Intracerebral haemorrhage: mechanisms of injury and therapeutic targets

Abstract

Intracerebral haemorrhage accounts for about 10-15% of all strokes and is associated with high mortality and morbidity. No successful phase 3 clinical trials for this disorder have been completed. In the past 6 years, the number of preclinical and clinical studies focused on intracerebral haemorrhage has risen. Important advances have been made in animal models of this disorder and in our understanding of mechanisms underlying brain injury after haemorrhage. Several therapeutic targets have subsequently been identified that are now being pursued in clinical trials. Many clinical trials have been based on limited preclinical data, and guidelines to justify taking preclinical results to the clinic are needed.

Conflict of interest statement

Conflicts of interest

We have no conflicts of interest.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Figures

Figure 1

CT scan showing perihaematomaloedema (hypodensity zone) at 14 days after intracerebral haemorrhage. Note the marked perihaematomaloedema with midline shift.

Figure 2

CT scan showing marked brain tissue loss (atrophy) at day 90 after intracerebral haemorrhage. Note the dilated ipsilateral ventricle, fluid filled cavity and enlarged sulci.

Figure 3

Current clinical trials for ICH in relation to proposed injury mechanisms. Note that surgical removal of the haematoma and prevention of haematoma expansion may potentially reduce injury by affecting multiple downstream mechanisms. Pioglitazone accelerates haematoma resolution in rodents but it also has multiple other effects (on free radical and inflammation induced damage. Similarly, as well as inhibiting inflammation, simvastatin has multiple actions on different systems and albumin has effects on edema and vascular integrity as well as cell injury. ICH, intracerebral haemorrhage; tPA, tissue plasminogen activator, TUDCA, tauroursodeoxycholic acid.

Figure 4

After an ICH [1], erythrocytes may eventually be engulfed by microglia/macrophages [2] or lyse [3] because of complement activation or energy depletion. Erythrocyte lysis will result in the release of haemoglobin [4] and other intracellular contents such as carbonic anhydrase 1 [5]. Haeme from haemoglobin is degraded by haeme oxygenase [6] to release iron. Both iron and carbonic anhydrase 1 have been implicated in inducing brain injury after ICH [7] and [8].

Figure 5

Iron histochemistry (Perls’ staining) in the brain 3 days after intracerebral haemorrhage in pigs. Asterisk indicates the haematoma. Insets in C and F: hematoxylin and eosin staining. Scale bar (A–F)=50 µm. Figure reprinted with permission from Gu et al., Stroke, 2009;40:2241–2243.

Figure 6

Deferoxamine reduces reddish zone around haematoma at day 3 and day 7 in a pig intracerebral haemorrhage model. Values are means ± SD, n=4, # pStroke, 2009;40:2241–2243.