Complement‐derived anaphylatoxin C5a protects against glutamate‐mediated neurotoxicity

Abstract

Previous work from this laboratory indicates a role for the complement component C5 in neuroprotection against excitotoxicity. In the present study, we tested the hypothesis that the C5-derived anaphylatoxin C5a protects against kainic acid (KA)-induced neurodegeneration and investigated the mechanism of C5a neuronal activity in vitro. Brain intraventricular infusion of KA into adult mice caused neuronal morphological features of apoptosis in the pyramidal layer of the hippocampal formation as indicated by counts of neurons with pyknotic/condensed nuclei associated with cytoplasmic eosinophilia. Co-intraventricular infusion of human recombinant C5a with KA resulted in a marked reduction of morphological features of apoptotic neuronal death. In vitro studies confirmed C5a neuroprotection: treatment of primary murine corticohippocampal neurons with human or mouse recombinant C5a reduced glutamate neurotoxicity, as measured by trypan blue exclusion assay. This protection concurred with inhibition of glutamate-mediated induction of the caspase-3-related cysteine protease and coincided with marked reduction of neurons with morphological features of apoptosis, as found in vivo. Our studies indicate that C5a may inhibit glutamate-mediated neuronal death through partial inhibition of caspase-3 activity. These findings suggest a novel noninflammatory role for C5a in modulating neuronal responses to excitotoxins.

The complement‐derived anaphylatoxin C5a increases microglial GLT‐1 expression and glutamate uptake in a TNF‐α‐independent manner

“…Complement‐derived peptides C3a and C5a have been shown to provide a defence against neurotoxicity both in vivo and in vitro (Pasinetti et al. , 1996; Osaka et al. , 1999; van Beek et al.…”

Differential cytokine expression of human retinal pigment epithelial cells in response to stimulation by C5a

“…Although we identified C5aR on primary cultured RPE cells and showed that C5a induces the generation of several cytokines in this report, there may be other roles that C5a has in the eye. In view of findings that neurons express C5aR [39,40] and a recent report [52] that C5a has a protective effect in glutamate‐mediated neurotoxicity in the brain, it is possible that in addition to being an inducer/regulator of inflammation, it may have a similar role on RPE cells or other C5aR + cells in the eye. Another recent report has shown that C5a is required for hepatocyte regeneration after toxic injury [53].…”

Signaling through C5aR is not involved in basal neurogenesis

“…Both receptors are expressed on several CNS cell types, including microglia, astrocytes, oligodendrocytes, and neurons (Davoust et al, 1999; Nataf et al, 1999, 2001; O'Barr et al, 2001), but the effects of C3a and C5a in the CNS are not fully understood. C5a is neuroprotective against glutamate and β‐amyloid peptide‐mediated toxicity in vitro (Osaka et al, 1999; O'Barr et al, 2001), and C5‐deficient mice show increased neurodegeneration in response to intraventricular injection of kainic acid, another excitotoxin (Pasinetti et al, 1996). C3a has been reported to protect neurons against N‐methyl‐D‐aspartate‐induced toxicity (van Beek et al, 2001) and to induce production of the neutrophin nerve growth factor from human microglial cells in vitro (Heese et al, 1998).…”