Forsøksdyr: Neuroprotective role of HCAR1/GPR81 after hypoxia-ischemia

Godkjenningsdato 15.08.2018

Godkjenningsperiode 15.08.2018-14.08.2022

This application is an extension of application # 6750.

Physical exercise, which increases lactate levels in the blood and brain, has positive effects on brain function, especially in the aging brain, but the mechanisms for this are not known. The hydroxycarboxylic acid receptor 1 (HCAR1) (previously termed G-protein coupled receptor 81, GPR81) is a lactate receptor recently identified in adipose, muscle, brain and cancer cells. Recent studies suggest that HCAR1 may be involved in the positive effects of exercise on the brain. However, the functional role of HCAR1 in the brain is still not well characterized. In particular, it is unclear whether HCAR1 may have a protective role during and after an ischemic injury such as stroke.

The aim of this project is to determine whether HCAR1 has a neuroprotective role in cerebral ischemia. We will test this by inducing cerebral ischemia in the mice by permanent occlusion of the left common carotid artery followed by systemic hypoxia at postnatal day 9 (P9) in wild type (C57BL/6N, WT) and HCAR1 knockout (KO) mice. After the induced ischemia, we will compare the acute brain damage, as well as the recovery, between WT and HCAR1 KO mice. The model used for cerebral ischemia is already well established in our lab and has been optimized such that the expected strain on the animals will be moderate and the number of animals needed is reduced to a minimum. To test whether there is a difference between WT and HCAR1 KO in the availability of stem cells (which will influence the ability to regenerate brain tissue), we will also inject the proliferation marker Bromodeoxyuridine (BrdU) before cerebral ischemia. After BrdU- or cerebral ischemia experiments, the animals will be euthanized and tissue will be analyzed by immunohistochemistry and proteome analysis. These methods are well established in our lab and will involve minimal strain on the animals. Most analyses are performed after the mice have been euthanized. To reduce the total number of mice, we will gather as many relevant samples as possible per animal. The total number of animals applied for here is 818 (including HCAR1 KO mice and WT).

Ischemic stroke is the main cause of disability in Norway. This project will increase our knowledge on how the lactate receptor HCAR1 may be protective in stroke, and could potentially lead to developments of new stroke therapy that target the lactate receptor.