A Single Bolus of Docosahexaenoic Acid Promotes Neuroplastic Changes in the Innervation of Spinal Cord Interneurons and Motor Neurons and Improves Functional Recovery after Spinal Cord Injury

Abstract

Docosahexaenoic acid (DHA) is an -3 polyunsaturated fatty acid that is essential in brain development and has structural and signaling roles. Acute DHA administration is neuroprotective and promotes functional recovery in animal models of adult spinal cord injury (SCI). However, the mechanisms underlying this recovery have not been fully characterized. Here we investigated the effects of an acute intravenous bolus of DHA delivered after SCI and characterized DHA-induced neuroplasticity within the adult injured spinal cord. We found robust sprouting of uninjured corticospinal and serotonergic fibers in a rat cervical hemisection SCI model. A mouse pyramidotomy model was used to confirm that this robust sprouting was not species or injury model specific. Furthermore, we demonstrated that corticospinal fibers sprouting to the denervated side of the cord following pyramidotomy contact V2a interneurons. We also demonstrated increased serotonin fibers and synaptophysin in direct contact with motor neurons. DHA also increased synaptophysin in rat cortical cell cultures. A reduction in phosphatase and tensin homolog (PTEN) has been shown to be involved in axonal regeneration and synaptic plasticity. We showed that DHA significantly upregulates miR-21 and downregulates PTEN in corticospinal neurons. Downregulation of PTEN and upregulation of phosphorylated AKT by DHA were also seen in primary cortical neuron cultures and were accompanied by increased neurite outgrowth. In summary, acute DHA induces anatomical and synaptic plasticity in adult injured spinal cord. This study shows that DHA has therapeutic potential in cervical SCI and provides evidence that DHA could exert its beneficial effects in SCI via enhancement of neuroplasticity.

A nutrient combination designed to enhance synapse formation and function improves outcome in experimental spinal cord injury

“…The lack of correlation may also be due to the fact that some of the improvements seen after intervention are not directly linked to the protection of the spinal cord tissue, but to systemic and/or neuroplasticity effects of the treatment. We have documented recently that even a single intravenous bolus of DHA delivered immediately after a rat cervical hemisection or a mouse pyramidotomy could induce robust sprouting of uninjured corticospinal and serotonergic fibres to the denervated side of the cord, contacting interneurons that are key to locomotor control and coordination, or making direct contacts with motor neurons (Liu et al, 2015). We report here that chronic supplementation with FC modified the biochemical composition of the scar border towards less reactive astrogliosis and decreased levels of inhibitory CSPGs.…”

Specific behavioral and cellular adaptations induced by chronic morphine are reduced by dietary omega-3 polyunsaturated fatty acids

“…A similar effect may be induced by the abused drug itself; methamphetamine induces region-specific changes in brain DHA content [61, 62]. Drugs of abuse also reduce metabolic status, brain lipid microviscosity, alter dendritic spine morphology, and increase neuroinflammation [63–71], changes which supplemental DHA may reverse [72–76]. Supplementary DHA also decreases stress, anxiety and aggression, behaviors often associated with relapse [77–79].…”

Non-coding RNAs and neuroprotection after acute CNS injuries

“…1). The miR-21 was shown to be significantly upregulated in corticospinal neurons following treatment with docosahexaenoic acid in parallel with enhancement of neural plasticity following SCI (Liu et al, 2015e). The increased expression of miR-21 might improve the functional recovery by targeting PTEN that has been linked to SCI pathophysiology (Liu et al, 2015e).…”