Exogenous Ketone Supplements Improved Motor Performance in Preclinical Rodent Models.

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-ßHB) 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-ßHB 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.

Exogenous Ketones Lower Blood Glucose Level in Rested and Exercised Rodent Models.

Diseases involving inflammation and oxidative stress can be exacerbated by high blood glucose levels. Due to tight metabolic regulation, safely reducing blood glucose can prove difficult. The ketogenic diet (KD) reduces absolute glucose and insulin, while increasing fatty acid oxidation, ketogenesis, and circulating levels of ß-hydroxybutyrate (ßHB), acetoacetate (AcAc), and acetone. Compliance to KD can be difficult, so alternative therapies that help reduce glucose levels are needed. Exogenous ketones provide an alternative method to elevate blood ketone levels without strict dietary requirements. In this study, we tested the changes in blood glucose and ketone (ßHB) levels in response to acute, sub-chronic, and chronic administration of various ketogenic compounds in either a post-exercise or rested state. WAG/Rij (WR) rats, a rodent model of human absence epilepsy, GLUT1 deficiency syndrome mice (GLUT1D), and wild type Sprague Dawley rats (SPD) were assessed. Non-pathological animals were also assessed across different age ranges. Experimental groups included KD, standard diet (SD) supplemented with water (Control, C) or with exogenous ketones: 1, 3-butanediol (BD), ßHB mineral salt (KS), KS with medium chain triglyceride/MCT (KSMCT), BD acetoacetate diester (KE), KE with MCT (KEMCT), and KE with KS (KEKS). In rested WR rats, the KE, KS, KSMCT groups had lower blood glucose level after 1 h of treatment, and in KE and KSMCT groups after 24 h. After exercise, the KE, KSMCT, KEKS, and KEMCT groups had lowered glucose levels after 1 h, and in the KEKS and KEMCT groups after 7 days, compared to control. In GLUT1D mice without exercise, only KE resulted in significantly lower glucose levels at week 2 and week 6 during a 10 weeks long chronic feeding study. In 4-month and 1-year-old SPD rats in the post-exercise trials, blood glucose was significantly lower in KD and KE, and in KEMCT groups, respectively. After seven days, the KSMCT group had the most significantly reduced blood glucose levels, compared to control. These results indicate that exogenous ketones were efficacious in reducing blood glucose levels within and outside the context of exercise in various rodent models of different ages, with and without pathology.

Delaying latency to hyperbaric oxygen-induced CNS oxygen toxicity seizures by combinations of exogenous ketone supplements.

Central nervous system oxygen toxicity (CNS-OT) manifests as tonic-clonic seizures and is a limitation of hyperbaric oxygen therapy (HBOT), as well as of recreational and technical diving associated with elevated partial pressure of oxygen. A previous study showed that ketone ester (1,3-butanediol acetoacetate diester, KE) administration delayed latency to seizures (LS) in 3-month-old Sprague-Dawley (SD) rats. This study explores the effect of exogenous ketone supplements in additional dosages and formulations on CNS-OT seizures in 18 months old SD rats, an age group correlating to human middle age. Ketogenic agents were given orally 60 min prior to exposure to hyperbaric oxygen and included control (water), KE (10 g/kg), KE/2 (KE 5 g/kg + water 5 g/kg), KE + medium-chain triglycerides (KE 5 g/kg + MCT 5 g/kg), and ketone salt (Na+ /K+ ßHB, KS) + MCT (KS 5 g/kg + MCT 5 g/kg). Rats were exposed to 100% oxygen at 5 atmospheres absolute (ATA). Upon seizure presentation (tonic-clonic movements) experiments were immediately terminated and blood was tested for glucose and D-beta-hydroxybutyrate (D-ßHB) levels. While blood D-ßHB levels were significantly elevated post-dive in all treatment groups, LS was significantly delayed only in KE (P = 0.0003), KE/2 (P = 0.023), and KE + MCT (P = 0.028) groups. In these groups, the severity of seizures appeared to be reduced, although these changes were significant only in KE-treated animals (P = 0.015). Acetoacetate (AcAc) levels were also significantly elevated in KE-treated animals. The LS in 18-month-old rats was delayed by 179% in KE, 219% in KE + MCT, and 55% in KE/2 groups, while only by 29% in KS + MCT. In conclusion, KE supplementation given alone and in combination with MCT elevated both ßHB and AcAc, and delayed CNS-OT seizures.

Calcaneocuboid Joint Arthritis of the Midfoot Precedes Tibiotalar Joint Arthritis.

Surgical models have best shown the relationship between ankle and mid-foot osteoarthritis, although findings regarding the calcaneocuboid joint have varied. To the authors' knowledge, no studies have evaluated the relationship between degenerative changes across the tibiotalar and calcaneocuboid joints. The goal of this study was to determine whether such a relationship exists and which joint degenerates first. A single examiner evaluated 694 tibiotalar and calcaneocuboid joints to determine the presence of osteoarthritis. Multiple linear regression analysis was conducted with a standard P value cutoff (P<.05) and 95% confidence interval. The average incidence of tibiotalar and calcaneocuboid osteoarthritis in specimens older than 40 years was compared with the incidence in those 40 years and younger. A positive correlation between tibiotalar and calcaneocuboid osteoarthritis was noted. African-American subjects were less likely than white subjects to have tibiotalar osteoarthritis. The finding of right and left tibiotalar and calcaneocuboid osteoarthritis in subjects 40 years and younger showed that midfoot arthritis was significantly more common than arthritis of the ankle. The prevalence of calcaneocuboid osteoarthritis remains stable after 40 years of age, and the prevalence of tibiotalar osteoarthritis approaches that of calcaneocuboid osteoarthritis. Calcaneocuboid osteoarthritis precedes tibiotalar osteoarthritis. Altered biomechanics involved in calcaneocuboid osteoarthritis are transferred to the tibiotalar joint, leading to tibiotalar osteoarthritis as the subject ages. Early education, surveillance, physical therapy, shoe adjustment, and orthotics may help to reduce the forces across the midfoot and prevent ankle arthritis in the long term. [Orthopedics. 2016; 39(6):e1112-e1116.].

Ipsilateral Tibiotalar Joint Osteoarthritis Transferred to the Contralateral Tibiotalar Joint.

Classically, it is thought that pain or disability in one leg can stress the contralateral leg, leading to similar symptoms. The mechanism of action for subsequent dysfunction in the healthy limb is thought to involve compensatory changes that are used as a means to reduce stance phase time on the injured limb. This is believed to increase the forces distributed across the healthy limb, ultimately leading to injury. This belief has been challenged, as supportive literature is sparse. The goal of this study was to determine whether an association between tibiotalar (TT) osteoarthritis (OA) in the right vs left lower extremity exists, and whether injury to one lower extremity leads to degeneration in the contralateral lower extremity. The authors evaluated 704 TT joints to determine the presence of OA. A multiple linear regression was performed using a standard P value cutoff (P<.05) and 95% confidence interval. The absolute value of the difference between right and left TT OA was compared for specimens in each decade of life. Multiple regression analysis revealed a positive correlation between right and left TT OA, after correcting for age, sex, and race. Right TT vs left TT had a slope of 0.489 with a P value approaching 0. Findings indicated the absolute value of the difference between right and left TT OA was not zero, and this difference remains significant throughout life. Based on these findings, OA in one ankle does not appear to lead to accelerated OA in the contralateral ankle. [Orthopedics. 2016; 39(4):e664-e667.].