Ketogenic diet improves forelimb motor function after spinal cord injury in rodents.
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.
International Collaboration on Repair Discoveries (ICORD), Blusson Spinal Cord Center, Vancouver, British Columbia, Canada.
Femke
F
Streijger
Ward T
WT
Plunet
Jae H T
JH
Lee
Jie
J
Liu
Clarrie K
CK
Lam
Soeyun
S
Park
Brett J
BJ
Hilton
Bas L
BL
Fransen
Keely A J
KA
Matheson
Peggy
P
Assinck
Brian K
BK
Kwon
Wolfram
W
Tetzlaff
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D003373:Coumaric Acids / Q000494:pharmacology; D055423:Diet, Ketogenic; D004195:Disease Models, Animal; D005552:Forelimb / Q000503:physiopathology*; D015870:Gene Expression; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D009043:Motor Activity / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013119:Spinal Cord Injuries / Q000097:blood / Q000503:physiopathology*; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D000099233:Monocarboxylate Transport Protein 1
D020155:3-Hydroxybutyric Acid; D019208:Brain-Derived Neurotrophic Factor; D003373:Coumaric Acids; D051272:Glucose Transporter Type 1; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D042461:Vascular Endothelial Growth Factor A; D000099233:Monocarboxylate Transport Protein 1; C495679:Slc2a1 protein, rat; C007175:alpha-cyano-4-hydroxycinnamate