The neuroprotective effect of perampanel in lithium-pilocarpine rat seizure model

Wu, Ting; Ido, Katsutoshi; Osada, Yoshihide; Kotani, Susumu; Tamaoka, Akira; Hanada, Takahisa

doi:10.1016/j.eplepsyres.2017.06.002

Cited by 24 publications

(28 citation statements)

References 54 publications

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“…Perampanel is also approved for monotherapy use for focal seizures in the United States. 18 To our knowledge, this has not been demonstrated in humans with SE. 18 To our knowledge, this has not been demonstrated in humans with SE.…”

Section: Intermsoftheunderlyingpathophysiologysemightarisefrommentioning

confidence: 78%

“…8,15 InEurope,perampanel,aselective,non-competitiveAMPAreceptor antagonist, is indicated as an adjunctive treatment for focal seizures, with or without secondarily generalized seizures, in pa-tientsaged≥12years,andfortheadjunctivetreatmentofprimary generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy aged ≥12years. Studies in the rat lithium-pilocarpine model of SE have suggested that perampanel may have efficacy in terminating prolonged seizures 17,18 while providing neuroprotection, though the level of neuroprotective effects varied by region. Studies in the rat lithium-pilocarpine model of SE have suggested that perampanel may have efficacy in terminating prolonged seizures 17,18 while providing neuroprotection, though the level of neuroprotective effects varied by region.…”

Section: Intermsoftheunderlyingpathophysiologysemightarisefrommentioning

confidence: 99%

“…Perampanel is also approved for monotherapy use for focal seizures in the United States. Studies in the rat lithium-pilocarpine model of SE have suggested that perampanel may have efficacy in terminating prolonged seizures 17,18 while providing neuroprotection, though the level of neuroprotective effects varied by region. 18 To our knowledge, this has not been demonstrated in humans with SE.…”

Section: Intermsoftheunderlyingpathophysiologysemightarisefrommentioning

confidence: 99%

“…Studies in the rat lithium-pilocarpine model of SE have suggested that perampanel may have efficacy in terminating prolonged seizures 17,18 while providing neuroprotection, though the level of neuroprotective effects varied by region. 18 To our knowledge, this has not been demonstrated in humans with SE. Furthermore, modified expres-sionoftheAMPAsubunitsGluA1andGluA2andalteredCa 2+ permeability have been observed in animal models of SE.…”

Section: Intermsoftheunderlyingpathophysiologysemightarisefrommentioning

confidence: 99%

“…perampanel has previously been reported in SE, 20 and intravenous delivery has been achieved in rats. 17,18 Inourcases,nasogastricde- There are few published cases of perampanel treatment of SE. [19][20][21][22] Rohracheretalreportedtreatmentresponsein5/30(16.7%)perampanel-treated patients with RSE and SRSE, of whom two received higher doses (20 and 24 mg); however, decreased bioavailability and late administration may have diminished the potential effects of perampanel.…”

Section: Perampanel Responders (N = 19)mentioning

confidence: 99%

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Perampanel for treatment of status epilepticus in Austria, Finland, Germany, and Spain

et al. 2019

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Objective Novel treatments are needed to control treatment‐resistant status epilepticus (SE). We report a summary of clinical cases where perampanel was used in established SE, refractory SE (RSE), or super‐refractory SE (SRSE). Methods Medical records were retrospectively reviewed for perampanel administration in SE at five European hospitals between 2011 and 2015. Results Of 1319 patients identified as experiencing SE, 52 (3.9%) received perampanel. Median latency from SE onset to perampanel initiation was 10 days. Patients with SE had previously failed benzodiazepines (when received) and a median of five other antiepileptic drugs (AEDs). Median initial perampanel dose was 6 mg/d, up‐titrated to a median maximum dose of 10 mg/d. Perampanel was the last drug added in 32/52 (61.5%) patients, with response attributed to perampanel in 19/52 (36.5%) patients. A greater proportion of perampanel non‐responders had SRSE (51.5%; 17/33) vs perampanel responders (31.6%; 6/19), and had failed a higher mean number of AEDs before initiating perampanel (5.9 vs 5.1, respectively). Most commonly reported adverse effects during perampanel treatment were dizziness (n = 1 [1.9%]) and somnolence (n = 1 [1.9%]). No serious adverse effects were documented, and none led to discontinuation of perampanel. Conclusions Perampanel was administered to patients with established SE, RSE, or SRSE at greater initial doses than those administered in clinical practice to patients with epilepsy. The SE cases reported here represent a refractory and heterogeneous population, and rate of seizure cessation attributed to perampanel treatment (36.5%) represents a notable response. These data should be confirmed in a larger patient population.

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Section: Intermsoftheunderlyingpathophysiologysemightarisefrommentioning

confidence: 78%

Section: Intermsoftheunderlyingpathophysiologysemightarisefrommentioning

confidence: 99%

Section: Intermsoftheunderlyingpathophysiologysemightarisefrommentioning

confidence: 99%

Section: Intermsoftheunderlyingpathophysiologysemightarisefrommentioning

confidence: 99%

Section: Perampanel Responders (N = 19)mentioning

confidence: 99%

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Perampanel for treatment of status epilepticus in Austria, Finland, Germany, and Spain

et al. 2019

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Effects of GABA_B receptor positive allosteric modulator BHF177 and IRS‐1 on apoptosis of hippocampal neurons in rats with refractory epilepsy via the PI3K/Akt pathway

Wang

Nan

Zhang

et al. 2022

Cell Biology International

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The present study was conducted to determine the effects of the γ‐aminobutyric acid B (GABAB) receptor positive allosteric modulator BHF177 on refractory epilepsy (RE). An RE rat model was initially established via treatment with lithium‐pilocarpine. The RE rats were then treated with BHF177 or the GABAB receptor antagonist CGP46381, followed by recording of their seizure rate and assessment of their spatial learning in the Morris water maze test. Treatment of BHF177 reduced the seizure intensity, whereas this effect was revered upoj treatment with CGP46381. Immunohistochemistry revealed that BHF177 treatment diminished P‐glycoprotein (P‐gp) expression in the hippocampal tissues of RE rats. Next, we found that BHF177 activated GABAB receptor, resulting in upregulated expression of insulin receptor substrate 1 (IRS‐1) and PI3K, as well as antiapoptotic factors (Bcl‐2 and mTOR), along with suppression of the apoptosis factors Bax and cleaved caspase‐3 in the hippocampal tissues. Further, activation of GABAB receptors by BHF177 alleviated the inflammatory response in hippocampal tissues of RE rats, as evidenced by reduced VCAM‐1, ICAM‐1, and tumor necrosis factor‐α levels. Next, we treated primary cultured rat hippocampal neurons with BHF177 and the IRS‐1 selective inhibitor NT157. BHF177 inhibited hippocampal apoptosis in rat hippocampal neurons by regulating the IRS‐1/PI3K/Akt axis through crosstalk between GABAB and insulin‐like growth factor‐1 receptors. Collectively, our findings indicate that the BHF177 inhibited neuron apoptosis, thus protecting against RE through the IRS‐1/PI3K/Akt axis, which may present a new therapeutic channel for RE.

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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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The neuroprotective effect of perampanel in lithium-pilocarpine rat seizure model

Abstract: PER exhibited a strong neuroprotective effect in a drug-refractory SE model, and this effect was correlated with its attenuation of seizure.

Cited by 24 publications

References 54 publications

Perampanel for treatment of status epilepticus in Austria, Finland, Germany, and Spain

Perampanel for treatment of status epilepticus in Austria, Finland, Germany, and Spain

Effects of GABA_B receptor positive allosteric modulator BHF177 and IRS‐1 on apoptosis of hippocampal neurons in rats with refractory epilepsy via the PI3K/Akt pathway

Neurodegenerative pathways as targets for acquired epilepsy therapy development

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The neuroprotective effect of perampanel in lithium-pilocarpine rat seizure model

Abstract: PER exhibited a strong neuroprotective effect in a drug-refractory SE model, and this effect was correlated with its attenuation of seizure.

Cited by 24 publications

References 54 publications

Perampanel for treatment of status epilepticus in Austria, Finland, Germany, and Spain

Perampanel for treatment of status epilepticus in Austria, Finland, Germany, and Spain

Effects of GABAB receptor positive allosteric modulator BHF177 and IRS‐1 on apoptosis of hippocampal neurons in rats with refractory epilepsy via the PI3K/Akt pathway

Neurodegenerative pathways as targets for acquired epilepsy therapy development

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Resources

About

Effects of GABA_B receptor positive allosteric modulator BHF177 and IRS‐1 on apoptosis of hippocampal neurons in rats with refractory epilepsy via the PI3K/Akt pathway