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

Benson, Melissa J.; Thomas, Nicola; Talwar, Sahil; Hodson, Mark P.; Lynch, Joseph W.; Woodruff, Trent M.; Borges, Karin

doi:10.1016/j.nbd.2015.02.004

Cited by 58 publications

(68 citation statements)

References 63 publications

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“…This pharmacological evidence has been substantiated by changes in intrinsic seizure susceptibility of transgenic mice with functional alterations in these pathways [52,77,110]. However, differently from acute discrete seizures, interference with the same inflammatory pathways was in general not effective in reducing SE severity or its incidence, with a few notable exceptions.…”

Section: Influence Of Brain and Systemic Inflammation On Status Epileptmentioning

confidence: 99%

Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application

Vezzani

Dingledine

Rossetti

2015

Expert Review of Neurotherapeutics

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Status epilepticus (SE) is a life-threatening neurological emergency often refractory to available treatment options. It is a very heterogeneous condition in terms of clinical presentation and causes, which besides genetic, vascular and other structural causes also include CNS or severe systemic infections, sudden withdrawal from benzodiazepines or anticonvulsants and rare autoimmune etiologies. Treatment of SE is essentially based on expert opinions and antiepileptic drug treatment per se seems to have no major impact on prognosis. There is, therefore, urgent need of novel therapies that rely upon a better understanding of the basic mechanisms underlying this clinical condition. Accumulating evidence in animal models highlights that inflammation ensuing in the brain during SE may play a determinant role in ongoing seizures and their long-term detrimental consequences, independent of an infection or auto-immune cause; this evidence encourages reconsideration of the treatment flow in SE patients.

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Section: Influence Of Brain and Systemic Inflammation On Status Epileptmentioning

confidence: 99%

Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application

Vezzani

Dingledine

Rossetti

2015

Expert Review of Neurotherapeutics

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“…Activation of complement system occurs in animal models of limbic epilepsy (37). Complement 5a receptor 1 (C5aR1) was found to be upregulated in the kainic acid and pilocarpine models of epilepsy, and the C5aR1 antagonist, PMX53, reduced electrographic spontaneous seizures in the kainic acid model, and decreased the severity and mortality associated with pilocarpine-induced SE (40). PMX53 also had anticonvulsant effects in the 6 Hz and corneal kindling models of acute seizures (40).…”

Section: Complement Proteinsmentioning

confidence: 99%

Novel Targets for Developing Antiseizure and, Potentially, Antiepileptogenic Drugs

2017

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Epilepsy is a devastating neurological disorder affecting nearly 65 million people worldwide. The etiology of epilepsy is heterogeneous in nature and a variety of factors-such as infection, stroke, traumatic brain injury, brain tumors, cerebral ischemia, and importantly, mutations in genes that are crucial for the development, migration, and function of neurons and glia-may cause seizures and lead to the development of epilepsy. Over 25 drugs are clinically available for the symptomatic treatment of the seizures that are the defining criteria of epilepsy. However, most of these drugs tend to optimize the balance between excitatory and inhibitory neurotransmission by modulating the functions of ion channels, receptors, enzymes, and transporters expressed by neurons (1). Importantly, around one-third of epilepsy patients are still pharmacoresistant, and many patients who respond to antiseizure drugs (ASDs) often present with significant adverse effects (2). In addition, people with epilepsy also suffer from co-morbidities such as anxiety, depression, and cognitive impairment. Many ASDs either do not address or, in some instances, aggravate these co-morbidities. Therefore, future ASD development efforts should 1) include novel mechanisms of action for ASDs, 2) evaluate potential therapeutic targets for disease modification, and 3) identify potential therapeutic interventions for the prevention of epilepsy. There are several promising targets for developing novel drugs that might prevent or impede epileptogenesis. Some of these novel targets are discussed in this brief review. Transforming Growth Factor β (TGFβ)Sustained damage to the blood brain barrier (BBB) is associated with increased incidence of seizures (3). Animal studies show that the activation of the TGFβ signaling pathway, mainly in astrocytes by albumin extravasated into brain parenchyma following BBB injury, disrupts regulatory functions of astrocytes and causes hyperexcitability in cortical and limbic structures (4). Direct activation of the TGFβ signaling pathway by TGFβ1 also causes epileptiform activity in rats, whereas TGFβ receptor blockers ameliorate TGFβ1-or albumin-induced epileptiform activity (5). Mice overexpressing TGFβ1 specifically in astrocytes develop seizures (6). It was recently found that losartan, which inhibits TGFβ1 signaling, decreased the number of rats developing albumin-induced chronic spontaneous seizures and inhibited epileptogenesis in this vascular injury-induced model of epilepsy (7). It is evident from these animal studies that inhibition of the TGFβ signaling pathway might be an effective strategy to inhibit seizures and epilepto-

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“…61 The concentrations of lupus serum, C5a, and C5aRa were based on the response obtained in our previous studies. 62 Clinical samples were obtained from children attending the paediatric rheumatology clinics at the Women and Children's Hospital of Buffalo.…”

Section: Treatment Of Cellsmentioning

confidence: 99%

C5a induces caspase‐dependent apoptosis in brain vascular endothelial cells in experimental lupus

et al. 2016

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SummaryBlood-brain barrier (BBB) dysfunction complicates central nervous system lupus, an important aspect of systemic lupus erythematosus. To gain insight into the underlying mechanism, vascular corrosion casts of brain were generated from the lupus mouse model, MRL/lpr mice and the MRL/MpJ congenic controls. Scanning electron microscopy of the casts showed loss of vascular endothelial cells in lupus mice compared with controls. Immunostaining revealed a significant increase in caspase 3 expression in the brain vascular endothelial cells, which suggests that apoptosis could be an important mechanism causing cell loss, and thereby loss of BBB integrity. Complement activation occurs in lupus resulting in increased generation of circulating C5a, which caused the endothelial layer to become 'leaky'. In this study, we show that C5a and lupus serum induced apoptosis in cultured human brain microvascular endothelial cells (HBMVECs), whereas selective C5a receptor 1 (C5aR1) antagonist reduced apoptosis in these cells, demonstrating C5a/C5aR1-dependence. Gene expression of initiator caspases, caspase 1 and caspase 8, and proapoptotic proteins death-associated protein kinase 1, Fas-associated protein (FADD), cell death-inducing DNA fragmentation factor 45 000 MW subunit A-like effector B (CIDEB) and BCL2-associated X protein were increased in HBMVECs treated with lupus serum or C5a, indicating that both the intrinsic and extrinsic apoptotic pathways could be critical mediators of brain endothelial cell apoptosis in this setting. Overall, our findings suggest that C5a/C5aR1 signalling induces apoptosis through activation of FADD, caspase 8/3 and CIDEB in brain endothelial cells in lupus. Further elucidation of the underlying apoptotic mechanisms mediating the reduced endothelial cell number is important in establishing the potential therapeutic effectiveness of C5aR1 inhibition that could prevent and/or reduce BBB alterations and preserve the physiological function of BBB in central nervous system lupus.

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

Cited by 58 publications

References 63 publications

Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application

Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application

Novel Targets for Developing Antiseizure and, Potentially, Antiepileptogenic Drugs

C5a induces caspase‐dependent apoptosis in brain vascular endothelial cells in experimental lupus

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