Effect of HCAR1 lactate treatment on brain inflammation

Inflammation has been associated with several mood related disorders including anxiety, depression, and chronic stress (Steptoe et al., 2008, Pan et al., 2014, Kim and Jeon, 2017), in addition to other diseases affecting the brain, such as Alzheimer’s disease (Schmidt et al., 2002), Parkinson’s disease (Codolo et al., 2013), multiple sclerosis (Furlan et al., 1999), ischaemic stroke (Abulafia et al., 2009), and epilepsy (Tan et al., 2015). One cause of systemic inflammation is the bacterium causing periodontitis, Porphyromonas gingivalis (Genco et al., 1998). Both the bacteria and the inflammatory mediators can spread throughout the body through blood vessels and airways, and probably enter the brain through the blood brain barrier and lead to an inflammatory response (Ishida et al., 2017). Interestingly, it has been shown that brain inflammation caused by P. gingivalis-LPS infection can lead to learning and memory impairment in mice (Zhang et al., 2018). Physical exercise has been found to have an anti-inflammatory effect (Taaffe et al., 2000). Exercising muscles produce lactate, and some of the exercise related benefits of high intensity training have recently been mimicked by injection of lactate. Our group identified a lactate receptor, hydroxycarboxylic acid receptor 1 (HCAR1) also called GPR81, in the mammalian brain (Lauritzen et al., 2014; Morland et al., 2015). Of particular interest is that lactate has been shown to protect against inflammatory damage in mice with hepatitis through activation of HCAR1 (Hoque et al., 2014). In this project, we wish to find out if HCAR1 stimulation can be a key target for anti-inflammation. This knowledge can be used to develop new and improved therapeutics and is therefore of high interest to the society. We plan to do this by infecting 80 mice with knockout of HCAR1 (HCAR1 KO) or wild type (wt) mice with the P. gingivalis bacteria or control, and then treat them with a HCAR1 agonist or saline control. To find out at which earliest time point we can find inflammation in the brain caused by P. gingivalis infection, we will first do a pilot experiment with 18 wt mice. This will reduce the total number of animals used. The working team is well trained and able to successfully perform animal research. Ethical concerns will be fully addressed according to law and civil regulations.