Eighteen-hour inhibitory effect of s-ketamine on potassium- and ischemia-induced spreading depolarizations in the gyrencephalic swine brain

• Verfasst von: Sánchez-Porras, Renán [VerfasserIn]
• Verfasst von: Kentar, Modar [VerfasserIn]
• Verfasst von: Zerelles, Roland [VerfasserIn]
• Verfasst von: Geyer, Martina [VerfasserIn]
• Verfasst von: Trenado Colin, Carlos Alberto [VerfasserIn]
• Verfasst von: Hartings, Jed A. [VerfasserIn]
• Verfasst von: Woitzik, Johannes [VerfasserIn]
• Verfasst von: Dreier, Jens P. [VerfasserIn]
• Verfasst von: Santos, Edgar [VerfasserIn]
• Titel: Eighteen-hour inhibitory effect of s-ketamine on potassium- and ischemia-induced spreading depolarizations in the gyrencephalic swine brain
• Verf.angabe: Renán Sánchez-Porras, Modar Kentar, Roland Zerelles, Martina Geyer, Carlos Trenado, Jed A. Hartings, Johannes Woitzik, Jens P. Dreier, Edgar Santos
• E-Jahr: 2022
• Jahr: 5 July 2022
• Umfang: 14 S.
• Fussnoten: Gesehen am 10.11.2022
• Titel Quelle: Enthalten in: Neuropharmacology
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1970
• Jahr Quelle: 2022
• Band/Heft Quelle: 216(2022), Artikel-ID 109176, Seite 1-14
• ISSN Quelle: 1873-7064
• DOI: doi:10.1016/j.neuropharm.2022.109176
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Electrocorticography
• Sach-SW: Gyrencephalic brain
• Sach-SW: Ketamine
• Sach-SW: Neuromonitoring
• Sach-SW: Spreading depolarization
• Sach-SW: Stroke
• K10plus-PPN: 1821596137

Abstract

Spreading depolarizations (SDs) are characterized by near-complete breakdown of the transmembrane ion gradients, cytotoxic edema, and glutamate release. SDs are associated with poor neurological outcomes in cerebrovascular diseases and brain trauma. Ketamine, a N-methyl-d-aspartate receptor antagonist, has shown to inhibit SDs in animal models and in humans. However, little is known about its SD-inhibitory effect during long-term administration. Lissencephalic animal models have shown that ketamine loses its SD-blocking effect after some minutes to hours. Physio-anatomical differences between lissencephalic and the more evolved gyrencephalic animals may affect their SDs-blocking effect. Therefore, information from the last may have more translational potential. Therefore, the aim of this study was to investigate the 18 h-effect of s-ketamine as a basis for its possible long-term clinical use for neuroprotection. For this purpose, two gyrencephalic swine brain models were used. In one, SDs were elicited through topical application of KCl; in the other model, SDs were spontaneously induced after occlusion of the middle cerebral artery. S-ketamine was administered at therapeutic human doses, 2, 4 and 5 mg/kg BW/h for up to 18 h. Our findings indicate that s-ketamine significantly reduces SD incidence and expansion without clear evidence of loss of its efficacy. Pharmacological susceptibility of SDs to s-ketamine in both the ischemic gyrencephalic brain and well-perfused brain was observed. SDs were most potently inhibited by s-ketamine doses that are above the clinically recommended (4 mg/kg BW/h and 5 mg/kg BW/h). Nonetheless, such doses are given by neurointensivists in individual cases. Our results give momentum to further investigate the feasibility of a multicenter, neuromonitoring-guided, proof-of-concept clinical trial.