Our model of moderate thoracic contusion injury in female rats was designed to assess possible sex differences in expression of depressive phenotype using a behavioral battery of assessments, because all previous reports of post-SCI depression have been based on male rodents

Our model of moderate thoracic contusion injury in female rats was designed to assess possible sex differences in expression of depressive phenotype using a behavioral battery of assessments, because all previous reports of post-SCI depression have been based on male rodents.7,32,33 We tested for increased TNF in various brain regions that might be correlated with affective disorders such as depression. in the forced swim test. We then tested the efficacy of soluble TNF inhibition with XPro1595 treatment to prevent the depressive phenotype after SCI. Subcutaneous (s.c.) delivery of XPro1595 caused an exacerbation of depressive phenotype, with all treated clusters exhibiting increased forced swim immobility compared with saline-treated non-depressed rats. Intracerebroventricular (i.c.v.) administration of the drug did not prevent or enhance the development of depressive disorder after injury. These results suggest a complex role for TNF-based neuroinflammation in SCI-induced depressive disorder that needs to be further explored, perhaps in conjunction with a broader targeting of additional post-SCI inflammatory cytokines. [DSM-V]). Major depressive disorder (MDD) classically has been attributed to an imbalance of the serotonin system, which includes neurons of the dorsal raphe nucleus (DRN) involved in modulation of many important affective features associated with depression such as attention, working memory, and emotional control (reviewed in Hensler1). In addition to motor, sensory, and autonomic dysfunction, patients with spinal cord injury (SCI) are at three times the risk for MDD compared with the general populace.2 Current antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs) is largely ineffective in this populace and, despite the increased prevalence, there are few clinical guidelines to treat post-SCI depression.2 Comorbidity of depression and SCI has a profound impact on quality of life, even correlating with less functional improvement during rehabilitation.2 Elucidating possible underlying causes of MDD after SCI would allow for a more targeted therapeutic approach in these patients. SCI causes a strong and prolonged inflammatory response that extends well beyond the lesion epicenter.3C5 Evidence of remote, chronic inflammation after SCI has been found in supraspinal brain regions6,7 as well as in distal spinal cord more than 12 segments caudal to the lesion.8 Inflammation has also been implicated in MDD pathology, with frequently elevated levels of pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF) in the serum of patients with major depressive disorder.9C11 TNF signaling elicits a broad and pleiotropic inflammatory response and its inhibition has been effective in treating depression refractory to treatment with Sodium Aescinate SSRIs in a subset of patients demonstrating elevated baseline inflammation.12C14 Direct adminstration of TNF into the lateral cerebral ventricle of rodents can elicit many behaviors that mimic clinical depression, supporting its potential role in the development of MDD and SCI-depression. 15 Sodium Aescinate TNF is present in two biologically active forms, soluble and transmembrane, each with a diverse signaling cascade (reviewed in McCoy and Tansey16). The soluble form of TNF has a higher affinity for TNF receptor subtype 1 (TNFR1) and is more highly associated with pro-inflammatory and apoptotic effects.17C23 Transmembrane TNF has a higher affinity for TNFR2 and is associated with decreased inflammation and increased cell survival and axon remyelination.18,19,24C26 Additionally, TNFR2 is mostly located on immune cells, resulting in increased susceptibility to specific pathogens following global TNF inhibition.18,19,27 XPro1595 is a dominant-negative inhibitor of TNF with affinity for only the soluble form, leaving the neuroprotective functions of transmembrane TNF intact. Systemic administration of XPro1595 Sodium Aescinate has had therapeutic effects in Sodium Aescinate multiple animal models of neuroinflammatory disease, including increased dopaminergic neuron sparing in 6-OHDA induced Parkinson’s disease and increased axon preservation and myelination in experimental autoimmune encephalomyelitis (EAE).28,29 Interestingly, Novrup and colleagues30 exhibited that only local administration of XPro1595 via intrathecal pump Sodium Aescinate was sufficient to increase axonal sparing and locomotor function in a mouse model of SCI and intrathecal XPro1595 administration was shown recently to diminish maladaptive plasticity of the spinal sympathetic reflex circuit associated with Mouse monoclonal antibody to Pyruvate Dehydrogenase. The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzymecomplex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), andprovides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDHcomplex is composed of multiple copies of three enzymatic components: pyruvatedehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase(E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodesthe E1 alpha 1 subunit containing the E1 active site, and plays a key role in the function of thePDH complex. Mutations in this gene are associated with pyruvate dehydrogenase E1-alphadeficiency and X-linked Leigh syndrome. Alternatively spliced transcript variants encodingdifferent isoforms have been found for this gene post-SCI autonomic dysreflexia.31 It was hypothesized that the lack of efficacy with subcutaneous (s.c.) treatment in SCI may be due to the acute release of cytokines by immune cells in the central nervous system (CNS) within hours after injury and a systemic dosing regimen would not have provided an adequate acute level of drug in the spinal cord.30 Given the.