Mechanisms and novel therapies in cervical spinal cord injury.

Abstract

Recent epidemiological data indicate that more than half of SCI patients have injuries of the cervical spine. There is no satisfactory treatment for these injuries either in the acute or the chronic phase. Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid that is essential in brain development and has structural and signalling roles. Acute DHA administration has been shown to improve neurological functional recovery following injury in rodent thoracic spinal cord injury (SCI) animal models. In this thesis, we characterized a cervical SCI model comprising a hemisection lesion applied at the C4-5 level of the rat spinal cord, and tested the effects of an acute treatment with 250 nmol/kg DHA delivered intravenously 30 minutes after injury. The acute intravenous bolus of DHA not only increased the number of neuronal cells spared at three weeks following injury but also resulted in robust sprouting of uninjured corticospinal and serotonergic fibres. Next, we used a mouse pyramidotomy model to confirm that this robust sprouting was not species or injury model specific. We demonstrated that the number of V2a interneurons contacted by collateral corticospinal sprouting fibres is positively correlated with skilled motor recovery. To address the mechanism behind the neuroplasticity-promoting effect of DHA, we investigated the expression of miR-21 and phosphatase and tensin homolog (PTEN) in cortical neurons and raphe nuclei after DHA treatment. We found that DHA significantly up-regulates miR-21 and down-regulates PTEN in corticospinal neurons one day after SCI. Downregulation of PTEN by DHA was also seen in dorsal root ganglion (DRG) neuron 3 cultures and was accompanied by increased neurite outgrowth. Lastly, we investigated whether DHA treatment combined with specific-task rehabilitation maximized the recovery of skilled forelimb function following cervical SCI. The rats receiving combined therapy achieved greater skilled forelimb functional recovery compared to DHA treatment or rehabilitation only. In summary, 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