Low doses of Perampanel protect striatal and hippocampal neurons against in vitro ischemia by reversing the ischemia-induced alteration of AMPA receptor subunit composition

Mazzocchetti, Petra; Mancini, Andrea; Sciaccaluga, Miriam; Megaro, Alfredo; Bellingacci, Laura; Filippo, Massimiliano Di; Cesarini, Elena Nardi; Romoli, Michele; Carrano, Nicolò; Gardoni, Fabrizio; Tozzi, Alessandro; Calabresi, Paolo; Costa, Cinzia

doi:10.1016/j.nbd.2020.104848

Cited by 20 publications

(18 citation statements)

References 44 publications

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“…Perampanel, an orally active, noncompetitive, selective AMPAR antagonist, has been widely used for the treatment of epilepsy ( 23 ). Previous studies have revealed that AMPAR antagonists are important potential neuroprotective agents in preclinical models of ischemic stroke ( 39 ), spinal cord injury ( 40 ), and traumatic brain injury ( 27 ). However, while these early studies revealed that AMPAR antagonists could minimize brain injury and neuronal death following ICH, the potential molecular mechanisms and consequent effects were not explored.…”

Section: Discussionmentioning

confidence: 99%

Perampanel, an AMPAR antagonist, alleviates experimental intracerebral hemorrhage‑induced brain injury via necroptosis and neuroinflammation

et al. 2021

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Spontaneous intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality and morbidity due to the lack of effective therapies. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist perampanel has been reported to alleviate early brain injury following subarachnoid hemorrhage and traumatic brain injury by reducing reactive oxygen species, apoptosis, autophagy, and necroptosis. Necroptosis is a caspase-independent programmed cell death mechanism that serves a vital role in neuronal cell death following ICH. However, the precise role of necroptosis in perampanel-mediated neuroprotection following ICH has not been confirmed. The present study aimed to investigate the neuroprotective effects and potential molecular mechanisms of perampanel in ICH-induced early brain injury by regulating neural necroptosis in C57BL/6 mice and in a hemin-induced neuron damage cell culture model. Mortality, neurological score, brain water content, and neuronal death were evaluated. The results demonstrated that perampanel treatment increased the survival rate and neurological score, and increased neuron survival. In addition, perampanel treatment downregulated the protein expression levels of receptor interacting serine/threonine kinase (RIP) 1, RIP3, and mixed lineage kinase domain like pseudokinase, and of the cytokines IL-1β, IL-6, TNF-α, and NF-κB. These results indicated that perampanel-mediated inhibition of necroptosis and neuroinflammation ameliorated neuronal death in vitro and in vivo following ICH. The neuroprotective capacity of perampanel was partly dependent on the PTEN pathway. Taken together, the results of the present study demonstrated that perampanel improved neurological outcomes in mice and reduced neuronal death by protecting against neural necroptosis and neuroinflammation.

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Section: Discussionmentioning

confidence: 99%

Perampanel, an AMPAR antagonist, alleviates experimental intracerebral hemorrhage‑induced brain injury via necroptosis and neuroinflammation

et al. 2021

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“…This delayed damage is attributable to a reduction in expression of mRNA encoding the AMPAR subunit GluA2 (Pellegrini-Giampietro et al, 1992), indicating enhancement of CP-AMPARs and increased vulnerability of these neurons. More recently, other groups also found an increase in the prevalence of Ca 2+ -permeable GluA2-lacking AMPARs in hippocampal CA1 neurons after ischemic damage (Quintana et al, 2015;Koszegi et al, 2017;Mazzocchetti et al, 2020).…”

Section: Ischemiamentioning

confidence: 86%

Calcium Permeable-AMPA Receptors and Excitotoxicity in Neurological Disorders

Guo

Yao

2021

Front. Neural Circuits

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Excitotoxicity is one of the primary mechanisms of cell loss in a variety of diseases of the central and peripheral nervous systems. Other than the previously established signaling pathways of excitotoxicity, which depend on the excessive release of glutamate from axon terminals or over-activation of NMDA receptors (NMDARs), Ca2+ influx-triggered excitotoxicity through Ca2+-permeable (CP)-AMPA receptors (AMPARs) is detected in multiple disease models. In this review, both acute brain insults (e.g., brain trauma or spinal cord injury, ischemia) and chronic neurological disorders, including Epilepsy/Seizures, Huntington’s disease (HD), Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), chronic pain, and glaucoma, are discussed regarding the CP-AMPAR-mediated excitotoxicity. Considering the low expression or absence of CP-AMPARs in most cells, specific manipulation of the CP-AMPARs might be a more plausible strategy to delay the onset and progression of pathological alterations with fewer side effects than blocking NMDARs.

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“…LTP are related to activation of inotrophic glutamate receptors, especially activation of NMDA receptors and tra cking of AMPA receptors (Li et al 2019). It is con rmed that GluA1 subunit containing AMPAR aggregation at postsynaptic membrane contributes the maintenance of LTP (Mazzocchetti et al 2020).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that glutamate receptor tra cking is involved in ischemic/reperfusion injury. Mazzocchetti reported that OGD led to increase in hippocampal GluA1 but not GluA2 expression, whereas in U251-MG cells OGD induced degradation of GluA1 and GluA2 AMPAR subunits (Achzet et al 2021;Mazzocchetti et al 2020). As both phosphorylation and postsynaptic tra cking of GluA1 can enhance the glutamate receptor conductance, effects of Egb761, GA, GB and GC on GluA1 Ser831 phosphorylation and protein expression were detected.…”

Section: Cd)mentioning

confidence: 98%

Ginkgo Biloba Extracts Inhibit Ischemic LTP Through Attenuating EPSCs In Rat Hippocampus

Liu

Ding

Luan

et al. 2021

Preprint

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Ginkgo biloba extract 761 (Egb761), a standardized extract from the Ginkgo biloba leaf, is purported to inhibit NMDA receptor-mediated neuronal excitotoxicity and protect neurons form ischemic injury. However, the specific signal pathway involved in the effects of Egb761 on synaptic plasticity is still in dispute. In this article, effects of Egb761 and its monomer component Ginkgolide A (GA), Ginkgolide B (GB) and Ginkgolide C (GC) on rat hippocampal synaptic plasticity were studied. The evoked Excitatory postsynaptic currents (EPSCs) and miniature EPSCs were recorded on hippocampal slices from SD rats (14–21 days of age) by whole-cell patch-clamp recording and long-term potentiation (LTP) was induced by theta-burst stimulation. Acutely applied Egb761 inhibited the LTP, but bilaterally affect the EPSCs, that is EPSC increase at lower concentration of Egb761, then EPSC decrease at higher concentration of Egb761. Egb761 monomer component GA, GB and GC could also inhibit the TBS-induced LTP and EPSC amplitude but not paired-pulse ratio (PPR). Simultaneously, Egb761 and its monomer components inhibited the post-ischemic LTP (i-LTP) by inhibiting the EPSCs and the AMPA receptor subunit GluA1 expression on postsynaptic membrane. The results indicated that high concentration of Egb761 might inhibit LTP and i-LTP through inhibition effects of GA, GB and GC on AMPA receptors.

show abstract

Low doses of Perampanel protect striatal and hippocampal neurons against in vitro ischemia by reversing the ischemia-induced alteration of AMPA receptor subunit composition

Cited by 20 publications

References 44 publications

Perampanel, an AMPAR antagonist, alleviates experimental intracerebral hemorrhage‑induced brain injury via necroptosis and neuroinflammation

Perampanel, an AMPAR antagonist, alleviates experimental intracerebral hemorrhage‑induced brain injury via necroptosis and neuroinflammation

Calcium Permeable-AMPA Receptors and Excitotoxicity in Neurological Disorders

Ginkgo Biloba Extracts Inhibit Ischemic LTP Through Attenuating EPSCs In Rat Hippocampus

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