Lactate Neuroprotection against Transient Ischemic Brain Injury in Mice Appears Independent of HCAR1 Activation

Abstract

Lactate can protect against damage caused by acute brain injuries both in rodents and in human patients. Besides its role as a metabolic support and alleged preferred neuronal fuel in stressful situations, an additional signaling mechanism mediated by the hydroxycarboxylic acid receptor 1 (HCAR1) was proposed to account for lactate’s beneficial effects. However, the administration of HCAR1 agonists to mice subjected to middle cerebral artery occlusion (MCAO) at reperfusion did not appear to exert any relevant protective effect. To further evaluate the involvement of HCAR1 in the protection against ischemic damage, we looked at the effect of HCAR1 absence. We subjected wild-type and HCAR1 KO mice to transient MCAO followed by treatment with either vehicle or lactate. In the absence of HCAR1, the ischemic damage inflicted by MCAO was less pronounced, with smaller lesions and a better behavioral outcome than in wild-type mice. The lower susceptibility of HCAR1 KO mice to ischemic injury suggests that lactate-mediated protection is not achieved or enhanced by HCAR1 activation, but rather attributable to its metabolic effects or related to other signaling pathways. Additionally, in light of these results, we would disregard HCAR1 activation as an interesting therapeutic strategy for stroke patients.

Astrocyte-neuron lactate shuttle plays a pivotal role in sensory-based neuroprotection in a rat model of permanent middle cerebral artery occlusion

“…A major finding of this study is that ANLS is a pivotal neuroprotective component along with collateral blood flow during the hyperacute state following pMCAo. Most of the relevant preclinical and clinical work to date has focused on administrating exogenous lactate after ischemia, which enhances the neuroprotection by reducing the infarct lesion of ischemic region 19 , 64 – 72 . Our findings show that sensory-based stimulation of neurons and astrocytes in ischemic area allows for protection via ANLS without the need of external lactate administration, demonstrating the ability of the cortex to sustain itself following pMCAo, if neuronal stimulation is delivered within the critical time window for protection.…”

Cortistatin exerts an immunomodulatory and neuroprotective role in a preclinical model of ischemic stroke

“…The functional outcome of each mouse was assessed by a neurological score evaluation each 24 h after MCAO and before sacrifice. Severity was graded from 0 to 3 evaluating motor, sensory, reflex, and balance using a compendium of previously published scales [15,16].…”

“…Cresyl violet-stained sections (gradual hydration in ethanol, stained with 1 mg/ml of CV-acetate in distilled water, gradually dehydrated in ethanol, and clear in xylene) [15] were imaged under a Leica DM2000 Transmit stereomicroscope at 2.5x magnification. The infarct volume was calculated by multiplying the sum of the infarcted areas on each section by the spacing distance using the ImageJ Fiji free software.…”

“…Neurological assessments were conducted at 24h following MCAO and prior to sacrifice at 48h. Stroke severity was assessed on a scale from 0 (no signs) to 3 (death) determining motor, balance, reflex, and sensory functions using a compendium of scales previously published (Buscemi et al, 2022;Lee et al, 2014).…”

Blood and Brain Metabolites after Cerebral Ischemia

“…There is also evidence that the lack of lactate supply might strongly contribute to hypoxia-induced neurodegeneration, and a diminished lactate supply from astrocytes could facilitate stroke-induced neurodegeneration [64] (Figure 1). Further, many studies have proven the fact that lactate has beneficial effects on the recovery from damage caused by an ischemic brain injury, as demonstrated both in animal models [65][66][67][68][69][70] as well as in patients [71][72][73], and lactate's protective effect was proven in the reperfusion period when administered intracerebroventricularly [66,67] or intravenously into the bloodstream [74]. However, the mechanisms by which the administration Further, many studies have proven the fact that lactate has beneficial effects on the recovery from damage caused by an ischemic brain injury, as demonstrated both in animal models [65][66][67][68][69][70] as well as in patients [71][72][73], and lactate's protective effect was proven in the reperfusion period when administered intracerebroventricularly [66,67] or intravenously into the bloodstream [74].…”