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

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.

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

“…These results are in (partial) agreement with our previous report on the effect of HCAR1 agonists in the context of in vivo hypoxia–ischemia, where activation of the receptor failed to exert neuroprotection [ 22 ]. The lower susceptibility of the HCAR1 KO mice to the ischemic injury strengthens the idea that the activation of the receptor would not have a protective effect.…”

“…Regarding the HCAR1-mediated signaling effect, the lack of protection following the administration of HCAR1 agonists in vivo [ 22 ], together with the better outcome of HCAR1 KO mice subjected to MCAO presented here, strongly questions the positive role of this receptor related to both endogenous and exogenous lactate effects. Although, neither result can entirely preclude a signaling role in lactate-mediated neuroprotection.…”

“…In previous work, we tested whether HCAR1 stimulation could provide neuroprotection in vivo by administering two different HCAR1 agonists to mice subjected to transient hypoxia–ischemia [ 22 ]. We evaluated the effect of the agonists on the ischemic lesion size and neurological outcome when given after reperfusion.…”

DCA Protects against Oxidation Injury Attributed to Cerebral Ischemia‐Reperfusion by Regulating Glycolysis through PDK2‐PDH‐Nrf2 Axis

“…When the 24 h reperfusion was conducted, the neurological deficit received the assessment in accordance with the scoring standards [ 22 , 23 ]: 0: no neurological deficit; 1: falling to contralateral sides; 2: failing to have spontaneous activities; 3: failing to stretch the contralateral forelimb; 4: circling to paretic sides.…”

“…Overall proteins from the ischemic side cerebral cortex and HBMEC cells received the collection and the fractionation by using SDS-PAGE gels [ 23 ]. Subsequently, the protein received the incubation by using primary antibodies against PDK2 (1 : 1000, Abcam, USA), PDH (1 : 1000, Abcam, USA), ZO-1 (1 : 1000, Abcam, USA), occludin (1 : 1000, Abcam, USA), Nrf2 (1 : 500, Proteintech, Chicago, USA), HO-1 (1 : 500, Proteintech, Chicago, USA), and Tubulin (1 : 10000, BaoDragon, Hefei, China).…”