Preclinical Models of Intracerebral Hemorrhage: A Translational Perspective

Abstract

Intracerebral hemorrhage (ICH) is a devastating and relatively common disease affecting as many as 50,000 people annually in the United States alone. ICH remains associated with poor outcome, and approximately 40-50% of afflicted patients will die within 30 days. In reports from the NIH and AHA, the importance of developing clinically relevant models of ICH that will extend our understanding of the pathophysiology of the disease and target new therapeutic approaches was emphasized. Traditionally, preclinical ICH research has most commonly utilized two paradigms: clostridial collagenase-induced hemorrhage and autologous blood injection. In this article, the use of various species is examined in the context of the different model types for ICH, and a mechanistic approach is considered in evaluating the numerous breakthroughs in our current fund of knowledge. Each of the model types has its inherent strengths and weaknesses and has the potential to further our understanding of the pathophysiology and treatment of ICH. In particular, transgenic rodent models may be helpful in addressing genetic influences on recovery from ICH.

Experimental Intracerebral Hemorrhage: Avoiding Pitfalls in Translational Research

“…Clearly, autologous blood injection does not mimic spontaneous rupture and the time taken to reach the desired hematoma volume is significantly shorter than the development of spontaneous ICH in humans (Rosenberg et al, 1990). Further, as autologous blood injection does not emulate small vessel rupture often seen in human ICH, it cannot be used to evaluate microvascular breakdown effects (James et al, 2008). The collagenase model and cerebral blood vessel avulsion model do give rise to ICH from in situ vessels, but both models have drawbacks.…”

“…No current model perfectly mimics human ICH (James et al, 2008), and notable pathophysiological differences exist between the models themselves (NINDS ICH Workshop Participants, 2005). Interestingly, a study comparing cell death and inflammation following ICH in the autologous blood, collagenase, and cerebral vessel avulsion models demonstrated similar temporal profiles of cell death, inflammatory cell infiltration, and microglial reaction (Xue and Del Bigio, 2003).…”

Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage–induced secondary brain injury and as potential targets for intervention

“…146 Additional mechanisms for this secondary injury are believed to be due to the intraparenchymal accumulation of various blood components following ICH, activating cytotoxic, excitotoxic, oxidative, and inflammatory pathways. 61 As a result of increased awareness of this secondary injury, specific therapeutic targets have been identified in hopes of preventing further brain damage following ICH. In this review, we will discuss the various molecular mechanisms of secondary brain injury as a result of intraparenchymal blood, potential therapeutic targets, and the various treatment strategies currently under investigation.…”

Stem cell therapy in intracerebral hemorrhage rat model

“…The application of this protocol should be limited to blood toxicity and edema formation studies, once very important aspects of ICH pathology are absent, like small vessel rupture and hematoma expansion [54] . Moreover, especially in rats, ABI implies in exaggerated inflammatory response as a consequence of hemoglobin crystallization [55] .…”

“…Even though collagenase injection model mimics ICH with more success than ABI, both show relevant limitations [54] . As previously stated, the standard collagenase and blood site of injection is the striatum, which differs importantly from the human counterpart in biochemical and anatomical features [50] .…”