The individual and combined effects of creatine monohydrate and lithium chloride supplementation on brain creatine uptake in male and female rats.

Abstract

During ischemia and traumatic brain injuries (TBIs), phosphocreatine (PCr) acts as a temporal energy buffer preventing rapid decreases in intracellular ATP concentrations. Though, the brain has limited stored creatine and it therefore relies heavily on exogenous substrates. Moreover, creatine monohydrate (CrM) supplementation can significantly increase brain total creatine concentration (TCr). Creatine’s ability to enter the brain is dependent on creatine transporters, and limited evidence suggests lithium (Li), through GSK3 inhibition, upregulates this transport. Therefore, the purpose of this research was to investigate the individual and combined influences of in vivo creatine monohydrate and lithium chloride on creatine concentrations in the rat brain. 64 Sprague-Dawley rats (32 males, 32 females), given ad libitum access to a pelleted 14% certified protein rodent maintenance diet, were randomized into four experimental groups: control (CON), creatine (Cr), lithium (Li), and creatine-lithium (Cr-Li). CrM at 5g/L (0.412g/kg/day) and lithium chloride (LiCl) at 0.2g/L (0.018g/kg/day) were supplemented in the reverse osmosis drinking water. Brain [TCr] was greater with LiCl (p=0.0002), irrespective of CrM, and greater with CrM (p<0.0001), irrespective of LiCl. For slc6a8 mRNA expression, there was a trend for increased expression with LiCl (p=0.12). The female Li group also had a trend greater (p=0.06) than the Cr group. Relative daily CrM consumption was higher without LiCl (p<0.0001) and higher in females (p=0.0001). Relative daily LiCl consumption was higher among females than males (p<0.0001). LiCl inhibited GSK3 activity through an increase in pGSK3a, pGSK3b, ratio of pGSK3a:GSK3a, and ratio of pGSK3b:GSK3b and there was a trend for reduced total GSK3 activity (p=0.11) with LiCl. In conclusion, this study demonstrated that CrM and LiCl supplementation alone and in combination similarly increased brain TCr, with no synergistic or additive effects when combined.