Secondary mechanisms of injury and viable pathophysiological targets in intracerebral hemorrhage

Abstract

Intracerebral hemorrhage (ICH) can be divided into a primary and secondary phase. In the primary phase, hematoma volume is evaluated and therapies are focused on reducing hematoma expansion. In the secondary, neuroprotective phase, complex systemic inflammatory cascades, direct cellular toxicity, and blood-brain barrier disruption can result in worsening perihematomal edema that can adversely affect functional outcome. To date, all major randomized phase 3 trials for ICH have targeted primary phase hematoma volume and incorporated clot evacuation, intensive blood pressure control, and hemostasis. Reasons for this lack of clinical efficacy in the major ICH trials may be due to the lack of therapeutics involving mitigation of secondary injury and inflexible trial design that favors unilateral mechanisms in a complex pathophysiology. Potential pathophysiological targets for attenuating secondary injury are highlighted in this review and include therapies increasing calcium, antagonizing microglial activation, maintaining macrophage M1 versus M2 balance by decreasing M1 signaling, aquaporin inhibition, NKCCl inhibition, endothelin receptor inhibition, Sur1-TRPM4 inhibition, matrix metalloproteinase inhibition, and sphingosine-1-phosphate receptor modulation. Future clinical trials in ICH focusing on secondary phase injury and, potentially implementing adaptive trial design approaches with multifocal targets, may improve insight into these mechanisms and provide potential therapies that may improve survival and functional outcome.

Irisin ameliorates neuroinflammation and neuronal apoptosis through integrin αVβ5/AMPK signaling pathway after intracerebral hemorrhage in mice

“…Cilengitide trifluoroacetate, an inhibitor of integrin αVβ5 [ 24 ], was shown to significantly decrease the expression of p-AMPK and reversed the beneficial effects of irisin on neurobehavior deficits and neuroinflammation after ICH. In addition, our data showed that dorsomorphin, a selective phosphorylated AMPK inhibitor [ 3 ] significantly reversed the anti-inflammatory, anti-apoptotic effects and neurobehavior protection of irisin post-treatment. Collectively, these data suggested that irisin post-treatment alleviated neuroinflammation possibly through the integrin αVβ5/AMPK signaling pathway after ICH.…”

“…Intracerebral hemorrhage (ICH) is a severe fatal subtype of stroke accounting for approximately 10 to 15% of all stroke patients, with high rates of mortality and morbidity [ 1 , 2 ]. The formation of a huge hematoma and mechanical compression to surrounding brain tissues after sudden rupture of cerebral blood vessels results in intracranial hypertension and neurological deterioration, which is regarded as the primary brain injury [ 3 ]. However, surgical intervention of the hematoma in ICH patients used in clinical practice rarely improves the neurological prognosis of patients [ 4 ].…”

Mesenchymal Stem Cell Application and Its Therapeutic Mechanisms in Intracerebral Hemorrhage

“…Thrombin activation after ICH implies the vasculogenic edema formation associated with the destruction of endothelial cells and the BBB ( Wilkinson et al, 2018 ). Perihematomal edema (PHE), associated with a worse prognosis, has been recognized as an evident marker of SBI after ICH and a likely therapeutic pathophysiological target for attenuating SBI ( Brouwers and Greenberg, 2013 ; Bautista et al, 2021 ; Chen et al, 2021 ). Furthermore, it was displayed that intracranial hematoma expands to further and adjacent brain tissues through perivascular spaces, white matter tracts, and their perineurium ( Yin et al, 2013 ; Fu et al, 2021 ), particularly if ICH is combined with an intraventricular hemorrhage ( Bosche et al, 2020 ).…”

Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel—Part 2: TRPM4 in Health and Disease

“…A recent review summarizes all ion channels and transporters which can have a proposed role in mediating cerebral edema in acute ischemic stroke and TBI [211]. Moreover, in intracerebral hemorrhage, the potential targets for reducing secondary injury mechanisms were summarized [234]. These previous reviews also highlight the need for a good target and numerous attempts to find a suitable target.…”