**Csilla Ari 1,2,\*, Cem Murdun 3, Craig Goldhagen 3, Andrew P. Koutnik 3,4, Sahil R. Bharwani 1, David M. Diamond 1,3, Mark Kindy 5,6,7, Dominic P. D'Agostino 2,3,4 and Zsolt Kovacs <sup>8</sup>**


Received: 3 July 2020; Accepted: 13 August 2020; Published: 15 August 2020

**Abstract:** Nutritional ketosis has been proven effective for neurometabolic conditions and disorders linked to metabolic dysregulation. While inducing nutritional ketosis, ketogenic diet (KD) can improve motor performance in the context of certain disease states, but it is unknown whether exogenous ketone supplements—alternatives to KDs—may have similar effects. Therefore, we investigated the effect of ketone supplements on motor performance, using accelerating rotarod test and on postexercise blood glucose and *R*-beta-hydroxybutyrate (*R*-βHB) levels in rodent models with and without pathology. The effect of KD, butanediol (BD), ketone-ester (KE), ketone-salt (KS), and their combination (KE + KS: KEKS) or mixtures with medium chain triglyceride (MCT) (KE + MCT: KEMCT; KS + MCT: KSMCT) was tested in Sprague-Dawley (SPD) and WAG/Rij (WR) rats and in GLUT-1 Deficiency Syndrome (G1D) mice. Motor performance was enhanced by KEMCT acutely, KE and KS subchronically in SPD rats, by KEKS and KEMCT groups in WR rats, and by KE chronically in G1D mice. We demonstrated that exogenous ketone supplementation improved motor performance to various degrees in rodent models, while effectively elevated *R*-βHB and in some cases offsets postexercise blood glucose elevations. Our results suggest that improvement of motor performance varies depending on the strain of rodents, specific ketone formulation, age, and exposure frequency.

**Keywords:** ketone ester; ketogenic diet; ketone salt; MCT; rotarod; R-βHB
