Benefits of hypothermia in neonatal arterial ischemic strokes: A preclinical study

Abstract

Background There is currently no targeted treatment available for neonatal arterial ischemic strokes (NAIS). Epidemiological studies demonstrated that perinatal infection/inflammation, peripartum hypoxia, and occlusion of the internal carotid tree are the main determinants of NAIS. The well‐established benefit of therapeutic hypothermia (HT) in neonatal encephalopathy due to diffuse hypoxia‐ischemia provides a rationale for the potential use of HT as a neuroprotective strategy in NAIS. Methods We used a rat model to reproduce the most prevalent human physiopathological scenario of NAIS. The neuroprotective effect of HT was measured by morphometric magnetic resonance imaging, [18F] fluorodeoxyglucose (FDG) metabolic activity by positron emission tomography/computed tomography, and behavioral tests. Results HT (a) prevented the occurrence of 44% of NAIS, (b) reduced the volume of strokes by 37%, (c) enhanced [18F] FDG metabolic activity within the territory of the occluded carotid artery, and (d) improved motor behavior. Both morphometric and metabolic techniques showed consistently that HT provided a neuroprotective effect located in the motor cortex, hippocampus, and caudate‐putamen. Conclusion Through combining anatomical, metabolic imaging, and behavioral studies, our study provides evidence of neuroprotective effects of HT in NAIS. These results are potentially translational to human NAIS.

Necroptosis Blockade Potentiates the Neuroprotective Effect of Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy

“…A total of 88 Lewis rat pups at postnatal day (P)6 from 13 different litters, were obtained from Charles River Laboratories (Kingston, NY, USA). At P12, corresponding to the level of rat brain development equivalent to that of a term human newborn [ 43 , 44 ], HI was induced by permanent ligation of the right common carotid artery (RCCA) followed by 8% O 2 exposure at 36 °C for 1.5 h ( Figure 1 a) [ 35 , 36 , 37 , 38 , 39 , 45 ]. Nec-1 was purchased from Sigma-Aldrich (Oakville, ON, Canada) and was dissolved in DMSO.…”

“…A control (CTL) group received an equal volume of DMSO and saline, and underwent a sham surgery, consisting of the right common carotid artery exposure (i.e., without ligation, hypoxia, and HT) ( Figure 1 a). HT was induced 30 min after hypoxia, as previously described [ 35 , 37 , 39 , 45 ]. Pups were kept on a hot plate at 28 °C for four hours to lower their core body temperature to 32–33 °C ( Figure 1 b) [ 16 , 35 , 37 , 39 , 49 ].…”

“…HT was induced 30 min after hypoxia, as previously described [ 35 , 37 , 39 , 45 ]. Pups were kept on a hot plate at 28 °C for four hours to lower their core body temperature to 32–33 °C ( Figure 1 b) [ 16 , 35 , 37 , 39 , 49 ]. There was no mortality following surgery.…”

“…MRI scans were performed at P20-21 using the 7T Bruker BioSpec 70/30USR system (Bruker Biospin, Ettlingen, Germany) at the Research Institute of the McGill University Health Centre Small Animal Imaging Labs ( ) (accessed on 5 March 2020), as previously described [ 39 ]. Briefly, MRI studies were performed under 1.8–2% isoflurane with the respiration rate controlled at 55–60 breaths/min and the body temperature maintained at 37 ± 0.3 °C.…”

“…Altogether, these findings prompted us to focus our research on the unexplored role of necroptosis in HIE of term newborns using our well-established rat model of HIE [ 35 , 36 , 37 , 38 , 39 ].…”