A novel anticonvulsant mechanism via inhibition of complement receptor C5ar1 in murine epilepsy models

Benson, Melissa J, Thomas, Nicola K, Talwar, Sahil, Hodson, Mark P, Lynch, Joseph W, Woodruff, Trent M and Borges, Karin (2015) A novel anticonvulsant mechanism via inhibition of complement receptor C5ar1 in murine epilepsy models. Neurobiology of Disease, 76 87-97. doi:10.1016/j.nbd.2015.02.004

Author Benson, Melissa J
Thomas, Nicola K
Talwar, Sahil
Hodson, Mark P
Lynch, Joseph W
Woodruff, Trent M
Borges, Karin
Title A novel anticonvulsant mechanism via inhibition of complement receptor C5ar1 in murine epilepsy models
Journal name Neurobiology of Disease   Check publisher's open access policy
ISSN 1095-953X
Publication date 2015-04
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.nbd.2015.02.004
Open Access Status
Volume 76
Start page 87
End page 97
Total pages 11
Place of publication Maryland Heights, United States
Publisher Academic Press Inc.
Collection year 2016
Formatted abstract
The role of complement system-mediated inflammation is of key interest in seizure and epilepsy pathophysiology, but its therapeutic potential has not yet been explored. We observed that the pro-inflammatory C5a receptor, C5ar1, is upregulated in two mouse models after status epilepticus; the pilocarpine model and the intrahippocampal kainate model. The C5ar1 antagonist, PMX53, was used to assess potential anticonvulsant actions of blocking this receptor pathway. PMX53 was found to be anticonvulsant in several acute models (6 Hz and corneal kindling) and one chronic seizure model (intrahippocampal kainate model). The effects in the 6 Hz model were not found in C5ar1-deficient mice, or with an inactive PMX53 analogue suggesting that the anticonvulsant effect of PMX53 is C5ar1-specific. In the pilocarpine model, inhibition or absence of C5ar1 during status epilepticus lessened seizure power and protected hippocampal neurons from degeneration as well as halved SE-associated mortality. C5ar1-deficiency during pilocarpine-induced status epilepticus also was accompanied by attenuation of TNFα upregulation by microglia, suggesting that C5ar1 activation results in TNFα release contributing to disease. Patch clamp studies showed that C5a-induced microglial K+ outward currents were also inhibited with PMX53 providing a potential mechanism to explain acute anticonvulsant effects. In conclusion, our data indicate that C5ar1 activation plays a role in seizure initiation and severity, as well as neuronal degeneration following status epilepticus. The widespread anticonvulsant activity of PMX53 suggests that C5ar1 represents a novel target for improved anti-epileptic drug development which may be beneficial for pharmaco-resistant patients.
Keyword Anticonvulsant
Status epilepticus
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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