm.

Pharmacokinetics of controlled-release polymers in the subarachnoid space after subarachnoid hemorrhage in rabbits.

Implantation of controlled-release polymers into the subarachnoid space to deliver drugs for treatment of vasospasm after subarachnoid hemorrhage (SAH) is currently of interest. Among the issues regarding local delivery of drugs in the subarachnoid space, however, are the extent of diffusion and the rate of release of the loaded agents. In this study Evans blue dye (EBD) was loaded into controlled-release polymers and its pharmacokinetic properties were determined in vitro and in vivo by using a rabbit model of SAH. Ethylene-vinyl acetate copolymer (EVAc) was loaded 40% (w:w) with EBD and its pharmacokinetics were spectrophotometrically determined in vitro by examining three EBD-EVAc polymers. Additional polymers were implanted either into the frontal lobe or into the cisterna magna of 16 New Zealand White rabbits. Subarachnoid hemorrhage was induced in eight of the animals by an injection of 1.5 ml of arterial blood into the cisterna magna. The animals were killed 3 or 14 days postoperatively, their brains and spinal cords were harvested, and samples of each were placed in formamide for dye extraction and quantification. Specimens were examined macroscopically and the concentrations of EBD were determined with the aid of a spectrophotometer. The EBD-EVAc polymers continuously released EBD over a 133-day period. The controlled release of the dye into the subarachnoid space in either location resulted in staining of the entire central nervous system (CNS) in rabbits when the polymers were placed either on the frontal lobe or in the cisterna magna. The EBD diffusion covered a distance of at least 40 cm. The presence of blood in the subarachnoid space did not interfere with the diffusion. In this study the authors define the rate and extent of diffusion of EBD from controlled-release polymers placed in the subarachnoid space under conditions of SAH. Evans blue dye diffused through the entire rabbit CNS, covering a distance greater than that of the longest dimension of the hemicircumference of the subarachnoid space around the human brain. The pharmacokinetic properties of EBD-EVAc polymers are comparable to those of antivasospasm agents that are successfully used in animal models of SAH.

Prevention of delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

The delayed cerebral vasoconstriction known as cerebral vasospasm remains a significant cause of permanent neurological deficit and death following aneurysmal subarachnoid hemorrhage despite the best current medical therapies. The mechanism of cerebral vasospasm remains unknown. Several new drugs have been tested in animal models of subarachnoid hemorrhage, and these experimental studies have contributed to a better understanding of the potential mechanisms that lead to cerebral vasospasm. In this article, the authors highlight recent advances in the various treatment procedures for delayed cerebral vasospasm following subarachnoid hemorrhage. (c) 2001 Prous Science. All rights reserved.

Contribution of endothelin-1 to disruption of blood-brain barrier permeability in dogs.

We examined the effect of intracisternal application of endothelin-1 (ET-1) on the permeability of fluorescein into the cerebrospinal fluid (CSF) in beagle dogs in order to evaluate its role in disruption of blood-brain barrier (BBB) permeability seen in the subarachnoid hemorrhage animal model. Intracisternal application of their autologous blood for producing a canine two-hemorrhage model revealed an enhanced fluorescein permeability into the CSF together with the development of cerebral vasospasm. A single dose of ET-1 (40 pmol/animal) significantly increased penetration of fluorescein compared with that in normal dogs. Although its magnitude was much less than that in the two-hemorrhage model after the first administration of ET-1, the second challenge of the same dose of ET-1 with a 48-h interval produced marked disruption of BBB permeability similar to those in the animal model. Moreover, the ET-1-induced enhancement of fluorescein permeability into the CSF was completely prevented by intracisternal pretreatment with an endothelin ET(A)-receptor selective antagonist, S-0139 (0.03 mg/kg), as were the ET-1-induced cerebral vasoconstriction and behavioral changes as previously reported. Thus, we conclude that ET-1 acting on the adventitial site of brain in dogs contributes to the disruption of BBB permeability via endothelin ET(A)-receptor mediation.

Subarachnoid hemorrhage and myocardial damage clinical and experimental studies.

Subarachnoid hemorrhage (SAH) due to aneurysmal rupture is frequently complicated by cardiopulmonary episodes, including sudden death. We investigated the pathogenesis of cardiopulmonary complications from clinical observation of 715 cases with SAH. There was transient left ventricular asynergy in 9.4% (67/715) of the cases, which consisted of mechanical heart failure and myocardial necrosis. Plasma catecholamine concentration was higher in these patients compared with those without left ventricular asynergy. Transient left ventricular asynergy was considered to result from myocardial derangement: "a panic myocardium," due to a sudden burst of catecholamine. Concerning arrhythmia in SAH, cases with life-threatening arrhythmia, such as ventricular tachycardia or ventricular fibrillation, had higher concentrations not only of plasma catecholamine but also of serum CK-MB, myosin light chain and troponin T, compared with patients who had no ventricular arrhythmia. This implies that life-threatening arrhythmia in SAH would result from myocardial damage due to catecholamine. We devised a novel animal model of SAH in order to clarify the relation between sympathetic nervous activity and myocardial damage immediately after the onset of SAH. The animal experiments showed that sympathetic nervous activity as well as cardiac contractility were transiently elevated, but cardiac function subsequently declined. Serum CK-MB was increased from the onset of SAH and a high value was maintained throughout the entire experimental period. In conclusion, extraordinary transient enhancement of sympathetic nervous activity induces myocardial damage resulting from what is characterized by "a panic myocardium."

Subarachnoid Hemorrhage: Medical and Surgical Management

Subarachnoid Hemorrhage: Medical and Surgical Management edited by Takehiko Yanagihara, David G. Piepgras, and John L.D. Atkinson , 584 pp., ill., New York, Marcel Dekker, 1998, $195.00 This multiauthored textbook on subarachnoid hemorrhage and its management includes 18 chapters on topics such as animal models of subarachnoid hemorrhage and vasospasm, epidemiology of subarachnoid hemorrhage, intracranial …

Spasmolytic effect of acidic fibroblast growth factor in early cerebral vasospasm in the rat

In animal models of subarachnoid hemorrhage (SAH), basilar artery spasm has been described. Since fibroblast growth factors (FGFs) dilate rat basilar artery in vivo, we tested whether systemic administration of acidic fibroblast growth factor (aFGF) can reverse the basilar artery spasm following rat SAH. SAH was mimicked by injecting autologous blood into the cisterna magna. We used a digital substraction angiography system in order to evaluate the spasmolytic effect of aFGF administered via the axillary artery 7 minutes after the injection of the autologous blood. Control animals received vehicle solution in the same manner. Intraarterial bolus injection of 2.6 micrograms aFGF, but not the solvent, reverses the acute basilar artery narrowing caused by SAH (23.05% of the baseline value at 5 minutes post-SAH). Our results suggest an important role for FGFs in the cerebral tone regulation and support a clinical interest of FGFs in preventing cerebral ischemia following SAH, particularly if these vasoactive effects are added to the known neuroprotective effects of FGFs.

Possibilities of brain protection with tirilazad after cardiac arrest.

Cardiac arrest and resuscitation often create a cerebral insult caused by the initial cessation of blood flow, followed by the incomplete ischemia of cardiopulmonary resuscitation (low flow), and, following the return of spontaneous circulation, by the post-resuscitation syndrome. A cascade of physiologic, vascular, and biochemical events is set in motion, including changes in neuropeptides, electrolytes such as calcium and magnesium, excitatory neurotransmitters such as glutamate and acetylcholine, lymphokines such as interleukin-1, and arachidonic acid metabolites such as prostaglandins and leukotrienes; and formation of oxygen free radicals and lactic acid. Oxygen free radical-induced lipid peroxidation appears to increase tissue injury during and after brain ischemia. The 21-aminosteroid U74006F (tirilazad mesylate) is a novel inhibitor of lipid membrane peroxidation induced by oxygen free radicals, which has been shown, in animal models of subarachnoid hemorrhage, central nervous system trauma, and cerebral ischemia, to limit the extent of secondary tissue damage, thus improving functional recovery. Since tirilazad appears to have little or no behavioral or physiologic side effects, it appears to be an ideal agent for widespread brain ischemia prophylaxis. Tirilazad mesylate studies in out-of-hospital cardiac arrest are currently being planned.

Phase II trial of tirilazad in aneurysmal subarachnoid hemorrhage

Tirilazad mesylate, a 21-aminosteroid free-radical scavenger, has been shown to ameliorate cerebral vasospasm and reduce infarct size in animal models of subarachnoid hemorrhage (SAH) and focal cerebral ischemia. In preparation for performing large-scale clinical trials in humans with aneurysmal SAH, the safety of varying doses of tirilazad was tested in a randomized, double-blind, vehicle-controlled, sequential dose-escalation study at 12 Canadian neurosurgical centers. Two hundred forty-five patients with an aneurysmal SAH documented by angiography were enrolled in the study sequentially within 72 hours of hemorrhage. The patients were assigned to one of three dosage tiers: receiving 0.6 mg/kg, 2 mg/kg, or 6 mg/kg tirilazad or vehicle per day intravenously in divided doses through Day 10 following the SAH. All patients also received oral nimodipine. No serious side effects of tirilazad treatment were identified at any of the three doses, despite close monitoring of hepatic and cardiac toxicity. A trend toward improvement in overall 3-month patient outcome was seen in the 2 mg/kg per day tirilazad-treated group compared to the outcomes in the vehicle-treated groups. We conclude that tirilazad mesylate is safe in SAH patients at doses up to 6 mg/kg per day for up to 10 days and is a promising drug for the treatment of patients with aneurysmal SAH.