Ubiquitin Reduces Contusion Volume after Controlled Cortical Impact Injury in Rats

Abstract

Recent data suggest that ubiquitin has anti-inflammatory properties and therapeutic potential after severe trauma and brain injuries. However, direct evidence for its neuroprotective effects has not yet been provided. We hypothesized that ubiquitin treatment is neuroprotective, and thus reduces brain edema formation and cortical contusion volume after closed traumatic brain injuries. To test this hypothesis, a focal cortical contusion was induced using a controlled cortical impact (CCI) model in Sprague-Dawley rats. Animals (n = 27) were randomized to either 1.5 mg/kg ubiquitin or vehicle (placebo) intravenously within 5 min after CCI. Blood pressure, arterial blood gases (ABG) and intracranial pressure (ICP) were monitored. Ubiquitin serum and cerebrospinal fluid levels were measured by ELISA. Brain water content was quantified gravimetrically after 24 h and cerebral contusion volume was determined in triphenyltetrazolium-chloride stained brains after 7 days. All animals recovered to normal activity. ICP and cerebral perfusion pressures were normal at the end of the observation period. Ubiquitin serum and CSF levels at 24 h and 7 days after CCI were similar in both groups. With ubiquitin brain water content of the injured hemisphere was slightly lower (n = 6/group; 79.97 +/- 0.29% vs. 81.11 +/- 0.52%; p = 0.08). Cortical contusion volume was significantly lower with ubiquitin (n = 7-8/group; 32.88 +/- 2.1 mm(3) vs. 43.96 +/- 4.56 mm(3); p = 0.025). This study shows that ubiquitin treatment after brain injury has direct neuroprotective effects, as demonstrated by improved brain morphology 7 days after brain injury. In connection with its beneficial effects in our previous studies, these data suggest ubiquitin as a promising candidate protein therapeutic for the treatment of brain injuries.

Initial Assessment of the Role of CXC Chemokine Receptor 4 after Polytrauma

“…It also prevented the increase in blood lactate levels that was detectable in animals after vehicle and AMD3100 administration, suggesting that CXCR4 activation with exogenous ubiquitin normalizes impaired tissue metabolism during the shock phase (66)(67)(68)(69). Thus, in combination with the therapeutically relevant effects of SDF-1α, SDF-1α-derived proteins and ubiquitin, which have been reported previously (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), the findings from the present study further point toward CXCR4 as a promising drug target for trauma patients. …”

“…AMD3100 (generic name Plerixafor) was approved by the U.S. Food and Drug Administration to be used in combination with granulocytecolony stimulating factor to mobilize hematopoietic stem cells to the bloodstream in patients with non-Hodgkin lymphoma and multiple myeloma (36). On the basis of available data on the role of endogenous extracellular ubiquitin after trauma in patients (16,17), its inhibitory effects on leukocyte function upon pattern recognition receptor (PRR) activation (16,25,37) and the therapeutically relevant actions of CXCR4 agonists in various animal models (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), we hypothesized that blockade of ligand binding to CXCR4 will enhance proinflammatory responses of leukocytes and result in adverse effects when animals are subjected to severe trauma. Thus, we studied the pathophysiological response to trauma after blockade of CXCR4 with AMD3100 in a large animal model, which was designed to mimic the typical blunt polytrauma patient.…”

“…Although the regulation of SDF-1α levels after trauma and its association with clinical outcomes are largely unknown, administration of SDF-1α and of various SDF-1α mimetic proteins have been shown to result in beneficial effects in models of acute infectious and sterile inflammation in vivo (18)(19)(20)(21)(22). Similarly, treatment with exogenous ubiquitin has been shown to attenuate inflammation and to confer organ protection in animal models, including various models of trauma and hemorrhage (23)(24)(25)(26)(27)(28)(29)(30). Collectively, these studies imply CXCR4 as a promising drug target for trauma patients and suggest that CXCR4 may play an important role during the inflammatory response to tissue injury.…”

Structural Determinants of Ubiquitin-CXC Chemokine Receptor 4 Interaction

“…Administration of the cognate ligand of CXCR4, stromal cell-derived factor-1␣ (SDF-1␣; chemokine (CXC motif) ligand 12) and of ubiquitin has been shown to result in anti-inflammatory and organ protective effects in various disease models (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Despite these similarities, we showed previously that ubiquitin, unlike SDF-1␣, does not reduce HIV-1 infectivity (23).…”

Immunoproteasome in the blood plasma of children with acute appendicitis, and its correlation with proteasome and UCHL1 measured by SPR imaging biosensors

“…This opinion seems not to be in line with data published by Sixt et al [12], indicating that: 'cell damage and haemolysis are the major sources of the increased extracellular ubiquitin concentrations measured under various pathological conditions' [66][67][68][69]. Conversely, Roth et al [64] concluded that because no significantly elevated proteasome concentrations after abdominal surgery and high levels of proteasome are found in patients suffering from trauma and sepsis, the cause of increased levels of 20S proteasome is immunological activity, rather than cellular damage.…”