Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA)
The acute administration of eicosapentaenoic acid is neuroprotective after spinal cord compression injury in rats
Introduction
Spinal cord injury (SCI) is a catastrophic event which can result in permanent disability. Currently there are no effective treatments, although intensive rehabilitation can facilitate some recovery of function. Major progress has been made in preclinical studies on neuroprotection and regeneration [17], [26], but this progress has not yet been translated to the clinic.
We have previously shown that the omega-3 polyunsaturated fatty acids (PUFAs) α-linolenic acid and docosahexaenoic acid (DHA) confer potent neuroprotection following hemisection and compression SCI in rats [14], [16]. Eicosapentaenoic acid (EPA), a biosynthetic precursor of DHA, has also been shown to have anti-inflammatory and neuroprotective properties in animal models of neuroinflammation [29], and has recently been reported to improve the prognosis after subarachnoid haemorrhage in patients [31]. It is important to identify whether any therapeutic benefit for SCI may be obtained through EPA administration. We have carried out a preliminary investigation of the effects of acute treatment with EPA in a rat compression SCI model [13], tested at the same dose chosen for our DHA studies. We monitored the locomotor outcome and examined neuronal and oligodendrocyte survival, axonal injury and the inflammatory reaction, in the lesion epicenter and adjacent tissue.
Section snippets
Preparation of EPA
1 M stock aliquots of EPA free fatty acid (Sigma, Dorset, UK) were prepared under 100% nitrogen and were made up in absolute ethanol. 5 μl stock aliquots were kept at −20 °C in light sensitive, airtight glass containers (Agilent, Stockport, UK) to prevent oxidation. On the day of surgery, solutions were diluted to the required concentration (250 nmol/kg body weight; injection volume 5 ml/kg) with physiological saline (NaCl 0.9%), and adjusted to pH 7.4.
Animals and compression SCI
All animal procedures were approved by the
Neuronal survival
Examination of NeuN labeling at 7 days post-injury showed that animals that received an EPA injection 30 min after injury had substantially more labeled cells in the dorsal horns (Fig. 1b and e) and ventral horns in the epicenter compared to saline-injected controls. Quantitative analyses confirmed these differences, with animals receiving EPA resulting in significantly more NeuN labeled cells in the compression epicenter than saline controls in the dorsal horns (673±90 vs. 406±66; P<0.05; Fig. 1
Discussion and conclusions
This study demonstrates for the first time that EPA is neuroprotective in spinal cord trauma. Intravenous administration of EPA 30 min after compression SCI resulted in decreased axonal injury, and increased neuronal and oligodendrocyte survival, in the lesion epicenter. The neuroprotective effect of EPA was also seen rostrally and caudally to the compression site, supporting the idea that EPA reduced the extent of secondary damage. Furthermore, the BBB scores showed a significantly improved
Conflict of interest statement
None of the authors has any conflict of interest related to this study.
Acknowledgement
We gratefully acknowledge support from the Corporate Action Trust, UK and Chang Gung Memorial Hospital, Taiwan (CMRPG360621)
References (32)
- et al.
Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection
Exp. Neurol.
(1996) Cellular morphology of chronic spinal cord injury in the cat: analysis of myelinated axons by line-sampling
Neuroscience
(1983)Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale
Biochimie
(2009)- et al.
Dietary enrichment with omega-3 polyunsaturated fatty acids reverses age-related decreases in the GluR2 and NR2B glutamate receptor subunits in rat forebrain
Neurobiol. Aging
(2007) - et al.
The relationships among the severity of spinal cord injury, residual neurological function, axon counts, and counts of retrogradely labeled neurons after experimental spinal cord injury
Exp. Neurol.
(1995) - et al.
PPAR-alpha modulate the anti-inflammatory effect of glucocorticoids in the secondary damage in experimental spinal cord trauma
Pharmacol. Res.
(2009) - et al.
Pathophysiology and pharmacologic treatment of acute spinal cord injury
Spine J.
(2004) - et al.
Linolenic acid prevents neuronal cell death and paraplegia after transient spinal cord ischemia in rats
J. Vasc. Surg.
(2003) - et al.
Fish oil decreases macrophage tumor necrosis factor gene transcription by altering the NF kappa B activity
J. Surg. Res.
(1999) - et al.
Stimulation by eicosapentaenoic acids of leptin mRNA expression and its secretion in mouse 3T3-L1 adipocytes in vitro
Biochem. Biophys. Res. Commun.
(2000)
Diffusion of docosahexaenoic and eicosapentaenoic acids through the blood–brain barrier: an in situ cerebral perfusion study
Neurochem. Int.
Dietary eicosapentaenoic acid and docosahexaenoic acid equally incorporate as decosahexaenoic acid but differ in inflammatory effects
Nutrition
Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation
J. Immunol.
Function and activation of NF-kappa B in the immune system
Annu. Rev. Immunol.
Traumatic spinal cord injury induces nuclear factor-kappaB activation
J. Neurosci.
Anatomical correlates of return of locomotor function after partial spinal cord lesions in cats
Exp. Brain Res.
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2015, Neurobiology of DiseaseCitation Excerpt :An ideal agent for treatment should protect the spinal cord against the secondary damage, and stimulate or support neurite growth. We have shown previously that long-chain omega-3 PUFAs, such as DHA and EPA, are neuroprotective when administered acutely following SCI in rodents (King et al., 2006; Lim et al., 2010). Acute administration combined with dietary supplementation of DHA for 6 weeks post-SCI led to even better functional outcome and tissue protection (Huang et al., 2007a).