Extended preclinical investigation of lactate for neuroprotection after ischemic stroke

Clinical and Translational Neuroscience

Original Research

Hongxia Lei¹  Pierre J Magistretti²  Camille Blochet³  Melanie Price³  Lara Buscemi³  Lorenz Hirt³ 

[1] Center for Biomedical Imaging (CIBM), Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland;Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia;Department of Psychiatry, Lausanne University Hospital Centre and University of Lausanne, Lausanne, Switzerland;Stroke Laboratory, Neurology Service, Department of Clinical Neurosciences, Lausanne University Hospital Centre and University of Lausanne, Lausanne, Switzerland;Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland;

关键词: Neuroprotection;    stroke;    lactate;    rtPA;    MCAO;   

DOI  :  10.1177/2514183X20904571

来源: Sage Journals

【 摘 要 】

Lactate has been shown to have beneficial effect both in experimental ischemia–reperfusion models and in human acute brain injury patients. To further investigate lactate’s neuroprotective action in experimental in vivo ischemic stroke models prior to its use in clinics, we tested (1) the outcome of lactate administration on permanent ischemia and (2) its compatibility with the only currently approved drug for the treatment of acute ischemic stroke, recombinant tissue plasminogen activator (rtPA), after ischemia–reperfusion. We intravenously injected mice with 1 µmol/g sodium l-lactate 1 h or 3 h after permanent middle cerebral artery occlusion (MCAO) and looked at its effect 24 h later. We show a beneficial effect of lactate when administered 1 h after ischemia onset, reducing the lesion size and improving neurological outcome. The weaker effect observed at 3 h could be due to differences in the metabolic profiles related to damage progression. Next, we administered 0.9 mg/kg of intravenous (iv) rtPA, followed by intracerebroventricular injection of 2 µL of 100 mmol/L sodium l-lactate to treat mice subjected to 35-min transient MCAO and compared the outcome (lesion size and behavior) of the combined treatment with that of single treatments. The administration of lactate after rtPA has positive influence on the functional outcome and attenuates the deleterious effects of rtPA, although not as strongly as lactate administered alone. The present work gives a lead for patient selection in future clinical studies of treatment with inexpensive and commonly available lactate in acute ischemic stroke, namely patients not treated with rtPA but mechanical thrombectomy alone or patients without recanalization therapy.

【 授权许可】

CC BY-NC   
© The Author(s) 2020

【 图 表 】

Figure 2.

Figure 1.

Figure 4.