It has been suggested that glial activation not only might be the potential cause of acute, reversible alterations in the mental status, such as delirium, but also may lead to long-term cognitive dysfunction [ 26 ]. In our CLP model, the brain samples of the septic rats showed markedly increased gliosis. By contrast, cerebral apoptosis and gliosis were significantly diminished in parallel in the septic rats treated with IgG and IgGAM. The link between C5a receptor activation and development of apoptosis and gliosis is well known.
Moreover, toxic products released by active glial cells might cause neuronal apoptosis [ 34 ]. IVIg treatment appears to ameliorate septic encephalopathy by interrupting this chain of action. As in our previous experimental trials, we used two different types of immunoglobulin preparations IgG and IgGAM that are available in clinical practice. Both in vivo and in vitro trials in sepsis immunology demonstrated a trend towards a better activity of IgM in comparison to IgG [ 6 ].
Among immunoglobulin types, pure IgM was also shown to be most effective in preventing complement disposition, followed by IgG [ 35 ]. However, both immunoglobulin preparations were equally effective in reversing behavioral deficits induced by sepsis [ 12 ].
Similarly, in the current study, there were no remarkable differences between the clinical and molecular effects of two preparations with the exception that IVIgG treatment exerted a more pronounced and prolonged suppression effect on cerebral C5a receptor expression than IVIgGAM treatment. As usual, animal models might not strictly mimic the human disorder and thus the validity of our results need to be confirmed using postmortem brain tissue and cerebrospinal fluid samples of septic encephalopathy patients.
Another limitation of our study is the absence of mechanistic studies that would more firmly demonstrate the crucial involvement of C5aR-activated intracellular pathways in septic encephalopathy. Numerous C5aR antagonists are currently available and have been tested for treatment of inflammatory disorders [ 36 ]. The efficacy of these molecules needs to be scrutinized using the septic encephalopathy animal model in future studies.
The results of the present study indicate that IVIg treatment exerts its beneficial effects on sepsis-induced neuronal dysfunction primarily through reduction of C5a-mediated gliosis and apoptosis. The exact apoptosis, survival, and inflammation pathways involved in sepsis-induced neuronal dysfunction still remain to be elucidated. Crit Care Clin — Article PubMed Google Scholar. Intensive Care Med — Ann Intensive Care Dis Markers Flierl MA, Stahel PF, Rittirsch D et al Inhibition of complement C5a prevents breakdown of the blood—brain barrier and pituitary dysfunction in experimental sepsis.
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Parasit Vectors Blood — Recent Pat Antiinfect Drug Discov — Download references. FE and MK planned and designed the research.
FE and ET wrote the paper. PEO and FE have also revised the whole manuscript with grammatical checking and technical design. All authors read and approved the final manuscript.
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