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Functional deficits and chronic neuropathic pain after peripheral nerve injuries pose major clinical challenges. For preclinical evaluation of novel treatments, reliable methods for assessing functional recovery and robust animal models with high translational potential are crucial. Following peripheral nerve injury reinnervation of denervated target organs is not only achieved by regeneration of the original nerve, but also by collateral sprouting of adjacent intact nerves. In this study motor and sensory recovery was analyzed in a rat model of median nerve injury and repair using distinct functional test. Ten male Wistar rats underwent bilateral median nerve transection. In one forelimb the nerve was repaired using epineurial sutures, while in the contralateral forelimb the nerve remained unrepaired and served as internal control. For 12 weeks post-surgery, the Von Frey Test, the Grasping Test and CatWalk gait analysis were performed weekly. Sensory reinnervation and mechanical allodynia were evaluated with the Von Frey Test in distinct predefined test areas considering the innervation of the forepaws, allowing for indirect assessment of collateral nerve sprouting. Early mechanical allodynia developed within two weeks after median nerve injury in all innervation areas of the forepaw. This was associated with significant alterations of Print Width, Print Area, Duty Cycle, Swing Speed, Swing Time and Stand Index. From week 6 onward late mechanical allodynia paralleled with gait improvements and return of measurable grasping strength on the reconstructed side. The methodology utilized in our study, is feasible to comprehensively assess motor and sensory nerve regeneration paving the way for valid evaluation of future therapeutic strategies in a rat median nerve injury model.

Oxidative modifications of low-density lipoprotein (ox-LDL) play a key role in initial steps of atheroprogression possibly via specific scavenger receptors on inflammatory and endothelial cells. Amongst others, CD68 might play a crucial role in this leading to fatty streak formation. Different CD68-Fc fusion proteins were cloned, expressed and tested in vitro for their oxLDL binding properties as a decoy for endogenous oxLDL. Physiological functions were tested in foam cell assays with human monocytes in culture and by binding oxLDL from human blood. The best suited candidate FcIgG2-FL-CD68 was injected twice weekly in LDL receptor and ApoBec deficient mice (LDLR /Apobec ), and the oxLDL content was measured in peripheral blood, in different cell types of the spleen and aortic wall by specific oxLDL antibodies using flow cytometry. Different variants of the CD68-Fc bound to copper-oxided LDL (oxLDL), LDL and to a lesser extent HDL with different efficacy in an ELISA based binding assay in vitro. Native oxLDL content in human blood derived from patients with extended atherosclerosis was reduced after passage through a specific protein G column conjugated with the different CD68-Fc fusion proteins. Foam cell formation from human peripheral blood monocyte-platelet co-culture was reduced by the most effective CD68-Fc fusion proteins. oxLDL was not increased in the blood but markedly increased in the vessel wall from LDLR /Apobec mice at an early stage of atherosclerosis. Platelet-like cells in the vessel well contributed most to the increase in tissue oxLDL. FcIgG2-FL-CD68, reduced oxLDL content of aortic vessel wall cells from LDLR /Apobec mice. However a tissue specific reduction on the oxLDL content in peripheral blood, the spleen or cells from the aortic vessel by FcIgG2-FL-CD68 could not be shown. Platelets contribute to increased tissue oxLDL in the aortic wall but not in peripheral blood. CD68 seems to play a role in the oxLDL metabolism in the vessel wall at early stages of atherosclerosis. FcIgG2-FL-CD68 could serve as a novel therapeutic option to modify the oxLDL content in the vessel wall.

Platelet activation plays a critical role in thrombosis. Inhibition of platelet activation is a cornerstone in treatment of acute organ ischemia. Platelet ACKR3 surface expression is independently associated with all-cause mortality in CAD patients. In a novel genetic mouse strain, we show that megakaryocyte/platelet-specific deletion of ACKR3 results in enhanced platelet activation and thrombosis in vitro and in vivo. Further, we performed ischemia/reperfusion experiments (transient LAD-ligation and tMCAO) in mice to assess the impact of genetic ACKR3 deficiency in platelets on tissue injury in ischemic myocardium and brain. Loss of platelet ACKR3 enhances tissue injury in ischemic myocardium and brain and aggravates tissue inflammation. Activation of platelet-ACKR3 via specific ACKR3 agonists inhibits platelet activation and thrombus formation and attenuates tissue injury in ischemic myocardium and brain. Here we demonstrate that ACKR3 is a critical regulator of platelet activation, thrombus formation and organ injury following ischemia/reperfusion. ACKR3 is a critical regulator of platelet-mediated thrombosis and organ injury following ischemia/reperfusion. Platelet ACKR3 surface expression is independently associated with all-cause mortality in patients with cardiovascular diseases.