title: A novel anticonvulsant mechanism via inhibition of complement receptor C5ar1 in murine epilepsy models.
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 (6Hz and corneal kindling) and one chronic seizure model (intrahippocampal kainate model). The effects in the 6Hz 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.
authors: Department of Pharmacology, School of Biomedical Sciences, The University of Queensland, Skerman Building, St Lucia, Queensland 4072, Australia.
authors: Melissa J
authors: MJ
authors: Benson
authors: Department of Pharmacology, School of Biomedical Sciences, The University of Queensland, Skerman Building, St Lucia, Queensland 4072, Australia.
authors: Nicola K
authors: NK
authors: Thomas
authors: Queensland Brain Institute, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors: Sahil
authors: S
authors: Talwar
authors: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors: Mark P
authors: MP
authors: Hodson
authors: Queensland Brain Institute, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors: Joseph W
authors: JW
authors: Lynch
authors: Department of Pharmacology, School of Biomedical Sciences, The University of Queensland, Skerman Building, St Lucia, Queensland 4072, Australia.
authors: Trent M
authors: TM
authors: Woodruff
authors: Department of Pharmacology, School of Biomedical Sciences, The University of Queensland, Skerman Building, St Lucia, Queensland 4072, Australia. Electronic address: k.borges@uq.edu.au.
authors: Karin
authors: K
authors: Borges
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000188:drug therapy*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007608:Kainic Acid; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000032:analysis; D010862:Pilocarpine; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors* / Q000235:genetics; D012640:Seizures / Q000188:drug therapy; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D000927:Anticonvulsants; C000591759:C5ar1 protein, mouse; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D014409:Tumor Necrosis Factor-alpha; D010862:Pilocarpine; D007608:Kainic Acid
keywords: Anticonvulsant; C5a; C5ar1; Complement; Epilepsy; Neurodegeneration; PMX53; Seizure; Status epilepticus