Bioactive lipids as novel therapeutic targets for pain in sickle cell disease

Abstract: Sickle cell disease(SCD) is the world's most lethal genetic blood disorder. The effect of this simple change is catastrophic for those with the disease, many of whom face lifelong debilitating chronic pain and multiple organ damage. However, there is a gap in understanding the molecular mechanisms of changes in SCD RBC lipds composition and their impact in noceceptor pain signaling patway. Previous studies have shown that a high dietary intake of omega-3 fatty acids is negatively associated with the incidence of pain severity in SCD. Omega-3 fatty acids are essential for the normal development and function of the brain. However,the factors associated for the Low levels of DHA in the SCD red blood cells and their impact on neuronal cells and especially pain per option is undetermined. Deficiency of DHA in SCD RBCs may play a major role in the pain and inflammation of sickle cell disease. Low DHA in RBCs and plasma of SCD patients with pain warrant further investigation the impact of mitohondrial ROS-mediated bioactive membrane lipid changes and GABARAPs.Reduction of omega-3 PUFA in SCD mice and patients positively correlated with the levels of hemolysis, ROS, and pain markers. A similar trend was observed in preclinical; RBC DHA levels were modulated for SCD mice. This indicates that in addition to omega-3 PUFA, an abnormal increase of omega-6 PUFA(pro-inflammatory) in SCD mice and patients positively correlates with pain severity. These results indicate that the red blood cell membranes of RBCs of SCD have an imbalance fatty acid composition characterized by a high ratio of pro-inflammatory Omega-6 arachidonic acid (ARA) to anti-inflammatory omega-3 fatty acids of EPA and DHA. These results, therefore, have the potential targets to reduce pain episodes. This novel strategy would open the possibilities of preventive approaches for pain in SCD and other similar severe pain conditions.