P2X7 receptor antagonism reduces the severity of spontaneous seizures in a chronic model of temporal lobe epilepsy

Amhaoul, Halima; Ali, Idrish; Mola, Marco; Eetveldt, Annemie Van; Szewczyk, Krystyna; Missault, Stephan; Bielen, Kenny; Kumar‐Singh, Samir; Rech, Jason C.; Lord, Brian; Ceusters, Marc; Bhattacharya, Anindya

doi:10.1016/j.neuropharm.2016.01.018

Cited by 55 publications

(54 citation statements)

References 53 publications

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“…Inflammation‐induced dysregulation of Cx GJs not only impacts glutamatergic neurotransmission (Abudara et al, ; Mandolesi et al, ; Schwaller et al, ; Takaki et al, ; Takeuchi et al, ; Toyoda et al, ), but also underlies disorders of excitation, such as epilepsy (Bedner et al, ). However, the role of Cx and Panx HCs in purinergic signaling and excitotoxicity remains conflicted, exhibiting a model‐dependent effect on the result of ionotropic purinergic receptor activation (Amhaoul et al, ; Kim & Kang, ; Thompson et al, ). Furthermore, the contribution of microglial Cxs and Panxs to both homeostatic and disease processes remains largely unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Physiologic seizure resistance was restored in P2X 7 ‐KO mice by inhibition of intracellular Ca 2+ release by the ryanodine receptor antagonist dantrolene (Kim & Kang, ). In contrast, P2X 7 antagonism by JNJ‐42253432 resulted in a less severe seizure profile in the kainate model of epilepsy, with decreased seizure severity, but not frequency, in Sprague‐Dawley rats (Amhaoul et al, ). These studies suggest that purinergic signaling in epilepsy may be complicated by the choice of model and potentially species examined.…”

Section: A Little Too Excited: Connexin and Pannexin Dysregulation Anmentioning

confidence: 99%

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Connexins and pannexins: At the junction of neuro‐glial homeostasis & disease

Lapato

Tiwari‐Woodruff

2017

J of Neuroscience Research

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In the central nervous system (CNS), connexin and pannexin gap junctions and hemichannels are an integral component of homeostatic neuronal excitability and synaptic plasticity. Neuronal connexin (Cx) gap junctions form electrical synapses across biochemically similar GABAergic networks, allowing rapid and extensive inhibition in response to principle neuron excitation. Glial Cx gap junctions link astrocytes and oligodendrocytes in the pan-glial network that is responsible for removing excitotoxic ions and metabolites. In addition, Cx gap junctions between glia help constrain excessive excitatory activity in neurons and facilitate astrocyte Ca2+ slow wave propagation. Pannexins (Panxs) do not form gap junctions in vivo, but Panx hemichannels participate in autocrine and paracrine gliotransmission alongside connexin hemichannels. ATP and other gliotransmitters released by Cx and Panx hemichannels maintain physiologic glutamatergic tone by strengthening synapses and mitigating aberrant high frequency bursting. Under pathological depolarizing and inflammatory conditions, gap junctions and hemichannels become dysregulated, resulting in aberrant neuronal firing and seizure. In this review, we present known contributions of Cxs and Panxs to physiologic neuronal excitation and explore how disruption of gap junctions and hemichannels lead to aberrant glutamatergic transmission, purinergic signaling, and seizures.

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Section: Discussionmentioning

confidence: 99%

Section: A Little Too Excited: Connexin and Pannexin Dysregulation Anmentioning

confidence: 99%

Connexins and pannexins: At the junction of neuro‐glial homeostasis & disease

Lapato

Tiwari‐Woodruff

2017

J of Neuroscience Research

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“…Osmotic pumps with drug or vehicle were implanted beneath the subcutaneous tissue on the back of the rats under isoflurane anesthesia 4 hours after KASE, as described previously. 9 An additional subcutaneous injection of saline or KYP-2047 (loading dose of 17 mg/kg) was administered immediately after pump implantation. The osmotic pumps (Alzet, 2 mL delivery in 2 weeks; Charles River, France) delivered KYP-2047 (34 mg/kg/day) or saline for 2 weeks continuously.…”

Section: Induction Of Se and Pump Implantationmentioning

confidence: 99%

“…Current antiepileptic drugs are only symptomatic and around one-third of patients do not respond to treatment, highlighting the need to explore new therapies. 9,10 Moreover, antiinflammatory approaches during epileptogenesis in animal models of acquired epilepsy can affect seizure development. Brain inflammation is a key mechanism for repair after an insult, and it plays an important role in the pathology of various types of epilepsy.…”

Section: Introductionmentioning

confidence: 99%

“…7,8 It has been shown that there is a positive correlation between the expression of translocator protein (TSPO), a biomarker of neuroinflammation, and seizure burden in a rat model of temporal lobe epilepsy (TLE), emphasizing the role of inflammation in epilepsy. 9,10 Moreover, antiinflammatory approaches during epileptogenesis in animal models of acquired epilepsy can affect seizure development. 2,11,12 Prolyl oligopeptidase (PREP), a proline-specific endooligopeptidase, has been proposed to be involved in neurodegeneration, cell proliferation, differentiation, and neuroinflammation.…”

Section: Introductionmentioning

confidence: 99%

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Spatiotemporal expression and inhibition of prolyl oligopeptidase contradict its involvement in key pathologic mechanisms of kainic acid–induced temporal lobe epilepsy in rats

et al. 2018

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Summary Objective Prolyl oligopeptidase (PREP) has been implicated in neuroinflammatory processes and neuroplasticity and has been suggested as a target for the treatment of neurodegenerative disease. The aim of this investigation was to explore the involvement of PREP in the neuropathologic mechanisms relevant to temporal lobe epilepsy (TLE) using a PREP inhibitor in a well‐established rat model. Methods PREP activity and expression was studied in Sprague‐Dawley rats 2 and 12 weeks following kainic acid–induced status epilepticus (KASE). Continuous video‐electroencephalography monitoring was performed for 2 weeks in the 12‐week cohort to identify a relationship of PREP expression/activity with epileptic seizures. In addition, the animals included in the 2‐week time point were treated with a specific inhibitor of PREP, KYP‐2047, or saline continuously, starting immediately after SE. PREP activity and its expression were analyzed in rat brain by using enzyme kinetics and western blot. In addition, markers for microglial activation, astrogliosis, cell loss, and cell proliferation were evaluated. Results Enzymatic activity of PREP was unchanged following induction of SE after 2 and 12 weeks in rats. PREP activity in epileptic rats did not relate to the number of seizures/day at the 12‐week time point. Moreover, continuous inhibition of PREP for 2 weeks after KASE did not alter the SE‐mediated neuroinflammatory response, cell loss, or cell proliferation in the hippocampal subgranule zone measured at the 2‐week time point. Significance PREP inhibition does not affect key pathologic mechanisms, including activation of glial cells, cell loss, and neural progenitor cell proliferation, in this KASE model of TLE. The results do not support a direct role of PREP in seizure burden during the chronic epilepsy period in this model.

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Neurodegenerative pathways as targets for acquired epilepsy therapy development

2020

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There is a growing body of clinical and experimental evidence that neurodegenerative diseases and epileptogenesis after an acquired brain insult may share common etiological mechanisms. Acquired epilepsy commonly develops as a comorbid condition in patients with neurodegenerative diseases such as Alzheimer's disease, although it is likely much under diagnosed in practice. Progressive neurodegeneration has also been described after traumatic brain injury, stroke, and other forms of brain insults. Moreover, recent evidence has shown that acquired epilepsy is often a progressive disorder that is associated with the development of drug resistance, cognitive decline, and worsening of other neuropsychiatric comorbidities. Therefore, new pharmacological therapies that target neurobiological pathways that underpin neurodegenerative diseases have potential to have both an anti-epileptogenic and diseasemodifying effect on the seizures in patients with acquired epilepsy, and also mitigate the progressive neurocognitive and neuropsychiatric comorbidities. Here, we review the neurodegenerative pathways that are plausible targets for the development of novel therapies that could prevent the development or modify the progression of acquired epilepsy, and the supporting published experimental and clinical evidence. K E Y W O R D SAMPA, amyloid-β, glutamate, mTOR, neuroinflammation, tau

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P2X7 receptor antagonism reduces the severity of spontaneous seizures in a chronic model of temporal lobe epilepsy

Cited by 55 publications

References 53 publications

Connexins and pannexins: At the junction of neuro‐glial homeostasis & disease

Connexins and pannexins: At the junction of neuro‐glial homeostasis & disease

Spatiotemporal expression and inhibition of prolyl oligopeptidase contradict its involvement in key pathologic mechanisms of kainic acid–induced temporal lobe epilepsy in rats

Neurodegenerative pathways as targets for acquired epilepsy therapy development

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