Hydroxycarboxylic Acid Receptor 1 and Neuroprotection in a Mouse Model of Cerebral Ischemia-Reperfusion.

Lara Buscemi,Pierre J Magistretti,Camille Blochet,Lorenz Hirt

doi:10.3389/fphys.2021.689239

Abstract

Lactate is an intriguing molecule with emerging physiological roles in the brain. It has beneficial effects in animal models of acute brain injuries and traumatic brain injury or subarachnoid hemorrhage patients. However, the mechanism by which lactate provides protection is unclear. While there is evidence of a metabolic effect of lactate providing energy to deprived neurons, it can also activate the hydroxycarboxylic acid receptor 1 (HCAR1), a Gi-coupled protein receptor that modulates neuronal firing rates. After cerebral hypoxia-ischemia, endogenously produced brain lactate is largely increased, and the exogenous administration of more lactate can decrease lesion size and ameliorate the neurological outcome. To test whether HCAR1 plays a role in lactate-induced neuroprotection, we injected the agonists 3-chloro-5-hydroxybenzoic acid and 3,5-dihydroxybenzoic acid into mice subjected to 30-min middle cerebral artery occlusion. The in vivo administration of HCAR1 agonists at reperfusion did not appear to exert any relevant protective effect as seen with lactate administration. Our results suggest that the protective effects of lactate after hypoxia-ischemia come rather from the metabolic effects of lactate than its signaling through HCAR1.

Highlights

Lactate, a presumed trivial metabolite of glycolysis, has gained a lot of interest in neuroscience in recent years
We evaluated the effect on the ischemic lesion size and the neurological outcome of two different compounds, the synthetic 3-chloro-5-hydroxybenzoic acid (CHBA) and 3,5-dihydroxybenzoic acid (DHBA), a metabolic product of the β-oxidation of alkylresorcinols found in cereals such as rye and wheat (Ross et al, 2004), both of them considered hydroxycarboxylic acid receptor 1 (HCAR1) full agonists
The administration of lactate receptor HCAR1 agonists to mice subjected to a transient ischemic insult did not appear to exert a protective effect in terms of lesion size or neurological outcome

Summary

Introduction

A presumed trivial metabolite of glycolysis, has gained a lot of interest in neuroscience in recent years. While there is evidence that lactate has a beneficial metabolic effect providing energy to deprived neurons (Schurr et al, 1997, 1999; Roumes et al, 2020), it can activate the hydroxycarboxylic acid receptor 1 (HCAR1), a Gi-coupled protein receptor (Cai et al, 2008; Ahmed et al, 2009) that modulates neuronal firing rates (Bozzo et al, 2013; Herrera-Lopez and Galvan, 2018; de Castro Abrantes et al, 2019). We have in vivo and in vitro evidence that D-lactate exerts neuroprotection, and in vitro evidence that the activation of the Gi-coupled lactate receptor without any direct effect on metabolism can have a neuroprotective effect after oxygen and glucose deprivation (OGD; Castillo et al, 2015)

Methods

Results

Conclusion