Protein kinase C-inhibition reduces critical weight loss and improves functional outcome after experimental subarachnoid haemorrhage

Jesper P Bömers; Anja Holm; Spyridoula Kazantzi; Lars Edvinsson; Tiit I Mathiesen; Kristian A Haanes

doi:10.1016/j.jstrokecerebrovasdis.2024.107728

Protein kinase C-inhibition reduces critical weight loss and improves functional outcome after experimental subarachnoid haemorrhage

J Stroke Cerebrovasc Dis. 2024 Apr 19;33(7):107728. doi: 10.1016/j.jstrokecerebrovasdis.2024.107728. Online ahead of print.

Authors

Jesper P Bömers¹, Anja Holm², Spyridoula Kazantzi³, Lars Edvinsson⁴, Tiit I Mathiesen⁵, Kristian A Haanes⁶

Affiliations

¹ Department of Neurosurgery, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Clinical Experimental Research Unit, Translational Research Centre, Copenhagen University Hospital - Rigshospitalet, Glostrup, Denmark. Electronic address: jesper.peter.boemers@regionh.dk.
² Clinical Experimental Research Unit, Translational Research Centre, Copenhagen University Hospital - Rigshospitalet, Glostrup, Denmark; Center for RNA Medicine, Aalborg University, Copenhagen, Denmark.
³ Clinical Experimental Research Unit, Translational Research Centre, Copenhagen University Hospital - Rigshospitalet, Glostrup, Denmark.
⁴ Clinical Experimental Research Unit, Translational Research Centre, Copenhagen University Hospital - Rigshospitalet, Glostrup, Denmark; Department of Clinical Sciences, Lund University, Lund, Sweden.
⁵ Department of Neurosurgery, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁶ Clinical Experimental Research Unit, Translational Research Centre, Copenhagen University Hospital - Rigshospitalet, Glostrup, Denmark; Department of Biology, University of Copenhagen, Copenhagen, Denmark.

PMID: 38643942
DOI: 10.1016/j.jstrokecerebrovasdis.2024.107728

Abstract

Objectives: Subarachnoid haemorrhage (SAH) carries a high burden of morbidity and mortality. One in three patients develop vasospasm, which is associated with Delayed Cerebral Ischemia. The pathophysiology includes vasoconstrictor receptor upregulation in cerebral arteries. The protein kinase C - inhibitor RO-31-7549 reduces the expression of several vasoconstrictor receptors and normalizes cerebral blood flow in experimental SAH but functional and behavioural effects are unknown. This study was undertaken to analyse functional outcomes up to 14 days after experimental SAH.

Materials and methods: 54 male rats were randomised to experimental SAH or sham, using the pre-chiasmatic, single injection model, and subsequent treatment or vehicle. 42 remained for final analysis. The animals were euthanized on day 14 or when reaching a humane endpoint. The primary endpoint was overall survival, defined as either spontaneous mortality or when reaching a predefined humane endpoint. The secondary outcomes were differences in the rotating pole test, weight, open field test, novel object recognition and qPCR of selected inflammatory markers.

Results: In the vehicle group 6/15 rats reached the humane endpoint of >20 % weight loss compared to 1/14 in the treatment group. This resulted in a significant reduced risk of early euthanasia due to >20 % weight loss of HR 0.15 (0.03-0.66, p = 0.04). Furthermore, the treatment group did significantly better on the rotating pole test, RR 0.64 (0.47-0.91, p = 0.02).

Conclusion: RO-31-7549 improved outcomes in terms >20 % weight loss and rotating pole performance after experimental SAH and could be investigated.

Keywords: In vivo; PKC-inhibitor; Rodent; Subarachnoid hemorrhage; early brain injury.