White Matter Injury after Intracerebral Hemorrhage: Pathophysiology and Therapeutic Strategies

Abstract

Intracerebral hemorrhage (ICH) accounts for 10%-30% of all types of stroke. Bleeding within the brain parenchyma causes gray matter (GM) destruction as well as proximal or distal white matter (WM) injury (WMI) due to complex pathophysiological mechanisms. Because WM has a distinct cellular architecture, blood supply pattern and corresponding function, and its response to stroke may vary from that of GM, a better understanding of the characteristics of WMI following ICH is essential and may shed new light on treatment options. Current evidence using histological, radiological and chemical biomarkers clearly confirms the spatio-temporal distribution of WMI post- ICH. Although certain types of pathological damage such as inflammatory, oxidative and neuro-excitotoxic injury to WM have been identified, the exact molecular mechanisms remain unclear. In this review article, we briefly describe the constitution and physiological function of brain WM, summarize evidence regarding WMI, and focus on the underlying pathophysiological mechanisms and therapeutic strategies.

Keywords: axonal damage; demyelination; intracerebral hemorrhage; pathophysiology; treatment; white matter injury.

Figure 1

The possible pathophysiological mechanisms of WMI following ICH. The pathophysiology of WMI is summarized according to the available literature. ICH causes WMI via primary and secondary injury. Mass effect during hematoma formation and mechanical barotrauma mechanism are responsible for the primary WMI. Later on, secondary cascades including neuroinflammation characterized by inflammatory cell infiltration and cytokines and chemokines release, oxidative stress induced by hemoglobin and its metabolites, and glutamate-mediated neuro-excitotoxicity further deteriorate WMI. Although the detailed molecular mechanisms remain unclear, MMP-9 and JNK mediated events play important roles. The final consequences are disintegration of WM with demyelination and axonal damage. ICH, intracerebral hemorrhage; WMI, white matter injury; MMP-9, matrix metalloproteinase 9; JNK, Jun N-terminal kinase.

Figure 2

The potential therapeutic and diagnostic strategies. MSH, morphogen Sonic hedgehog; MAG, myelin-associated glycoprotein; OMGP, oligodendrocyte myelin glycoprotein; DGF10, differentiation factor 10; GPCR, cell-type-specific G protein-coupled receptor; BDNF, brain-derived neurotrophic factor; LIF, leukemia inhibitory factor-like protein; STAT 3, signal transducer and activator of transcription 3; CNTF, ciliary neurotrophic factor; TNFR2, tumor necrosis factor receptor 2; GM, gray matter; WM, white matter; MRS, Magnetic resonance spectroscopy; CEST, Chemical Exchange Saturation Transfer; CMD, cerebral microdialysis. ↓ downregulate; ↑ upregulate; M1→M2, switch from pro-inflammatory M1 and the late anti-inflammatory M2.