Traumatic brain injury (TBI) has become an increasingly unmet clinical need due to intense military conflicts worldwide. Directly impacted brain cells suffer massive death, with neighboring cells succumbing to progressive neurodegeneration accompanied by inflammatory and other secondary cell death events. Subsequent neurodegenerative events may extend to normal areas beyond the core of injury, thereby exacerbating the central nervous system’s inflammatory response to TBI. Recently CD-36 (cluster of differentiation 36/fatty acid translocase (FAT), a class B scavenger receptor of modified low-density lipoproteins (mLDLs) in macrophages, has been implicated in lipid metabolism, atherosclerosis, oxidative stress, and tissue injury in cerebral ischemia, and in certain neurodegenerative diseases. Accordingly, we proposed that CD-36 has a pivotal role in the neuroinflammatory cascade that further contributes to the pathology of TBI. First, we explored the neuroinflammatory role of CD-36 after acute and chronic stages of TBI. Second, we employed a neuroinflammatory model to test the therapeutic effect of the soluble receptor of advanced end-glycation product (sRAGE); previously shown to abrogate increased CD-36 expression in stroke. Third, we further examined ameliorating TBI related inflammation as a therapeutic pathway by combination of stem cell therapy and sRAGE. At acute stages of TBI, we observed brain co-localization of CD-36, monocyte chemoattractant protein 1 (MCP-1) and ionized calcium-binding adapter molecule 1 (Iba-1) on impacted cortical areas, significant increases of CD-36 and MCP-1 positive cells in the ipsilateral vs. contralateral hemispheres of TBI animals in acute, but no significant increases of Iba-1 expressing cells over time. In early acute stages of TBI immunoblotting showed overexpression of CD-36 in brain cortex when comparing ipsilateral and contralateral hemispheres vs. sham. Spleen CD-36 protein expression at acute post-TBI stages showed no significant difference between TBI and sham groups. In addition, immunohistochemistry revealed minimal CD-36 detection on the cortical area of impact on our chronic group. Spleen immunohistochemistry also showed co-localization of CD-36 and MCP-1 in the red pulp of spleen in acute stages of TBI animals when compared to sham. Ongoing ischemic and hyperlipidemic rodent models suggest that infiltrating monocytes/macrophages from the periphery are the major source of CD-36 in the post-ischemic brain. Likewise, CD-36 expressing monocytes in the spleen after TBI may suggest its role in peripheral immune response, which may exacerbates the inflammatory response after TBI. Therefore, CD-36 may play a key role as a pathological link between inflammation and TBI. Our results suggest an intimate involvement of CD-36 mediated inflammation in TBI, providing novel insights into the understanding of disease neuroinflammation and as a potent therapeutic target for TBI treatment. The critical timing (i.e., 24-48 hours) of CD-36 expression (from downregulation to upregulation) may signal the transition of functional effects of this immune response from pro-survival to cell death. This observed dynamic CD-36 expression also suggests the therapeutic window for TBI. The detection of CD-36 expression in brain areas proximal, as well as distal, to the site of impacted injury suggests its role in both acute and progressive evolution of TBI. CD-36 neuroinflammatory role has clinical relevance for treating patients who have suffered any TBI condition at acute and chronic stages.

Long-chain fatty acids (LCFA) are the primary energy source in the myocardium and an imbalance in the LCFA and glucose utilization could cause cardiovascular diseases. More than 50% of LCFA uptake by the heart is mediated by the fatty acid translocase CD36 and disruption of its function has been shown to impair cardiovascular functions. The spontaneously hypertensive rat (SHR) harbors a deletion variant of the Cd36 gene that results in reduced LCFA transport into myocytes. Therefore, the main aim of this thesis was to investigate the importance of a functional CD36 to sustain normal physiological functions of the heart. We used SHR and two genetic modified SHR strains, the congenic SHR-4 and the transgenic SHR-Cd36, with fully functional CD36. They differ in the CD36 expression and in the manner how they were derived from the SHR. CD36 has been proven to play a role in the pathogenesis of insulin resistance. Therefore we analyzed the effect of a functional CD36 on insulin resistance and protein kinase C (PKC) expression, which is known to be involved in the mechanism of insulin resistance, in the heart of SHR-4 and SHR. We showed that the SHR-4 had lower serum free fatty acids (FFA) and triacylglycerols (TAG) concentrations, indicating improved insulin sensitivity. Furthermore, SHR-4 had increased...