Reduced Pain and Inflammation in Juvenile and Adult Rats Fed a Ketogenic Diet

Abstract

The ketogenic diet is a high-fat, low-carbohydrate regimen that forces ketone-based rather than glucose-based cellular metabolism. Clinically, maintenance on a ketogenic diet has been proven effective in treating pediatric epilepsy and type II diabetes, and recent basic research provides evidence that ketogenic strategies offer promise in reducing brain injury. Cellular mechanisms hypothesized to be mobilized by ketone metabolism and underlying the success of ketogenic diet therapy, such as reduced reactive oxygen species and increased central adenosine, suggest that the ketolytic metabolism induced by the diet could reduce pain and inflammation. To test the effects of a ketone-based metabolism on pain and inflammation directly, we fed juvenile and adult rats a control diet (standard rodent chow) or ketogenic diet (79% fat) ad libitum for 3–4 weeks. We then quantified hindpaw thermal nociception as a pain measure and complete Freund's adjuvant-induced local hindpaw swelling and plasma extravasation (fluid movement from the vasculature) as inflammation measures. Independent of age, maintenance on a ketogenic diet reduced the peripheral inflammatory response significantly as measured by paw swelling and plasma extravasation. The ketogenic diet also induced significant thermal hypoalgesia independent of age, shown by increased hindpaw withdrawal latency in the hotplate nociception test. Anti-inflammatory and hypoalgesic diet effects were generally more robust in juveniles. The ketogenic diet elevated plasma ketones similarly in both age groups, but caused slowed body growth only in juveniles. These data suggest that applying a ketogenic diet or exploiting cellular mechanisms associated with ketone-based metabolism offers new therapeutic opportunities for controlling pain and peripheral inflammation, and that such a metabolic strategy may offer significant benefits for children and adults.

Ketogenic diets, mitochondria, and neurological diseases

“…Specifi cally, both chronic pain and epilepsy are characterized by enhanced neuronal excitability, and whatever the relevant mechanisms may be, metabolic approaches toward treatment (e.g., the KD, inhibition of glycolysis through fasting or 2-DG, etc.) can alleviate neuropathic pain ( 14,176 ). Additionally, ASDs are often prescribed for chronic pain, further suggesting similarities in the pathophysiology of these two disorders ( 177 ).…”

“…Additionally, ASDs are often prescribed for chronic pain, further suggesting similarities in the pathophysiology of these two disorders ( 177 ). In juvenile and adult rats, the KD reduced pain, as assessed by increased latency to hind-paw withdrawal in a test of thermal nociception, and infl ammation, as measured by hind-paw swelling in response to injection of the immune-potentiator, Freund's complete adjuvant ( 176 ). Despite attaining similar levels of circulating ketone bodies, the anti-infl ammatory and hypo-algesic effects of the KD were more prominent in juvenile mice ( 176 ).…”

Impaired glucose tolerance in rats fed low-carbohydrate, high-fat diets

“…Furthermore, a greater relative improvement in insulin sensitivity has been observed in obese patients following a LC-HF diet than in those on a calorie-and fat-restricted diet with normal carbohydrate content (44). In patients with type 2 diabetes, low-carbohydrate diets have been shown to improve glycemic control (24,26,27,42) and are suggested to reduce the likelihood of exacerbating existing hyperinsulinemia (38). It has also been suggested that LC-HF diets could protect against the development of type 2 diabetes mellitus (1,29).…”

“…These diets are used to treat epilepsy in children but are currently also under intense research as a potential treatment option for brain (48) and prostate cancer (23) and neurodegenerative diseases such as Alzheimer's and Parkinson's diseases (50). In addition, it has been suggested that ketogenic diets may offer a new therapeutic opportunity for controlling pain and peripheral inflammation (42). Animal studies allow investigation of diet effects in a more controlled and standardized environment than can be achieved in humans.…”

The Fat is in the Fire: Ketogenic Diet for Refractory Status Epilepticus

“…As a nonpharmacologic therapy, the ketogenic diet also does not have any known interactions with antibiotics or anticonvulsants. Lastly, some evidence would suggest a possible anti-inflammatory action, which may explain its success specifically for status epilepticus caused by encephalitis (10).…”