The acute administration of eicosapentaenoic acid is neuroprotective after spinal cord compression injury in rats.

The aim of the present study was to investigate the effects of treatment with eicosapentaenoic acid (EPA) after spinal cord compression injury in adult rats. Saline or EPA (250 nmol/kg) was administered intravenously 30 min after compression injury. Locomotor recovery was assessed daily using the BBB open-field locomotor score. One week after injury, animals were sacrificed and the spinal cord tissue containing the compression epicenter, and the adjacent rostral and caudal segments, was immunostained using specific markers for neurons, oligodendrocytes, axonal injury, and macrophages/microglia. Administration of EPA resulted in decreased axonal injury and increased neuronal and oligodendrocyte survival, in the lesion epicenter and adjacent tissue. The behavioural assessment mirrored the neuroprotective effects and showed a significantly improved functional recovery in animals treated with EPA compared to the saline-treated controls over the 7-day period. These observations suggest that EPA has neuroprotective properties when administered after spinal cord trauma.

Docosahexaenoic acid prevents white matter damage after spinal cord injury.

We have previously shown that the omega-3 fatty acid docosahexaenoic acid (DHA) significantly improves several histological and behavioral measures after spinal cord injury (SCI). White matter damage plays a key role in neurological outcome following SCI. Therefore, we examined the effects of the acute intravenous (IV) administration of DHA (250 nmol/kg) 30 min after thoracic compression SCI in rats, alone or in combination with a DHA-enriched diet (400 mg/kg/d, administered for 6 weeks post-injury), on white matter pathology. By 1 week post-injury, the acute IV DHA injection led to significantly reduced axonal dysfunction, as indicated by accumulation of ß-amyloid precursor protein (-55% compared to vehicle-injected controls) in the dorsal columns. The loss of cytoskeletal proteins following SCI was also significantly reduced. There were 43% and 73% more axons immunoreactive for non-phosphorylated 200-kD neurofilament in the ventral white matter and ventrolateral white matter, respectively, in animals receiving DHA injections than vehicle-injected rats. The acute DHA treatment also led to a significant improvement in microtubule-associated protein-2 immunoreactivity. By 6 weeks, damage to myelin and serotonergic fibers was also reduced. For some of the parameters measured, the combination of DHA injection and DHA-enriched diet led to greater neuroprotection than DHA injection alone. These findings demonstrate the therapeutic potential of DHA in SCI, and clearly indicate that this fatty acid confers significant protection to the white matter.

Arachidonyl trifluoromethyl ketone is neuroprotective after spinal cord injury.

In spinal cord injury (SCI), neuronal and oligodendroglial loss occurs as a result of the initial trauma and the secondary damage that is triggered by excitotoxicity, free radicals, and inflammation. There is evidence that SCI ellicits increased cytosolic phospholipase A(2) (cPLA(2)) activity. The cleavage of phospholipids by cPLA(2) leads to release of fatty acids, and in particular arachidonic acid (AA), the metabolites of which have been associated with increased inflammation and oxidative stress. The aim of our study was to investigate whether the inhibition of cPLA(2) following SCI leads to tissue protection and an improved functional outcome. Adult rats received compression SCI and 30 min after injury they were treated intravenously with either saline or the cPLA(2) inhibitor arachidonyl trifluoromethyl ketone (AACOCF3) (7.13 mg/kg). The animals were sacrificed at 7 days post-injury and the lesioned tissue was labeled using markers for neurons, oligodendrocytes, and macrophages/activated microglia. We also assessed locomotor recovery using the Basso-Beattie-Bresnahan (BBB) score. The number of surviving neurons and oligodendrocytes was significantly increased in animals treated with the cPLA(2) inhibitor compared to saline controls. The behavioral analysis mirrored the neuroprotective effects and showed that the inhibitor-treated group had better locomotor recovery compared to saline controls. Our results show that AACOCF3 has neuroprotective potential, and support the idea that cPLA(2) is critically involved in acute spinal injury.

Retinoid receptors in chronic degeneration of the spinal cord: observations in a rat model of amyotrophic lateral sclerosis.

Changes in distribution and expression of retinoid receptors may be part of a spinal cord protective response to acute injury and to chronic degeneration. In this study, we have combined RNA and protein expression analysis to characterize the expression profile of retinoid receptors in the lumbar spinal cord of the superoxide dismutase 1 G93A mutant rat model of amyotrophic lateral sclerosis, a fatal neurodegenerative disorder causing extensive motor neuron loss. We also report a nonsignificant change in RNA expression of binding proteins and metabolizing enzymes for retinol and retinoic acid in the mutant rat spinal cord at end-stage disease. Only retinoid X receptor beta (RXRbeta), and to a lesser extent retinoic acid receptor beta and alpha (RARbeta/alpha) were reliably detected in lumbar spinal cord at an early pre-symptomatic phase and throughout the disease progression. The expression of RXRbeta in lamina II neurons in the dorsal horn of transgenic and wild type (WT) animals was associated with extensive astrocyte staining in end-stage lumbar spinal cord from transgenic rats. RARbeta and RARalpha diffuse staining of large motor neurons in the pre-symptomatic transgenic and in the WT lumbar cord appear to decline in end-stage disease, when a selective and strong gamma motor neuron RARalpha staining becomes evident. As gliosis and motor neuron loss are key pathogenic features in amyotrophic lateral sclerosis, the selective expression of retinoid receptors in astrocytes and motor neurons may provide further clues to the role of retinoid signalling in neurodegeneration and suggest new treatment strategies based on retinoid-modulating agents.