Novel Therapies to Prevent Secondary Brain Injury After Spontaneous ICH

Mortality rates of spontaneous intracerebral hemorrhage (ICH) are as high as 40% after one month, and jump to 60% at one year, according to a study published in Stroke. But those who do survive are at risk for secondary brain injury, which can lead to functional impairment and an increased risk of intracerebral hematoma and cerebral edema.

To address this issue, researchers have been turning to neuroprotective therapies as a potential option to help improve outcomes in these patients. In their 2021 review published in Neurocritical Care, Kearns et al. summarized preclinical and clinical evidence for neuroprotective therapies aimed at post-ICH secondary brain injury pathways and determined directions for future studies.

Here are some of the therapy options they reviewed:

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs are able to inhibit the enzyme cyclooxygenase (COX). COX-2 immunoreactivity is thought to increase after the onset of ICH and is time-dependent.

In a 2008 retrospective cohort study in South Korea, Park et al. examined the effects of celecoxib (COX-2 selective inhibitor) on 34 patients admitted to the hospital within 48 hours after the onset of primary spontaneous intracerebral hemorrhage.

They found that celecoxib significantly reduced volumes of cerebral edema seen on follow-up brain CT scans compared to the control group. It also reduced the ratio of initial intracerebral hematoma and cerebral edema volumes to follow-up volumes compared to the control groups.

Adverse events were not different between the celecoxib group and the control group, suggesting that celecoxib may be safe for patients with primary ICH. Given that celecoxib was shown to have reduced cerebral edema and intracerebral hematoma volumes, Park et al. believe this suggests that celecoxib could function as a neuroprotective agent in targeting secondary brain injury. However, a large prospective study is needed to further validate these results.

Complement Inhibitors

Complement activation, caused by the release of thrombin after the initial onset of spontaneous intracerebral hemorrhage, may be an important contributing factor to erythrolysis, which is thought to contribute to further secondary brain injury after ICH.

In their 2019 study published in Stroke, Wang et al. examined the effects of N-acetylheparin, a complement inhibitor without anticoagulant properties, on early erythrolysis in rats with spontaneous intracerebral hemorrhage. The N-acetylheparin group was found to have reduced erythrolysis, brain swelling, and neuronal death in the acute phase, and reduced brain atrophy and neurological deficits in the chronic phase. Further studies, the authors note, are needed to determine the effects of complement inhibitors given at different times after ICH.

Complement inhibitors have not yet been tested in humans, to the best of Kearns et al.’s knowledge.

Spingosine-1-Phosphate Receptor Modulators

Spingosine-1-phosphate is a ligand for the G-protein-coupled receptors (S1PR 1-5). S1PR modulators have been noted as a treatment for multiple sclerosis and have gained researchers’ interest as a potential neuroprotectant for spontaneous intracerebral hemorrhage patients.

In their 2014 pilot study of 23 ICH patients in China, Fu et al. analyzed the use of fingolimod, an FDA-approved S1PR modulator, to alleviate the effects of perihematomal edema (PHE) and neurologic defects in ICH patients.

They found that patients who were given fingolimod had a reduced neurological impairment, evidenced by regaining a Glasgow Coma Scale score of 15 by day 7. These patients also had significantly lower National Institutes of Health Stroke Scale scores than the control group at days 7, 14, and 30. PHE volume was significantly smaller in the fingolimod patients as well.

Overall, Fu et al. found that administering fingolimod within 72 hours of ICH onset was safe and promoted recovery, and patients had less complications than are typically seen with other therapies. However, further late-phase trials are needed to confirm the efficacy of fingolimod in preventing secondary brain injury in spontaneous intracerebral hemorrhage patients.

For additional neuroprotective therapies, read Kearns et al.’s complete study here.

Other Potential Neuroprotective Therapies After ICH

One year after Kearns et al. published their review, another study highlighted an additional therapy with the potential to prevent secondary brain injury after spontaneous ICH. As published in March 2022, Song et al. tested the use of lithium in mice with ICH to evaluate its protective effect on the blood-brain barrier (BBB). Cerebral edema from BBB damage is thought to further exacerbate the damaging effects of ICH, they note.

More than 100 mice were divided into four groups: a sham group where the mice just received a needle insertion; a sham and lithium chloride (LiCl) group where the mice received LiCl after needle insertion; an ICH and LiCl group, where ICH model animals received LiCl through intraperitoneal injection; and an ICH and vehicle group, where ICH animals received an equal volume of vehicle (saline) instead of the LiCl.

Among the ICH animals, intracerebral hematoma volume was found to be reduced in the LiCl group compared to the vehicle control group. LiCl was also found to reduce cerebral edema in the ipsilateral hemisphere and reduce neurological deficit scores. Examining the severity of BBB breakdown, LiCl was found to significantly reduce BBB breakdown and improve BBB function after acute hemorrhagic stroke.

Overall, Song et. al believe that their study, which to their knowledge is the first of its kind, has demonstrated that lithium has neuroprotective effects and can directly benefit ICH patients. From their results, they have concluded that lithium can be used as a possible treatment option in early-stage ICH.