Complement anaphylatoxin C5a neuroprotects through regulation of glutamate receptor subunit 2 in vitro and in vivo.
BACKGROUND
The complement system is thought to be involved in the pathogenesis of numerous neurological diseases. We previously reported that pre-treatment of murine cortico-hippocampal neuronal cultures with the complement derived anaphylatoxin C5a, protects against glutamate mediated apoptosis. Our present study with C5a receptor knock out (C5aRKO) mice corroborates that the deficiency of C5a renders C5aRKO mouse more susceptible to apoptotic injury in vivo. In this study we explored potential upstream mechanisms involved in C5a mediated neuroprotection in vivo and in vitro.


METHODS
Based on evidence suggesting that reduced expression of glutamate receptor subunit 2 (GluR2) may influence apoptosis in neurons, we studied the effect of human recombinant C5a on GluR2 expression in response to glutamate neurotoxicity. Glutamate analogs were injected into C5aRKO mice or used to treat in vitro neuronal culture and GluR2 expression were assessed in respect with cell death.


RESULTS
In C5aRKO mice we found that the neurons are more susceptible to excitotoxicity resulting in apoptotic injury in the absence of the C5a receptor compared to WT control mice. Our results suggest that C5a protects against apoptotic pathways in neurons in vitro and in vivo through regulation of GluR2 receptor expression.


CONCLUSIONS
Complement C5a neuroprotects through regulation of GluR2 receptor subunit.
Mukherjee
Piali
P
Department of Psychiatry, Mount Sinai School of Medicine, 1 Gustav L,, Levy Place, New York, NY 10029, USA. pim2001@med.cornell.edu
Thomas
Sunil
S
Pasinetti
Giulio Maria
GM
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D015936:Complement C5a / Q000235:genetics / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018698:Glutamic Acid / Q000633:toxicity; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018091:Receptors, AMPA / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D018690:Excitatory Amino Acid Agonists; D018091:Receptors, AMPA; D011994:Recombinant Proteins; D018698:Glutamic Acid; D015936:Complement C5a; C104722:glutamate receptor ionotropic, AMPA 2; D007608:Kainic Acid