Review

Search strategy and selection criteria

This Review focuses on research in intracerebral haemorrhage between January, 2005, and April, 2012. We searched Medline with the terms “intracerebral h(a)emorrhage” and “intracerebral h(a)ematoma” and retrieved all articles published in English. We selected articles for their conceptual importance and primacy. For controversial issues, evidence on both sides was sought.

collagenase-induced intracerebral haemorrhage was enhanced in Nrf2-knockout mice.

The use of drugs to upregulate defence mechanisms has attracted considerable interest. Nrf2 can be upregulated by several agents, including sulforaphane, which protects against intracerebral haemorrhageinduced brain injury in mice and rats via a Nrf2-dependent mechanism.141 Peroxisome proliferator-activated receptor γ (PPARγ) agonists might also exert some of their benefit after intracerebral haemorrhage by upregulation of cellular defence mechanisms, including catalase.142

Pluripotent agents

Some agents in preclinical trials have several actions, which could be beneficial for intracerebral haemorrhage. For example, minocycline acts as an iron chelator and an inhibitor of microglial activation,115 and pioglitazone a ects haematoma resolution and upregulates endogenous defence mechanisms.142 Erythropoietin, albumin, and statins are other pluripotent agents that reduce intracerebral haemorrhage-induced brain damage in animal models.143–145 Agents with more than one protective e ect are attractive as potential therapeutic agents, and some are in clinical trials—eg, pioglitazone (SHRINC)52 and albumin (ACHIEVE; NCT00990509).

Hypothermia is a standard therapeutic approach that a ects many treatments and has been studied in animal models of intracerebral haemorrhage. Prolonged mild hypothermia improved functional recovery and brain oedema without a ecting lesion size in the rat.146,147 A clinical trial is ongoing to investigate use of ibuprofen to aggressively lower temperature in patients with intracerebral haemorrhage and fever (NCT01530880).

Brain recovery after intracerebral haemorrhage

If patients survive the early days after an intracerebral haemorrhage, gradual clot resolution takes place, and they might recover some neurological function, although this recovery is almost always incomplete. Improvement of function could entail clot resolution, subsidence of the acute injury (eg, reduced oedema), neuronal plasticity with surviving neurons (including the contralateral hemisphere) taking on new functions, and possibly neurogenesis. Recovery of function can be pronounced, as in rodent models of intracerebral haemorrhage.148

Various methods have been used preclinically to enhance the process of recovery after intracerebral haemorrhage. Microglia and blood-derived macrophages play a part in clearance of extravasated erythrocytes by phagocytosis, thereby limiting release of potentially toxic lysate products into the extracellular space (figure 4). Zhao and colleagues have enhanced this phagocytosis process by administration of the PPARγ agonists rosiglitazone and pioglitazone.142,149 These agents accelerate haematoma resolution and reduce deficits induced by intracerebral haemorrhage in rodents.

The use of rehabilitation to maximise neurological recovery has also been widely studied. In rats with intracerebral haemorrhage, forced running had no e ect on outcome, but delayed exposure to an enriched environment and skilled reach training both improved neurological outcome and reduced lesion volume.150–152 This improvement was associated with increased dendritic complexity rather than neurogenesis.152

As for ischaemic stroke, the idea that stem cells might improve outcome after intracerebral haemorrhage has attracted much interest.153 Seyfried and co-workers154 reported that, after intracerebral haemorrhage in rats, bone-marrow cells injected intravenously migrated to the lesion site and improved neurological outcome. One factor that could restrict the e ect on outcome of exogenous stem cells is cell survival. Lee and colleagues155 noted that genetically modifying human neural stem cells to overexpress Akt1 increased their survival in a mouse model of intracerebral haemorrhage and enhanced their protective e ects on the brain. A clinical trial is ongoing in China to investigate the e ects of stem-cell transplantation in patients with intracerebral haemorrhage (NCT01389453).

Future directions

In the past two decades, a striking increase in the amount of preclinical and clinical research on intracerebral haemorrhage has been seen. This work has resulted in much new information about injury mechanisms and potential therapeutic targets. However, these data have yet to result in any treatment for intracerebral haemorrhage. The mechanisms believed to play a part in brain injury induced by intracerebral haemorrhage di er in type, magnitude, and timing from those for ischaemic stroke. These di erences should be taken into account when designing clinical trials. In the past, in some cases, very little published preclinical evidence in intracerebral haemorrhage has been available before a drug has been tested in patients (eg, dexamethasone,34 gavestinel [a glycine antagonist],38 and mannitol).35 Indeed, while many complaints have been made about animal models of cerebral ischaemia failing to predict therapeutic e cacy, only very recently have clinical trials in intracerebral haemorrhage been based on preclinical testing. Time will tell about the use of preclinical models of intracerebral haemorrhage for informing clinical trials.

8	www.thelancet.com/neurology Published online June 13, 2012 DOI:10.1016/S1474-4422(12)70104-7

Review

Contributors

All authors helped with the literature search and wrote the Review.

Conflicts of interest

We declare that we have no conflicts of interest.

Acknowledgments

This work was supported by grants NS-034709, NS-039866, NS-057539, and NS 073595 from the National Institutes of Health, and 0840016N from the American Heart Association.

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