Intracerebral Hemorrhage in Mice

Abstract

Intracerebral hemorrhage is the most devastating stroke subtype with high rates of mortality and morbidity. Furthermore, no clinically approved treatment exists that effectively increases survival or improves quality of life for survivors. Effective modeling is necessary to elucidate the pathophysiological mechanisms of intracerebral hemorrhage and evaluate potential therapeutic approaches. Rodent models are most utilized because of their cost-effectiveness, and because rodent brain development and structures are well documented. Herein, we describe two intracerebral hemorrhage mouse models: the autologous blood double-injection and collagenase infusion models.

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

“…These increases occurred in the regions around/adjacent to the core of hemorrhagic lesions in thalamic VPM and VPL ( Supplemental Figure 2 ). Results were similar after microinjection of autologous whole blood into thalamic VPM and VPL ( Figure 1, H–J ), another preclinical animal model of hemorrhage ( 15 , 16 ). The levels of Fgr protein and the density of Fgr-labeled immunoreactivities in the ipsilateral thalamus were increased by 2.2-fold ( Figure 1H ) and 31-fold ( Figure 1, I and J ), respectively, on day 3 after whole blood microinjection as compared with the saline microinjection.…”

“…Microinjection of either Coll IV or autologous whole blood into unilateral VPL and VPM regions of murine thalami leads to long-lasting pain hypersensitivities, including mechanical allodynia, heat hyperalgesia, and cold hyperalgesia on the contralateral side, which mimics thalamic pain caused by a hemorrhagic stroke in humans ( 15 – 17 , 22 ). Understanding the mechanisms of how this pain hypersensitivity genesis occurs may allow the development of novel therapeutic treatments for thalamic pain.…”

“…Whether Fgr contributes to CPSP, and thalamic pain in particular, remains unknown. In the present study, we first established whether the expression of Fgr at mRNA and protein levels was altered in the thalamus in a well-characterized mouse model of hemorrhage-induced thalamic pain induced by microinjection of type IV collagenase (Coll IV) or autologous whole blood into unilateral ventral posterior medial nucleus (VPM) and VPL of murine thalami ( 15 , 16 ). We then examined whether pharmacological inhibition or genetic knockdown of thalamic Fgr affected hemorrhage-induced pain hypersensitivities.…”

Rapid loss of perihematomal cell viability in the collagenase intracerebral hemorrhage model

“…The blood and collagenase doses were selected because they consistently produce loss of about half of striatal cells, a process that is largely complete by four days in both models (Chen-Roetling et al, 2014;Chen et al, 2011). Although the collagenase dose used was lower than in most rodent ICH studies (Klebe et al, 2018;MacLellan et al, 2008;Rosenberg et al, 1990), it is possible that an even lower dose would produce less microvascular destruction and more gradual viability loss. The rate of cell injury progression may be an important consideration for interventional ICH studies.…”

“…Blood injection creates a hematoma over minutes from a single point source, compressing adjacent tissue; however, the pressure increase is usually not sufficient to produce early ischemia even when relatively large volumes are infused (Qureshi et al, 1999). The catalytic activity of collagenase disrupts the microvessels it contacts, resulting in multiple punctate hemorrhages that coalesce over hours to give the appearance of a single hematoma (Klebe et al, 2018). The effect of this microvessel destruction on early tissue perfusion and viability is unknown.…”