the-stroke-preclinical-assessment-network-multi-laboratory-model

The Stroke Preclinical Assessment Network Multi-Laboratory Model of Thromboembolic Stroke with Thrombolysis: TE-MCAo

Current translational rodent stroke models induce middle cerebral artery occlusion (MCAo) using nylon filaments, injected emboli, intraluminal thrombin, ...

University of California, San Diego

Significant advances have been made in our understanding of the endolysosomal cycle. Disruption of this cycle leads to cell death. The objective of this study aims to investigate the role of disrupted endolysosomal cycle in brain ischemia-reperfusion injury.

Cathepsin B knockout confers significant brain protection in the mouse model of stroke.

Background: The objective of this study was to investigate whether transrectal intracolon (TRIC) cooling can prolong the survival duration in a rat hemorrhagic shock (HS) model. Methods: A lethal HS was induced by bleeding 47% of the total blood volume. A TRIC device was placed into the colon to maintain the intracolon temperature either at 37°C (TRIC37) or at 10°C (TRIC10) post-HS. In the surface cooling (SC) rats, the body temperatures were maintained at the same level as the esophageal temperature of the TRIC10 rats. A separated group of TRIC10 rats were resuscitated (Res) at 90 min post-HS. A total of six groups were as follows: (i) Sham TRIC37 (n = 5), (ii) Sham TRIC10 (n = 5), (iii) HS TRIC37 (n = 5), (iv) HS TRIC10 (n = 6), (v) HS SC (n = 6), and (vi) HS TRIC10 + Res (n = 6). Results: An average post-HS survival time was 18.4 ± 9.4 min in HS TRIC37 and 82 ± 27.82 min in the HS SC group. In striking contrast, the HS TRIC10 group exhibited an average survival time of 150.2 ± 66.43 min. The post-HS blood potassium level rose significantly in the HS TRIC37 and HS SC, whereas it remained unchanged in the TRIC10 groups. Post-HS intestinal damage occurred in HS TRIC37 and HS SC groups but virtually absent in HS TRIC10 groups. After resuscitation at 90 min post-HS, all HS TRIC10 rats were fully recovered from the lethal HS. Conclusions: TRIC10 reversed the high blood potassium level, prevented the intestinal damage, and prolonged the survival duration by sixfold relative to normothermia and by twofold compared with SC post-HS. All TRIC10 rats were successfully resuscitated at 90 min post-HS.

INTRACOLON COOLING INCREASES SURVIVAL RATE IN THE RAT MODEL OF LETHAL HEMORRHAGE.

Ischemic brain injury occurs in many clinical settings, including stroke, cardiac arrest, hypovolemic shock, cardiac surgery, cerebral edema, and cerebral vasospasm. Decades of work have revealed many important mechanisms related to ischemic brain injury. However, there remain significant gaps in the scientific knowledge to reconcile many ischemic brain injury events. Brain ischemia leads to protein misfolding and aggregation, and damages almost all types of subcellular organelles including mitochondria, endoplasmic reticulum, Golgi apparatus, lysosomes, etc. Irreparably damaged organelles and insoluble protein aggregates are normally removed by autophagy. The build-up of common autophagic components, such as LC3, p62, and ubiquitinated proteins, are generally observed in brain tissue samples in animal models of both global and focal brain ischemia, but the interpretation of the role of these autophagy-related changes in ischemic brain injury in the literature has been controversial. Many pathological events or mechanisms underlying dysfunctional autophagy after brain ischemia remain unknown. This review aims to provide an update of the current knowledge and future research directions regarding the critical role of dysfunctional autophagy in ischemic brain injury.

The role of autophagy in ischemic brain injury.

Ischemic white matter injury (WMI) is a significant concern in various clinical settings, particularly affecting the elderly and those with comorbidities such as hypoxia and hyperglycemia. Ischemic WMI can be caused either by primary WM ischemia, or secondary axonal injury as a result of the loss of the "remote" axonal parent neurons or the depletion of adhesive and neurotrophic molecules following post-synaptic neuronal death in the grey matter after focal ischemia. While neurons are highly vulnerable to ischemia, potentially undergoing cell death after an ischemic duration longer than a just few minutes, oligodendrocyte (OLG) lineage cells and axons show somewhat greater initial resistant to ischemia but ultimately suffer various degrees of damage after prolonged ischemia exposure. WMI typically progresses over time from initial demyelination to OLG death and axonal injury, followed by varying degrees of OLG biogenesis, remyelination, axonal sprouting, and synaptic reconnections. The severity of ischemic WMI is a key predictor of poor long-term outcome in brain ischemia-related conditions. Despite its clinical importance, ischemic WMI remains significantly understudied in preclinical animal models, creating a weak link in the field of ischemic brain injury animal research. Many molecular and pathological mechanisms underlying post-ischemic WMI remain poorly understood, and currently, no specific treatments exist for WMI patients. This review aims to stimulate WMI research by providing updated knowledge, emerging hypotheses, and future research directions to foster understanding the mechanisms and to guide the development of the effective therapeutic strategies.

Article	Year
Cathepsin B knockout confers significant brain protection in the mouse model of stroke. Experimental neurology\| PubMed ID: 37506756	2023
INTRACOLON COOLING INCREASES SURVIVAL RATE IN THE RAT MODEL OF LETHAL HEMORRHAGE. Shock (Augusta, Ga.)\| PubMed ID: 37878475	2023
The role of autophagy in ischemic brain injury. Autophagy reports\| PubMed ID: 40395988	2025
White matter injury after brain ischemia. Experimental neurology\| PubMed ID: 41109658	2026

Bingren Hu

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