A Comparison of Pathophysiology in Humans and Rodent Models of Subarachnoid Hemorrhage

Abstract

Non-traumatic subarachnoid hemorrhage (SAH) affects an estimated 30,000 people each year in the United States, with an overall mortality of ~30%. Most cases of SAH result from a ruptured intracranial aneurysm, require long hospital stays, and result in significant disability and high fatality. Early brain injury (EBI) and delayed cerebral vasospasm (CV) have been implicated as leading causes of morbidity and mortality in these patients, necessitating intense focus on developing preclinical animal models that replicate clinical SAH complete with delayed CV. Despite the variety of animal models currently available, translation of findings from rodent models to clinical trials has proven especially difficult. While the explanation for this lack of translation is unclear, possibilities include the lack of standardized practices and poor replication of human pathophysiology, such as delayed cerebral vasospasm and ischemia, in rodent models of SAH. In this review, we summarize the different approaches to simulating SAH in rodents, in particular elucidating the key pathophysiology of the various methods and models. Ultimately, we suggest the development of standardized model of rodent SAH that better replicates human pathophysiology for moving forward with translational research.

Keywords: aneurysm; heme; hemoglobin; iron; ischemia; stroke; vasospasm.

Figure 1

Representative illustrations of blood clot distribution in the cisterna magna and prechiasmatic cistern models. Images correspond to (a) cisterna magna control, (b) prechiasmatic cistern control, (c) cisterna magna experimental, and (d) prechiasmatic cistern experimental mouse brains. Cisterna magna and prechiasmatic cistern injections primarily result in blood clots surrounding the posterior and anterior circulations, respectively. The scale bar represents 2cm. Photo was obtained from Cai J. et al. (2012).

Figure 2

Temporal changes in CBF, ICP, MABP, and CPP over 1 h after induction of SAH with the x-axis representing the progression of time and the y-axis as relative change in each parameter. Due to the variation in the absolute values of these parameters after SAH (refer to Table 5), the relative changes in the variables are shown because these trends are preserved in nearly all preclinical studies and in humans. CBF and CPP sharply decrease shortly after SAH, followed by a return to near-baseline values within 1 h. Similarly, there is an acute increase in both ICP and MABP, followed by a return to baseline or near-baseline values within 1 h. Values for CBF were taken from studies that measured CBF using laser Doppler flowmetry.