Abstract
High fat, low carbohydrate ketogenic diets (KD) are validated non-pharmacological treatments for some forms of drug-resistant epilepsy. Ketones reduce neuronal excitation and promote neuroprotection. Here, we investigated the efficacy of KD as a treatment for acute cervical spinal cord injury (SCI) in rats. Starting 4 hours following C5 hemi-contusion injury animals were fed either a standard carbohydrate based diet or a KD formulation with lipid to carbohydrate plus protein ratio of 3:1. The forelimb functional recovery was evaluated for 14 weeks, followed by quantitative histopathology. Post-injury 3:1 KD treatment resulted in increased usage and range of motion of the affected forepaw. Furthermore, KD improved pellet retrieval with recovery of wrist and digit movements. Importantly, after returning to a standard diet after 12 weeks of KD treatment, the improved forelimb function remained stable. Histologically, the spinal cords of KD treated animals displayed smaller lesion areas and more grey matter sparing. In addition, KD treatment increased the number of glucose transporter-1 positive blood vessels in the lesion penumbra and monocarboxylate transporter-1 (MCT1) expression. Pharmacological inhibition of MCTs with 4-CIN (α-cyano-4-hydroxycinnamate) prevented the KD-induced neuroprotection after SCI, In conclusion, post-injury KD effectively promotes functional recovery and is neuroprotective after cervical SCI. These beneficial effects require the function of monocarboxylate transporters responsible for ketone uptake and link the observed neuroprotection directly to the function of ketones, which are known to exert neuroprotection by multiple mechanisms. Our data suggest that current clinical nutritional guidelines, which include relatively high carbohydrate contents, should be revisited.
Highlights
We have shown that Every-Other-Day-Fasting (EODF) improves neurological recovery in rats following cervical and thoracic spinal cord injury (SCI) [1,2,3]
After week 1, ketone levels slightly decreased in Ketogenic diets (KD) treated animals, but were still significantly higher compared to the standard diet (SD) group (t(16)=4.902, p
We demonstrated for the first time that post-injury treatment of KD with a 3:1 ratio of fat to carbohydrates and proteins promoted neuroprotection and improved neurologic outcomes following spinal cord injury (SCI); here a model of cervical hemicontusion
Summary
We have shown that Every-Other-Day-Fasting (EODF) improves neurological recovery in rats following cervical and thoracic SCI [1,2,3]. A physiologically low intake of carbohydrates causes a metabolic state of increased hepatic ketogenesis, which results in high levels of blood ketone bodies (β-hydroxybutyrate, acetoacetate and acetone) due to the breakdown of fatty acids [4,5]. These ketone bodies cross the blood brain barrier and enter neuronal and glial cells through monocarboxylic acid transporters (MCTs) of which MCT1 is the primary isoform found in astrocytes, oligodendrocytes, and endothelial cells. After uptake into the mitochondria, ketone bodies are converted to acetyl-CoA, to enter the tricarboxylic acid pathway for ATP generation [6,7,8,9,10,11,12,13]
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