Ketogenic Diet Improves Forelimb Motor Function after Spinal Cord Injury in Rodents

Streijger, Femke; Plunet, Ward T.; Lee, Jae H.T.; Liu, Jie; Lam, Clarrie K.; Park, Soeyun; Hilton, Brett J.; Fransen, Bas L.; Matheson, Keely A. J.; Assinck, Peggy; Kwon, Brian K.; Tetzlaff, Wolfram

doi:10.1371/journal.pone.0078765

Cited by 99 publications

(89 citation statements)

References 95 publications

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“…12 A limitation observed is the variability in firmly holding the spinal column using the clamps provided with the IH device, and some researchers have developed custom-built clamping systems to overcome this. 13 Although subtle movements should not theoretically influence injury mechanics of the force-controlled impactor, inconsistent parenchymal injury and functional deficits do occur.…”

Section: Infinite Horizon (Ih) Impactormentioning

confidence: 99%

Spinal cord injury models: a review

et al. 2014

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Background: Animal spinal cord injury (SCI) models have proved invaluable in better understanding the mechanisms involved in traumatic SCI and evaluating the effectiveness of experimental therapeutic interventions. Over the past 25 years, substantial gains have been made in developing consistent, reproducible and reliable animal SCI models. Study design: Review. Objective: The objective of this review was to consolidate current knowledge on SCI models and introduce newer paradigms that are currently being developed. Results: SCI models are categorized based on the mechanism of injury into contusion, compression, distraction, dislocation, transection or chemical models. Contusion devices inflict a transient, acute injury to the spinal cord using a weight-drop technique, electromagnetic impactor or air pressure. Compression devices compress the cord at specific force and duration to cause SCI. Distraction SCI devices inflict graded injury by controlled stretching of the cord. Mechanical displacement of the vertebrae is utilized to produce dislocation-type SCI. Surgical transection of the cord, partial or complete, is particularly useful in regenerative medicine. Finally, chemically induced SCI replicates select components of the secondary injury cascade. Although rodents remain the most commonly used species and are best suited for preliminary SCI studies, large animal and nonhuman primate experiments better approximate human SCI. Conclusion: All SCI models aim to replicate SCI in humans as closely as possible. Given the recent improvements in commonly used models and development of newer paradigms, much progress is anticipated in the coming years. Spinal Cord (2014) 52, 588-595; doi:10.1038/sc.2014.91; published online 10 June 2014 INTRODUCTIONSpinal cord injury (SCI) models have proved indispensible not only for investigating the efficacy of therapeutic interventions but also for better understanding the molecular pathways involved. SCI models have evolved significantly over the past century since Allen developed the first weight-drop contusion model in 1911. 1 SCI models aim to recreate features of human SCI as closely as possible. These models vary in terms of the animal utilized, site of injury infliction and injury mechanism.Rats are used most commonly in preliminary studies as they are relatively inexpensive, readily available and have demonstrated similar functional, electrophysiological, and morphological outcomes to humans following SCI. 2 Mice are particularly useful for genetic studies. 3 Nonhuman primate SCI models-including marmosets, macaques and squirrel monkeys-better approximate human SCI than rodent models, and they accommodate assessment of multiple recovery variables and rehabilitative therapy. 4 New world primates like marmosets confer advantages over old world primates as they are smaller, easier to handle, have a higher breeding efficiency and can be bred in experimental colonies. SCI models that incorporate large animals-such as pigs or dogs-can also be used when it is important for furth...

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Section: Infinite Horizon (Ih) Impactormentioning

confidence: 99%

Spinal cord injury models: a review

et al. 2014

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“…Adult male rats given a 3:1 ratio ketogenic diet (Bioserv F5848) for 12 weeks starting 4 h after cervical injury had decreased spinal lesions, increased expression of GLUT1 and MCT1 vascular transporters, and improved forelimb motor function ( 52 ). Ketosis induced by every other day fasting for 2-4 weeks improved functional recovery, decreased lesion size, and increased corticospinal tract sprouting in adult male rats with thoracic or cervical injury ( 53,54 ).…”

Section: Ketones As Alternative Substrate Early After Traumatic Spinamentioning

confidence: 99%

The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury

Prins

Matsumoto

2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org setting ( 2, 3 ). Thus, there is a signifi cant need to identify better strategies to improve global outcome after TBI. In addition, given the inherent differences between the developing brain in which dynamic processes such as synaptogenesis, myelination, and plasticity are ongoing, and the mature adult brain in which these processes have been completed, any potential neuroprotective treatment must be evaluated in an age-specifi c manner. To that end, we discuss the changes in cerebral glucose metabolism, which have been described in the aftermath of TBI, the age-related variation of this metabolic dysfunction, and the potential of using the natural ketone metabolism mechanisms to ameliorate these problems and improve global outcome. METABOLIC DYSFUNCTIONS AFTER TBIUpon impact, rapid movement of the brain within the skull initiates a series of neurochemical disruptions that alter cerebral metabolism. Within minutes after injury, the ionic equilibrium across the neuronal membranes is disrupted, with injury severity-dependent increases in the concentration of extracellular potassium and glutamate, as well as intracellular calcium accumulation ( 4, 5 ). This disruption of ionic equilibrium requires cellular energy to reestablish homeostasis, which is refl ected by increases in cerebral glucose uptake observed within 30 min after adult rodent fl uid percussion (FP) injury ( 6 ) and within 8 days after human TBI ( 7 ). This transient increase in glucose uptake is also known as "hyperglycolysis" and is followed by a prolonged period of glucose metabolic depression. These cerebral metabolic changes are a hallmark response described in both experimental and clinical brain trauma. Nationally, the incidence of traumatic brain injury (TBI) exceeds that of all other health diseases with an annual incidence of 1.7 million new cases ( 1 ). It is an injury that affects both genders across all age groups, producing long-term disabilities that negatively impact families and society. Recent years have seen a substantial increase in public awareness of the long-term cognitive, emotional, and functional consequences of TBI. However, several potential neuroprotective treatments, such as therapeutic hypothermia, have produced disappointing results when tested in the clinical

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“…Administration of a ketogenic diet increases glucose transporter 1 (GLUT1) expression in spinal cord endothelial cells and was associated with reduced lesion volume[20]. The chemical compound FM19G11, which activates the AKT pathway and induces GLUT4 activation, improved motor function by 4 weeks post-injury[21].…”

Section: Discussionmentioning

confidence: 99%

18F-FDG-PET imaging of rat spinal cord demonstrates altered glucose uptake acutely after contusion injury

Leden

Selwyn

Jaiswal

et al. 2016

Neuroscience Letters

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Spinal cord injury (SCI) results in an acute reduction in neuronal and glial cell viability, disruption in axonal tract integrity, and prolonged increases in glial activity and inflammation, all of which can influence regional metabolism and glucose utilization. To date, the understanding of glucose uptake and utilization in the injured spinal cord is limited. Positron emission tomography (PET)-based measurements of glucose uptake may therefore serve as a novel bio-marker for SCI. This study aimed to determine the acute and sub-acute glucose uptake pattern after SCI to determine its potential as a novel non-invasive tool for injury assessment and to begin to understand the glucose uptake pattern following acute SCI. Briefly, adult male Sprague-Dawley rats were subjected to moderate contusion SCI, confirmed by locomotor function and histology. PET imaging with [18F]Fluorodeoxyglucose (FDG) was performed prior to injury and at 6 and 24 hours and 15 days post-injury (dpi). FDG-PET imaging revealed significantly depressed glucose uptake at 6 hours post-injury at the lesion epicenter that returned to sham/naïve levels at 24 hours and 15 dpi after moderate injury. FDG uptake at 15 dpi was likely influenced by a combination of elevated glial presence and reduced neuronal viability. These results show that moderate SCI results in acute depression in glucose uptake followed by an increase in glucose uptake that may be related to neuroinflammation. This acute and sub-acute uptake, which is dependent on cellular responses, may represent a therapeutic target.

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Ketogenic Diet Improves Forelimb Motor Function after Spinal Cord Injury in Rodents

Cited by 99 publications

References 95 publications

Spinal cord injury models: a review

Spinal cord injury models: a review

The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury

18F-FDG-PET imaging of rat spinal cord demonstrates altered glucose uptake acutely after contusion injury

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