Experimental Intracerebral Hemorrhage: Avoiding Pitfalls in Translational Research

Abstract

Intracerebral hemorrhage (ICH) has the highest mortality of all stroke subtypes, yet treatments are mainly limited to supportive management, and surgery remains controversial. Despite significant advances in our understanding of ICH pathophysiology, we still lack preclinical models that accurately replicate the underlying mechanisms of injury. Current experimental ICH models (including autologous blood and collagenase injection) simulate different aspects of ICH-mediated injury but lack some features of the clinical condition. Newly developed models, notably hypertension-and oral anticoagulant therapy-associated ICH models, offer added benefits but further study is needed to fully validate them. Here, we describe and discuss current approaches to experimental ICH, with suggestions for changes in how this condition is studied in the laboratory. Although advances in imaging over the past few decades have allowed greater insight into clinical ICH, there remains an important role for experimental models in furthering our understanding of the basic pathophysiologic processes underlying ICH, provided limitations of animal models are borne in mind. Owing to differences in existing models and the failed translation of benefits in experimental ICH to clinical practice, putative neuroprotectants should be trialed in multiple models using both histological and functional outcomes until a more accurate model of ICH is developed.

A Critical Appraisal of Experimental Intracerebral Hemorrhage Research

“…While studies that induced hypothermia or hyperthermia after ICH in rodents have not revealed the dramatic effects seen in ischemia, we nonetheless recommend that temperature be measured at least during surgery and postoperatively to rule out confounding effects. The various other potential effects of commonly used anesthetics on outcome after ICH have been recently reviewed (Kirkman et al, 2011). Only a minority of studies examined other physiological variables either during or after ICH surgery.…”

“…This makes it more difficult for investigators to follow and test whether another laboratory's data replicates. Better transparency, sharing of standardized procedures, and multicenter animal studies are clearly needed (Kirkman et al, 2011;Macleod et al, 2009).…”

“…Some have already questioned whether current models, especially those in rodents, adequately reflect human pathology (Adeoye et al, 2011;Andaluz et al, 2002;James et al, 2008;Kirkman et al, 2011;NINDS ICH Workshop, 2005). The relative paucity of white matter in rodents compared with humans undoubtedly weakens the predictive value of these models.…”

“…Spontaneous nontraumatic ICH usually stems from vessel damage owing to hypertension and amyloid angiopathy (Adeoye et al, 2011;Broderick, 1994;Kirkman et al, 2011;Pezzini et al, 2009), among other causes. The underlying pathology determines the ICH location.…”

Hydrogen does not exert neuroprotective effects or improve functional outcomes in rats after intracerebral hemorrhage

“…Firstly, these studies used different experimental models, the blood injection rat model or the collagenase injection mouse model. The blood injection and collagenase injection models are most often used but differ in many aspects (12,(14)(15)(16). Hematoma rapidly accumulates in the brain parenchyma in the clinical setting.…”