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Ketogenesis controls mitochondrial gene expression and rescues mitochondrial bioenergetics after cervical spinal cord injury in rats.

ABSTRACT: A better understanding of the secondary injury mechanisms that occur after traumatic spinal cord injury (SCI) is essential for the development of novel neuroprotective strategies linked to the restoration of metabolic deficits. We and others have shown that Ketogenic diet (KD), a high fat, moderate in proteins and low in carbohydrates is neuroprotective and improves behavioural outcomes in rats with acute SCI. Ketones are alternative fuels for mitochondrial ATP generation, and can modulate signaling pathways via targeting specific receptors. Here, we demonstrate that ad libitum administration of KD for 7 days after SCI rescued mitochondrial respiratory capacity, increased parameters of mitochondrial biogenesis, affected the regulation of mitochondrial-related genes, and activated the NRF2-dependent antioxidant pathway. This study demonstrates that KD improves post-SCI metabolism by rescuing mitochondrial function and supports the potential of KD for treatment of acute SCI in humans.

SUBMITTER: Seira O

PROVIDER: S-EPMC8357839 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Ketogenesis controls mitochondrial gene expression and rescues mitochondrial bioenergetics after cervical spinal cord injury in rats.

Seira Oscar O Kolehmainen Kathleen K Liu Jie J Streijger Femke F Haegert Anne A Lebihan Stéphane S Boushel Robert R Tetzlaff Wolfram W

Scientific reports 20210811 1

A better understanding of the secondary injury mechanisms that occur after traumatic spinal cord injury (SCI) is essential for the development of novel neuroprotective strategies linked to the restoration of metabolic deficits. We and others have shown that Ketogenic diet (KD), a high fat, moderate in proteins and low in carbohydrates is neuroprotective and improves behavioural outcomes in rats with acute SCI. Ketones are alternative fuels for mitochondrial ATP generation, and can modulate signa ...[more]

PMID: 34381166

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Project description:The number of elderly patients with spinal cord injury without radiographic abnormalities (SCIWORA) has been increasing in recent years and common of most cervical spinal cord injuries. Basic research has shown the effectiveness of early decompression after spinal cord injury on the spinal cord without stenosis; no studies have reported the efficacy of decompression in models with spinal cord compressive lesions. The purpose of this study was to evaluate the effects of decompression surgery after acute spinal cord injury in rats with chronic spinal cord compressive lesions, mimicking SCIWORA. A water-absorbent polymer sheet (Aquaprene DX, Sanyo Chemical Industries) was inserted dorsally into the 4-5th cervical sublaminar space in 8-week-old Sprague Dawley rats to create a rat model with a chronic spinal compressive lesion. At the age of 16 weeks, 30 mildly myelopathic or asymptomatic rats with a Basso, Beattie, and Bresnahan score (BBB score) of 19 or higher were subjected to spinal cord compression injuries. The rats were divided into three groups: an immediate decompression group (decompress immediately after injury), a sub-acute decompression group (decompress 1 week after injury), and a non-decompression group. Behavioral and histological evaluations were performed 4 weeks after the injury. At 20 weeks of age, the BBB score and FLS (Forelimb Locomotor Scale) of both the immediate and the sub-acute decompression groups were significantly higher than those of the non-decompression group. There was no significant difference between the immediate decompression group and the sub-acute decompression group. TUNEL (transferase-mediated dUTP nick end labeling) staining showed significantly fewer positive cells in both decompression groups compared to the non-decompression group. LFB (Luxol fast blue) staining showed significantly more demyelination, and GAP-43 (growth associated protein-43) staining tended to show fewer positive cells in the non-decompression group. Decompression surgery in the acute or sub-acute phase of injury is effective after mild spinal cord injury in rats with chronic compressive lesions. There was no significant difference between the immediate decompression and sub-acute decompression groups.

Project description:BackgroundThere is emerging evidence that astaxanthin plays a significant role in protecting neuro-cells from apoptosis after central nervous system injury. Our study examined the effects of astaxanthin on neuro-cell apoptosis after spinal cord injury.MethodsOne hundred and forty-four healthy adult Sprague-Dawley rats were randomly divided into the experimental group, control group, and sham operation group (n=48). Spinal cord injury was induced using the modified Allen method in the control group and the experimental group; while in the sham operation group, the lamina was removed without spinal cord injury. The rats in the experimental group were given astaxanthin (75 mg/kg) by gavage immediately after the operation, and in the other groups were given the same amount of olive oil. Motor function was assessed by blood-brain barrier (BBB) scores. The malondialdehyde (MDA) content and the activity of superoxide dismutase (SOD) at 24 h was determined after the operation. The apoptosis index (AI) was determined at 6, 24, and 48 h after the operation. At 48 h after the operation, we calculated the water content of the spinal cord, the lesion ratio of the spinal cord, the ultrastructure of the spinal cord, and the ultrastructure score.ResultsThe BBB scores of the control and experimental groups were significantly lower than the sham operation group at each postoperative time (P<0.05), and the BBB score of the experimental group was significantly higher than the control group at 1-4 weeks postoperatively (P<0.05). At 24 hours postoperatively, MDA content was highest in the control group and lowest in the sham operation group, while SOD activity was highest in the sham operation group and lowest in the control group (P<0.05). At each time point postoperatively, the sham operation group had the lowest AI and the control group had the highest AI (P<0.05). At 48 h after the operation, the water content and the lesion ratio of the spinal cord, and the ultrastructure score were the lowest in the sham operation group and the highest in the control group (P<0.05).ConclusionsAstaxanthin significantly improved the motor function of rats with spinal cord injury.

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Ketogenesis controls mitochondrial gene expression and rescues mitochondrial bioenergetics after cervical spinal cord injury in rats.

Publications

Ketogenesis controls mitochondrial gene expression and rescues mitochondrial bioenergetics after cervical spinal cord injury in rats.

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