Abstract
ObjectiveTo investigate the effects of ketogenic metabolism on macrophage polarization, inflammation inhibition, and function recovery after acute spinal cord injury (SCI) in rats.MethodsSixty-four adult male Sprague–Dawley rats were randomly and equally divided into sham, standard diet (SD), ketone diet (KD), and 1, 3-butanediol (BD) groups. All animals underwent C5 unilateral laminectomy, whereas the SD, KD, and BD groups underwent C5 spinal cord hemi-contusion. The impact rod with a diameter of 1.5 mm was aligned 22.5° to the left and 1.4 mm to the midline, and then triggered to deliver a set displacement of 1.5 mm at a speed of 100 mm/s. The gene expression of inflammatory factors as well as the protein expression of inducible nitric oxide synthase, arginase-1, and inflammatory factors were measured at 1 week post-injury. Serum ketone and behavior were evaluated every second week for 12 weeks. Then, histological analyses of the gray and white matter at the epicenter were conducted at 12 weeks post-injury.ResultsThe serum ketone levels of the KD and BD groups were significantly increased when compared with the SD group. The gene and protein expression of TNF-α and IL-1β tended to increase after the SCI, but were inhibited in the KD and BD groups. The protein expression of inducible nitric oxide synthase, marker of M1 macrophage, was inhibited in the KD and BD groups; on the other hand, the expression of arginase-1, marker of M2 macrophage, was boosted in the KD and BD groups. The usage of the ipsilateral forelimb was higher in the KD group than in the SD group. The hemi-contusive injury resulted in an obvious ipsilateral lesion area at the epicenter, and there was no significant difference between groups regarding the lesion size. However, the spared gray matter area was significantly greater in the KD group than in the SD and BD groups.ConclusionThe present study suggests that ketogenic metabolism promotes macrophage polarization to M2, inhibits an inflammatory response, and alleviates the loss of gray matter after SCI. A higher ketone level, such as that induced by the ketogenic diet, seems to benefit function recovery after SCI.
Highlights
Ketone bodies, including acetoacetate, acetone, and betahydroxybutyrate, are generated in a state of starvation, fasting, or high-fat diet
Yarar-Fisher et al (2018) further proposed that ketogenic diet (KD) has anti-inflammatory and neuroprotective effects, and could promote the recovery of neural function post-spinal cord injury (SCI). It was verified by Streijger et al (2013) that KD was effective in promoting motor function, reducing the lesion area, and preserving greater spared gray matter after SCI in rats while Jeong et al (2011) reported that fasting every other day, another form of ketogenic metabolism, was beneficial in protecting neural function and facilitating motor recovery
The results indicated that ketone metabolism induced by KD presented benefit in terms of the improvement of motor function and the reservation of spinal gray matter after SCI
Summary
Ketone bodies, including acetoacetate, acetone, and betahydroxybutyrate (βOHB), are generated in a state of starvation, fasting, or high-fat diet. We investigated the tolerance of ketogenic diet (KD) and detected the serum ketone body levels in 10 patients with SCI in a clinical trial, confirming the safety and feasibility of KD (Guo et al, 2014). Yarar-Fisher et al (2018) further proposed that KD has anti-inflammatory and neuroprotective effects, and could promote the recovery of neural function post-SCI It was verified by Streijger et al (2013) that KD was effective in promoting motor function, reducing the lesion area, and preserving greater spared gray matter after SCI in rats while Jeong et al (2011) reported that fasting every other day, another form of ketogenic metabolism, was beneficial in protecting neural function and facilitating motor recovery. It is necessary to explore whether 1, 3-butanediol (BD), a ketone supplement that can promote the serum ketone level without interrupting normal diet (Kesl et al, 2016), possesses a neuroprotective effect and can offer a therapeutic alternative for SCI
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