Traumatic injuries to the nervous system, including the brain and spinal cord, lead to neurological dysfunction depending upon the severity of the injury. Due to the loss of motor (immobility) and sensory function (lack of sensation), spinal cord injury (SCI) and brain injury (TBI) patients may be bed-ridden and immobile for a very long-time. These conditions lead to secondary complications such as bladder/bowel dysfunction, the formation of pressure ulcers (PUs), bacterial infections, etc. PUs are chronic wounds that fail to heal or heal very slowly, may require multiple treatment modalities, and pose a risk to develop further complications, such as sepsis and amputation. This review discusses the role of oxidative stress and reactive oxygen species (ROS) in the formation of PUs in patients with TBI and SCI. Decades of research suggest that ROS may be key players in mediating the formation of PUs. ROS levels are increased due to the accumulation of activated macrophages and neutrophils. Excessive ROS production from these cells overwhelms intrinsic antioxidant mechanisms. While short-term and moderate increases in ROS regulate signal transduction of various bioactive molecules; long-term and excessively elevated ROS can cause secondary tissue damage and further debilitating complications. This review discusses the role of ROS in PU development after SCI and TBI. We also review the completed and ongoing clinical trials in the management of PUs after SCI and TBI using different technologies and treatments, including antioxidants.
Like other conditions affecting the central nervous system, spinal cord injury (SCI) is difficult to treat with molecular therapies because the blood-brain barrier makes intravenous treatments largely ineffective. For example, a synthetic peptide chain derived from the effector domain (ED) of myristoylated alanine-rich C-kinase substrate (MARCKS) has been found to improve functional recovery after SCI in female mice; however, peptides do not always pass the blood-brain barrier and are easily degraded due to natural proteases and are excreted during kidney filtration. Therefore, the ED peptide cannot access the central nervous system to exhibit its effects if administered intravenously. Instead of injecting the ED peptide into the bloodstream, we propose to find compounds that can pass the blood-brain barrier in place of the ED peptide, improving treatment compatibility. To find such alternatives, we screened compound libraries via competitive enzyme-linked immunosorbent assay (ELISA) and identified five potential ED peptide mimetics—compounds that mimic the structure and function of the ED peptide. We then used another competitive ELISA to verify their structural similarity to the peptide. After performing toxicity tests to determine the appropriate concentrations of the mimetics to use in functional assays, we found that all five mimetics trigger a significant increase in neurite length in neurons from female mice, but not male mice, when compared to the vehicle control solution. Although more functional tests are necessary, these results suggest that these mimetics trigger ED peptide functions and may provide a more efficient treatment alternative for SCI.
STUDY DESIGNAnimal studyOBJECTIVESFemale mice deficient in the adhesion molecule CHL1 recovered better than their wild-type female littermates after spinal cord injury (SCI). This observation was unexpected, because CHL1 increases neurite outgrowth in vitro in a homophilic, neuron-dependent manner. Yet, in SCI, CHL1 is upregulated in the glial scar which reduces axonal regrowth, showing that CHL1 on glia can block regrowth of CHL1 positive axons. This notion that was verified in co-cultures of astrocytes and neurons. Since these SCI experiments were confined to females in the previous study, we now sought to assess SCI in CHL1-deficient male mice.SETTINGSW.M. Keck Center for Collaborative Neuroscience at RutgersMETHODSMale CHL1-deficient and wild-type littermate mice received thoracic weight-drop SCI. Locomotor recovery was analyzed weekly by the Basso Mouse Scale and a single frame motion analysis up to six weeks after SCI, when lesion volumes were measured immunohistologically. Hematological analysis was performed at 24 hours after injury.RESULTSCHL1-deficient males did not recover better or worse than their male wild-type littermates. Primary and secondary lesion volumes were similar in the two genotypes under all conditions. In the peripheral blood at 24 h after SCI, leukocyte numbers in mutant males were slightly higher than in wild-type males, but monocyte and lymphocyte numbers did not differ between genders. Neutrophil numbers were higher in males than in females.CONCLUSIONThese results indicate that CHL1-deficient males and females differ in the number of neutrophils slightly in numbers of leukocytes, but not lymphocytes or monocytes.
CHL1 is a close homolog of L1, a cell adhesion molecule that plays major roles in neural and tumor cell functions. We had found that young adult female mice deficient in CHL1 recovered better than their wild-type female littermates after thoracic Spinal Cord Injury (SCI). This observation was surprising, because CHL1 increases neurite outgrowth in vitro. Injury of adult mouse central and peripheral nervous systems upregulate CHL1 expression in neurons and astrocytes, consistent with CHL1’s pro-active, homophilic interaction between CHL1 surface molecules in wild-type mice. After SCI, CHL1 expression was observed to increase in the glial scar, areas of axonal regrowth and remodeling of neural circuits. These observations were made only in females, and we therefore sought to analyze SCI in CHL1-deficient male mice. We now show that CHL1-deficient males did not recover better or worse than their male wild-type littermates. Primary and secondary lesion volumes were similar in the two genotypes, as seen in female mice which were studied in parallel with male mice. Assessment of peripheral leukocytes showed a significant increase in numbers of blood neutrophils at 24 h after SCI in males, but not in females. Lymphocyte numbers in mutant males increased slightly, but numbers of lymphocytes or monocytes did not differ significantly between males or females. These results indicate that CHL1-deficient males and females differ in the number of neutrophils but not lymphocytes or monocytes, suggesting that the difference between males and females is unlikely due to differences in leukocytes.
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