The lactate receptor HCAR1 in the regulation of neurogenesis and angiogenesis during stroke

Millions of people suffer from stroke every year, being a leading cause of morbidity and mortality worldwide. The current pharmacological and endovascular therapies in stroke aim to restore cerebral blood flow, but are not suitable for many stroke patients due to a number of risk factors. With the limited post-stroke rehabilitation treatments available, prevention of stroke will continue to be an area of research with a large impact. One of the best preventive strategies in stroke is exercise, which has shown to reduce risk factors and improve brain function through direct effects in the brain. Trophic growth factors are elevated after exercise which enhances neurogenesis and angiogenesis, and have been suggested to exert the neuroprotective effects in the ischaemic brain. The lactate receptor (HCAR1) has recently shown to be highly enriched in fibroblasts in the meninges, particularly the pia mater. Furthermore, activation of these receptors by lactate injections or high-intensity exercise, enhance cerebral vascular endothelial growth factor A (VEGF-A) levels and angiogenesis, and perhaps also directly enhance neurogenesis. Since HCAR1 can be stimulated by circulating lactate arriving from the blood as a result of exercise, this may explain the underlying beneficial effects of exercise in stroke. The present study aimed to examine the HCAR1-induced vascularization and neurogenesis in response to exercise in the neuroprotection of stroke. Wild-type mice and HCAR1 knockout mice were subjected to high-intensity exercise (at levels known to significantly increase blood-lactate levels), medium-intensity exercise, or intraperitoneal injections of lactate or saline (control) daily for 5 consecutive days a week for 7 weeks in total. Following the treatments, focal ischaemia was induced by permanent coagulation of the distal middle cerebral artery, and the mice were allowed a 3-weeks recovery phase before being sacrificed by perfusion fixation to collect the brains. Whole cresyl violet-stained sections were analysed for comparison of infarct volume. Interestingly, no significant differences between the treatment groups or genotypes were found. Possible reasons for the lack of observed effects are presented. In conclusion, preventive and prolonged exercise preconditioning or lactate injections do not protect against ischaemia-induced cell death 3 weeks after stroke. Moreover, the outcome was independent of HCAR1-mediated effects. Overall, these findings provide new insights of the long-lasting effects (3 weeks after stroke induction) on the stroke outcome of exercise preconditioning and lactate treatment, through the lactate receptor HCAR1