Rodent Models of Intracerebral Hemorrhage

Abstract

Abstract-The collagenase and whole blood intracerebral hemorrhage (ICH) models are widely used to identify mechanisms of injury and to evaluate treatments. Despite preclinical successes, to date, no treatment tested in phase III clinical trials has benefited ICH patients. These failures call into question the predictive value of current ICH models. By highlighting differences between these common rodent models of ICH, we sought to help investigators choose the more appropriate model for their study and to encourage the use of both whenever possible. For instance, we previously reported substantial differences in the bleeding profile, progression of cell death, and functional outcome between these models. These and other differences influence the efficacy and mechanisms of action of various treatment modalities. Thus, in this review, we also summarize neuroprotective and rehabilitation findings in each model. We conclude that differences between ICH models along with our current inability to identify the more clinically predictive model necessitate that preclinical assessments should normally be done in both. Such an approach, coupled with better assessment practices, will likely improve chances of future clinical success. Key Words: intracerebral hemorrhage Ⅲ rodent model Ⅲ neuroprotection Ⅲ rehabilitation I ntracerebral hemorrhage (ICH) is a devastating stroke with Ϸ50% mortality by 1 month, whereas most survivors remain disabled. 1,2 Animal models of ICH have significantly advanced our understanding of pathophysiology, thereby identifying numerous therapeutic targets. 3,4 Despite the use of these models, especially in rodents, and the efficacy reported in them, 4 no treatments have been proven to help ICH patients. Notably, recent clinical failures call into question whether these models accurately reflect human ICH and whether they will be useful in successfully translating treatments from the laboratory. Similar concerns have been raised for ischemic stroke.As with ischemia, no model perfectly reflects the complexity and heterogeneity of ICH in humans. Accordingly, preclinical studies should use several models to better understand pathophysiology and to predict clinical efficacy. This article briefly discusses the 2 most widely used rodent models of ICH. Although these can be compared on many facets, we focus on bleeding profile, progression of cell death, and changes in neuroplasticity, which are all of utmost importance to final outcome. Furthermore, we highlight how these model differences impact hypothermic neuroprotection and the effects of rehabilitation. Animal Models of ICHAnimal models of primary ICH have been developed using pigs, rabbits, dogs, cats, and rodents. The bleed is usually created in the striatum, but other regions have been targeted. Experiments with inert substances (eg, balloon inflation) and blood components (eg, thrombin), to evaluate their contribution to ICH outcome are widespread. However, the most commonly used models involve intraparenchymal infusion of either autologous blood...

Blood Glutamate Grabbing Does Not Reduce the Hematoma in an Intracerebral Hemorrhage Model but it is a Safe Excitotoxic Treatment Modality

“…Collagenase disrupts the basal lamina of blood vessels, which leads to the leaking of blood into the surrounding tissue. 26 To perform the model, rats were placed in a stereotaxic frame (Stoelting Co., Wood Dale, IL, USA) under sevoflurane anesthesia. A 1-cm-long midline incision was made in the scalp, beginning midway between the eyes and terminating behind the lambda.…”

A Critical Appraisal of Experimental Intracerebral Hemorrhage Research

“…Unfortunately, there is considerably less experimental data on these topics in the ICH field. Hypothermia is an established neuroprotectant in cerebral ischemia, but data in ICH models are inconclusive (MacLellan et al, 2009a(MacLellan et al, , 2010. Interestingly, hyperthermia protocols that aggravate ischemic brain injury (e.g., elevating temperature to 391C for 3 hours) cause no harmful effects in ICH models (MacLellan and Colbourne, 2005;Penner et al, 2011), while clinical data on post-ICH fever are inconclusive (Leira et al, 2004;Schwarz et al, 2000;Szczudlik et al, 2002;Wang et al, 2000Wang et al, , 2008a.…”

Experimental Intracerebral Hemorrhage: Avoiding Pitfalls in Translational Research

“…For example, when comparing the two commonest ICH models (autologous blood injection and collagenase injection) in a trial of therapeutic hypothermia, bleeding, tissue loss, and functional recovery differed between the two models (MacLellan et al, 2010). Further, in a trial of enriched rehabilitation, functional outcomes (assessed through a reaching task) in rats undergoing both autologous blood-induced ICH and collagenaseinduced ICH were improved, but the former model resulted in no changes in lesion volume or contralateral dendritic morphology (MacLellan et al, 2010(MacLellan et al, , 2011. Ongoing cell death observed in the collagenase model (MacLellan et al, 2008) is a potential target for neuroprotective agents and rehabilitation therapies (MacLellan et al, 2011).…”