Neural and Behavioural Consequences of Chronic Inflammation following Spinal Cord Injury
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This thesis investigated the influence of chronic inflammation on several neural/behavioural disorders following spinal cord injury (SCI) including depression, cognitive impairment, neuropathic pain, and somatic nerve deficits. Ample evidence exists to suggest that the immune system communicates with, and influences the nervous system both centrally and peripherally. Pro-inflammatory cytokines have been shown to influence the nervous system directly by altering ion channel kinetics, as well as indirectly by altering enzyme function thereby resulting in changes in critical neuroactive compounds. Proinflammatory mediators have been shown to up-regulate the enzyme indoleamine 2,3 dioxygenase (IDO) resulting in the accelerated degredation of serotonin precursor tryptophan (TRP) and increased production of TRP metabolites such as kynurenine (KYN). They have also been shown to upregulate the enzyme cyclooxygenase (COX) resulting in the increased production of pain inducing eicosanoids such as prostaglandin E2 (PGE2). Immune dysfunction in the form of chronic inflammation may therefore contribute to the severity of behavioural disorders such as depression and cognitive impairment, as well as neural disorders such neuropathic pain and somatic nerve deficits. SCI is typically associated with not only a state of chronic inflammation but also a drastically higher prevalence of each of the aforementioned neural and behavioural disorders. This makes SCI an ideal population to study the interaction between the immune and nervous systems, and assess the potential efficacy of novel treatment strategies which target the immune system for the management of such disorders. A 3-month anti-inflammatory diet was utilized as a treatment intervention for the purpose of reducing chronically elevated levels of pro-inflammatory mediators. This intervention allowed for the assessment of each of the outcome variables of interest at baseline (under an elevated inflammatory status) as well as at 1-month and 3-months during the intervention (under a reduced inflammatory state). Changes in inflammation were assessed by the quantification of serum pro (IL-1β, IL-2, IL-6, IFN-У, TNF-α, CRP) and anti-inflammatory (IL-4, IL-10, IL-1RA) cytokines. Cytokine-induced alterations in enzyme function and corresponding changes in neuroactive compounds were assessed by tryptophan (TRP), the competing amino acids phenylalanine (PHE), tyrosine (TYR), leucine (Leu), isoleucine (Ile), and valine (Val), the tryptophan metabolite kynurenine (KYN), and the pain-inducing eicosanoids prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). In addition to such molecular indices, actual changes in each of the outcome variables of interest were assessed. Levels of depression were assessed by questionnaire via the Center for Epidemiological Studies Depression Scale (CES-D). Cognitive function (in the form of verbal learning) and memory was assessed via the California Verbal Learning Test (CVLT). Neuropathic pain was assessed via the Neuropathic Pain Questionnaire (NPQ). Somatic nerve function was assessed by EMG, including the assessment of nerve conduction velocity and signal amplitude in both motor and sensory nerves. The intervention significantly reduced serum concentrations of pro-inflammatory mediators in the treatment group (n=12) by 28%, while no significant change was found in the control group (n=8). Among other changes in amino acids, the most notable was that the change in the KYN/TRP ratio (an indicator of IDO activity) and the TRP/LNAA ratio (an indicator of TRP availability for serotonin synthesis) was significantly different between groups. The treatment group showed a significant reduction in scores of depression, as well as a significant reduction in sensory neuropathic pain scores. No significant changes were observed in regards to somatic nerve conduction and most indices of cognitive function (with the exception of the ability to avoid incorrect responses on the CVLT). These results may suggest a substantial role for chronic inflammation in depression and neuropathic pain following SCI and provide a potential alternative treatment strategy for the management of such intractable disorders.