Mechanisms and novel therapies in cervical spinal cord injury.
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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
Authors
Liu, Zhuo-HaoCollections
- Theses [3706]