A mouse model of mechanical stress injury to the basal ganglia using thermosensitive PNIPAM hydrogel for intracerebral hemorrhage research.

BACKGROUND

Intracerebral hemorrhage (ICH) is frequently associated with poor clinical outcomes. White matter injury (WMI), particularly to the corticospinal tract (CST), plays a critical role in the development of hemiplegia. However, conventional ICH models tend to induce extensive damage and involve complex blood-derived components, highlighting the need for a model that can induce direct mechanical stress injury specific to white matter.

METHODS

We established a novel mouse model by stereotactically injecting thermosensitive poly(N-isopropylacrylamide) (PNIPAM) hydrogel into the internal capsule to induce localized mechanical stress on CST. Resulting injury was evaluated by gross pathological examination and transmission electron microscopy. Motor function was assessed using a series of behavioral tests. CST integrity was examined by motor evoked potential (MEP) and nerve tract tracing. The underlying molecular mechanisms were elucidated by RNA sequencing (RNA-seq) and Western blot.

RESULTS

The model consistently showed the induction of mechanical stress injury in internal capsule, leading to substantial WMI and motor deficits. MEP amplitude was reduced, and nerve tract tracing revealed severe disruption of the CST, which was more pronounced than that caused by the classical blood-injection ICH model. RNA-seq analysis identified the activation of mechanical stress-related pathways, including tumor necrosis factor (TNF) and fluid shear stress signaling pathways. Western blot assay confirmed the altered expression of WMI markers and upregulation of key molecules involved in these pathways.

CONCLUSIONS

This newly established model of mechanical stress injury effectively recapitulates the pathophysiology of CST damage following ICH. It also provides a simple and reproducible tool for conducting preclinical studies on mechanical stress-induced WMI in ICH.