Extended preclinical investigation of lactate for neuroprotection after ischemic stroke

What followup research was done on humans for this? Your doctor doesn't know the status? Then the complete leadership of the stroke hospital needs to be removed, starting with the board of directors.  Only 1.5 years old.

Extended preclinical investigation of lactate for neuroprotection after ischemic stroke

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Lara Buscemi, Camille Blochet, Melanie Price, ...

First Published February 24, 2020 Research Article 

https://doi.org/10.1177/2514183X20904571

Article information

Abstract

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.

Keywords

Neuroprotection, stroke, lactate, rtPA, MCAO

Introduction

Acute ischemic stroke, the most frequent type of stroke, happens when blood supply to the brain is blocked. The primary therapeutic strategy is timely recanalization of the initial occlusion, preserving maximal brain functionality. The two currently approved strategies for recanalization are thrombolysis with recombinant tissue plasminogen activator (rtPA), the only approved drug for acute ischemic stroke treatment and a typical time window of 4.5 h,¹ and mechanical thrombectomy, which allows substantial reperfusion when performed within 7.3 h from ischemia onset.² Recent trials have provided evidence that careful patient selection based on imaging properties of the ischemic brain leads to effective reperfusion treatment in extended time windows (9 h for thrombolysis³ and 24 h for thrombectomy⁴) and unknown-onset stroke patients.^5,6 Nevertheless, rtPA remains the standard of care as, even if thrombectomy is considered, rtPA-eligible patients should receive the drug if the inclusion criteria are fulfilled.⁷

The monocarboxylate lactate is obtained from glucose through glycolysis and is a source of metabolic energy as well as an important signaling molecule involved in a plethora of physiological and pathological conditions (for review, see in the literature^8,9). Evidence from in vitro and in vivo studies has shown that the healthy brain uses lactate as an efficient energy substrate that may even be preferred to glucose to maintain synaptic transmission.^10–12 Interestingly, lactate may also be the preferred energy substrate for recovery of neuronal function after insults like prolonged oxygen deprivation^13,14 such as in stroke, which likely plays a role in the brain’s attempt at self-healing. We and others have shown that l-lactate administration is neuroprotective in several preclinical models of acute brain injury, including hypoxia/ischemia,^14–17 intracerebral hemorrhage,¹⁸ or traumatic brain injury.¹⁹ Importantly, administration of hypertonic lactate solution to human acute brain injury patients has beneficial effects.^20–22

Further exploring the potential field of application of lactate prior to clinical testing, we investigated its effect in a permanent ischemia model, a situation with severe and permanent blood flow reduction, representing patients who cannot benefit from acute recanalization. Additionally, we examined whether lactate-induced neuroprotection is affected by the concomitant presence of rtPA in a model of ischemia–reperfusion. We tested the combined treatment in a suture-induced middle cerebral artery occlusion (MCAO) model with promptly restored blood flow. This model, previously used to test other neuroprotectants,^23,24 mimics the situation of patients who underwent thrombolysis with successful return of cerebral blood flow and who are eligible for potential neuroprotective therapy in the presence of residual rtPA, a situation that will be increasingly likely to happen.