Translating Basic Science Research to Clinical Application: Models and Strategies for Intracerebral Hemorrhage

Abstract

Preclinical stroke models provide insights into mechanisms of cellular injury and potential therapeutic targets. Renewed efforts to standardize preclinical practices and adopt more rigorous approaches reflect the assumption that a better class of compounds will translate into clinical efficacy. While the need for novel therapeutics is clear, it is also critical that diagnostics be improved to allow for more rapid treatment upon hospital admission. Advances in imaging techniques have aided in the diagnosis of stroke, yet current limitations and expenses demonstrate the need for new and complementary approaches. Intracerebral hemorrhage (ICH) exhibits the highest mortality rate, displays unique pathology and requires specialized treatment strategies relative to other forms of stroke. The aggressive nature and severe consequences of ICH underscore the need for novel therapeutic approaches as well as accurate and expeditious diagnostic tools. The use of experimental models will continue to aid in addressing these important issues as the field attempts to translate basic science findings into the clinical setting. Several preclinical models of ICH have been developed and are widely used to recapitulate human pathology. Because each model has limitations, the burden lies with the investigator to clearly define the question being asked and select the model system that is most relevant to that question. It may also be necessary to optimize and refine pre-existing paradigms, or generate new paradigms, as the future success of translational research is dependent upon the ability to mimic human sequelae and assess clinically relevant outcome measures as means to evaluate therapeutic efficacy.

Evacuation of intracerebral hemorrhages by neuroendoscopy with transparent sheath. Experimental study

“…Although in clinical practice, ICHs may be associated with subarachnoid hemorrhage, in experimental models subarachnoid extension may challenge its reproducibility, because different hematoma volumes may be generated with the same injected hematoma volume [25,26]. In this study, subarachnoid extension was detected in 50% of pigs with residual hematoma volume.…”

“…We consider that blood injection to 2 cm of cortical surface is appropriate, since only two pigs had cortex hemorrhage. And 3) a rapid blood injection rate that results in a variable reflux along the needle track [13,22,26]. This problem had been largely resolved by employing the double-injection technique [13,15,[25][26][27].…”

Intracerebral hemorrhage in mouse models: therapeutic interventions and functional recovery

“…Several animal models capture elements of human ICH to an extent, with each model having its own pros and cons (Krafft et al 2012; Leonardo et al 2012). Here we mention the two most commonly used models 1.…”

“…The collage-nase model is comparatively well studied due to its ease of approach and the fact that the source of the hemorrhage is a spontaneous vascular leak. However, this model has the drawback of disrupting a larger brain area due to multi-vessel damage and inducing a severe inflammatory response that might cause neuronal toxicity to adjacent areas (Leonardo et al 2012). Much of the animal modeling in ICH has been done in the rat.…”

Emerging experimental therapies for intracerebral hemorrhage: targeting mechanisms of secondary brain injury

“…Furthermore, this model does not achieve the rebleeding phenomenon that is typical of clinical ICH. 43 Finally, injection of whole blood produces a less severe neurological deficit than seen in the clinical setting 45 and can even allow for spontaneous recovery. 21,33,70 In the collagenase model, bacterial collagenase is injected into the caudate nucleus to erode the basal lamina of blood vessels and induce in situ hemorrhage.…”