Abstract
Stroke is the second leading cause of death worldwide. The prognostic influence of body temperature on acute stroke in patients has been recently reported; however, hypothermia has confounded experimental results in animal stroke models. This work aimed to investigate how body temperature could prognose stroke severity as well as reveal a possible mitochondrial mechanism in the association of body temperature and stroke severity. Lipopolysaccharide (LPS) compromises mitochondrial oxidative phosphorylation in cerebrovascular endothelial cells (CVECs) and worsens murine experimental stroke. In this study, we report that LPS (0.1 mg/kg) exacerbates stroke infarction and neurological deficits, in the mean time LPS causes temporary hypothermia in the hyperacute stage during 6 hours post-stroke. Lower body temperature is associated with worse infarction and higher neurological deficit score in the LPS-stroke study. However, warming of the LPS-stroke mice compromises animal survival. Furthermore, a high dose of LPS (2 mg/kg) worsens neurological deficits, but causes persistent severe hypothermia that conceals the LPS exacerbation of stroke infarction. Mitochondrial respiratory chain complex I inhibitor, rotenone, replicates the data profile of the LPS-stroke study. Moreover, we have confirmed that rotenone compromises mitochondrial oxidative phosphorylation in CVECs. Lastly, the pooled data analyses of a large sample size (n=353) demonstrate that stroke mice have lower body temperature compared to sham mice within 6 hours post-surgery; the body temperature is significantly correlated with stroke outcomes; linear regression shows that lower body temperature is significantly associated with higher neurological scores and larger infarct volume. We conclude that post-stroke body temperature predicts stroke severity and mitochondrial impairment in CVECs plays a pivotal role in this hypothermic response. These novel findings suggest that body temperature is prognostic for stroke severity in experimental stroke animal models and may have translational significance for clinical stroke patients - targeting endothelial mitochondria may be a clinically useful approach for stroke therapy.
Highlights
Stroke is the second leading cause of death and the leading cause of disability worldwide [1]
LPS exacerbates stroke outcomes and causes prognostic hypothermia in stroke We have previously reported that LPS compromises endothelial mitochondria and worsens stroke severity [12]
We investigated the relationship between body temperature and stroke outcomes in experimental stroke and revealed a mitochondrial mechanism in the hypothermic response to stroke
Summary
Stroke is the second leading cause of death and the leading cause of disability worldwide [1]. The prognostic influence of body temperature on acute stroke in patients has been recently reported [2]. Temperature management is an important topic for experimental animal studies in stroke. Hypothermia, Mitochondria and Stroke becuase it is unclear how body temperature is associated with stroke severity in animal models of experimental stroke, and the mechanisms are poorly understood. Mitochondrial damage has been documented in ischemic stroke patients [8, 9] and experimental stroke models [10, 11]. Our recent study demonstrates mitochondrial dysfunction opens the blood-brain barrier (BBB) in both in vitro and in vivo models and controls BBB permeability in acute experimental stroke in mice [12]. LPS compromises mitochondrial oxidative phosphorylation in cerebrovascular endothelial cells and worsens murine experimental stroke [12]. High doses of LPS induce hypothermia [14, 15] and have been used in animal models of sepsis [16], but the mechanism by which LPS induces hypothermia is controversial [17]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
