BACKGROUND

Perampanel is an antagonist of the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. It is currently FDA-approved to treat focal and generalized tonic-clonic seizures in epilepsy, but recent evidence suggests its potential in treating severe and refractory tremors.

To determine the safety and efficacy of perampanel in treating tremors via a systematic review of existing literature. 

We performed a literature search on five large databases (PubMed, Cochrane, Google Scholar, HERDIN, and Scopus) for clinical studies within the last 10 years and screened a total of 1,539 unique articles for full assessment. We filtered out papers on epilepsy as well as hypokinetic diseases and assessed nine articles for quality assessment and review.

A total of four case reports/series, four open-label trials, and one randomized controlled trial were assessed to be of fair to good quality. All trials showed that low-dose perampanel (2-4 mg/day) was safe and well-tolerated with minor adverse events reported by participants. A net benefit from baseline was observed in patients with essential and primary orthostatic tremors. However, current evidence is weak because the trials employed a non-randomized before-after study design with a small sample size and significant dropout rates.

Low-dose perampanel at 2-4 mg/day shows promising potential in treating refractory tremors and myoclonus in recent clinical studies, but current evidence is weak or anecdotal. Additional randomized controlled trials are needed to determine the conclusive benefit of perampanel for hyperkinesia.

BACKGROUND

Perampanel is an antagonist of the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. It is currently FDA-approved to treat focal and generalized tonic-clonic seizures in epilepsy, but recent evidence suggests its potential in treating severe and refractory tremors.

To determine the safety and efficacy of perampanel in treating tremors via a systematic review of existing literature. 

We performed a literature search on five large databases (PubMed, Cochrane, Google Scholar, HERDIN, and Scopus) for clinical studies within the last 10 years and screened a total of 1,539 unique articles for full assessment. We filtered out papers on epilepsy as well as hypokinetic diseases and assessed nine articles for quality assessment and review.

A total of four case reports/series, four open-label trials, and one randomized controlled trial were assessed to be of fair to good quality. All trials showed that low-dose perampanel (2-4 mg/day) was safe and well-tolerated with minor adverse events reported by participants. A net benefit from baseline was observed in patients with essential and primary orthostatic tremors. However, current evidence is weak because the trials employed a non-randomized before-after study design with a small sample size and significant dropout rates.

Low-dose perampanel at 2-4 mg/day shows promising potential in treating refractory tremors and myoclonus in recent clinical studies, but current evidence is weak or anecdotal. Additional randomized controlled trials are needed to determine the conclusive benefit of perampanel for hyperkinesia.

Epilepsy is a chronic neurological disorder affecting ~65 million individuals worldwide. Abnormal synaptic plasticity is one of the most important pathological features of this condition. We investigated how ubiquitin-specific peptidase 47 (USP47) influences synaptic plasticity and its link to epilepsy. We found that USP47 enhanced excitatory postsynaptic transmission and increased the density of total dendritic spines and the proportion of mature dendritic spines. Furthermore, USP47 inhibited the degradation of the ubiquitinated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit glutamate receptor 1 (GluR1), which is associated with synaptic plasticity. In addition, elevated levels of USP47 were found in epileptic mice, and USP47 knockdown reduced the frequency and duration of seizure-like events and alleviated epileptic seizures. To summarize, we present a new mechanism whereby USP47 regulates excitatory postsynaptic plasticity through the inhibition of ubiquitinated GluR1 degradation. Modulating USP47 may offer a potential approach for controlling seizures and modifying disease progression in future therapeutic strategies.
Animals ; Receptors, AMPA/metabolism* ; Neuronal Plasticity/physiology* ; Seizures/physiopathology* ; Disease Models, Animal ; Mice, Inbred C57BL ; Mice ; Ubiquitin Thiolesterase/genetics* ; Male ; Excitatory Postsynaptic Potentials/physiology* ; Ubiquitination ; Dendritic Spines/metabolism* ; Hippocampus/metabolism*

Neuropathic pain is frequently comorbidity with cognitive deficits. Neuralized1 (Neurl1)-mediated ubiquitination of CPEB3 in the hippocampus is critical in learning and memory. However, the role of Neurl1 in the cognitive impairment in neuropathic pain remains elusive. Herein, we found that lumbar 5 spinal nerve ligation (SNL) in male rat-induced neuropathic pain was followed by learning and memory deficits and LTP impairment in the hippocampus. The Neurl1 expression in the hippocampal CA1 was decreased after SNL. And this decrease paralleled the reduction of ubiquitinated-CPEB3 level and reduced production of GluA1 and GluA2. Overexpression of Neurl1 in the CA1 rescued cognitive deficits and LTP impairment, and reversed the reduction of ubiquitinated-CPEB3 level and the decrease of GluA1 and GluA2 production following SNL. Specific knockdown of Neurl1 or CPEB3 in bilateral hippocampal CA1 in naïve rats resulted in cognitive deficits and impairment of synaptic plasticity. The rescued cognitive function and synaptic plasticity by the treatment of overexpression of Neurl1 before SNL were counteracted by the knockdown of CPEB3 in the CA1. Collectively, the above results suggest that the downregulation of Neurl1 through reducing CPEB3 ubiquitination and, in turn, repressing GluA1 and GluA2 production and mediating synaptic plasticity impairment in hippocampal CA1 leads to the genesis of cognitive deficits in neuropathic pain.
Animals ; Male ; Neuralgia/metabolism* ; Rats ; Down-Regulation/physiology* ; Ubiquitination/physiology* ; Neuronal Plasticity/physiology* ; Rats, Sprague-Dawley ; CA1 Region, Hippocampal/metabolism* ; Cognitive Dysfunction/metabolism* ; RNA-Binding Proteins/metabolism* ; Receptors, AMPA/metabolism*

The CC chemokine ligand 2 (CCL2, also known as MCP-1) and its cognate receptor CCR2 have well-characterized roles in chemotaxis. CCL2 has been previously shown to promote excitatory synaptic transmission and neuronal excitability. However, the detailed molecular mechanism underlying this process remains largely unclear. In cultured hippocampal neurons, CCL2 application rapidly upregulated surface expression of GluA1, in a CCR2-dependent manner, assayed using SEP-GluA1 live imaging, surface GluA1 antibody staining, and electrophysiology. Using pharmacology and reporter assays, we further showed that CCL2 upregulated surface GluA1 expression primarily via Gα_q- and CaMKII-dependent signaling. Consistently, using i.p. injection of lipopolysaccharide to induce neuroinflammation, we found upregulated phosphorylation of S831 and S845 sites on AMPA receptor subunit GluA1 in the hippocampus, an effect blocked in Ccr2^-/- mice. Together, these results provide a mechanism through which CCL2, and other secreted molecules that signal through G-protein coupled receptors, can directly regulate synaptic transmission.
Animals ; Receptors, AMPA/metabolism* ; Chemokine CCL2/metabolism* ; Hippocampus/drug effects* ; Neurons/drug effects* ; Synaptic Transmission/drug effects* ; Mice ; Receptors, CCR2/metabolism* ; Protein Transport/drug effects* ; Mice, Inbred C57BL ; Cells, Cultured ; Mice, Knockout ; Excitatory Postsynaptic Potentials/drug effects* ; Rats

The purpose of this study was to investigate the effect of glutamate and its ionotropic receptor agonists on the response to acute hypoxia in rat carotid body in vitro. Briefly, after SD rats were anesthetized and decapitated, the bilateral carotid bifurcations were rapidly isolated. Then bifurcation was placed into a recording chamber perfused with 95% O₂-5% CO₂ saturated Kreb's solution. The carotid body-sinus nerve complex was dissected, and the carotid sinus nerve discharge was recorded using a suction electrode. To detect the response of carotid body to acute hypoxia, the chamber was perfused with 5% O₂-5% CO₂-90% N₂ saturated Kreb's solution for a period of 100 s at an interval of 15 min. To observe the effect of glutamate, ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor agonist AMPA or N-methyl-D-aspartate (NMDA) receptor agonist NMDA on the response to acute hypoxia in rat carotid body, the chamber was perfused with 5% O₂-5% CO₂-90% N₂ saturated Kreb's solution containing the corresponding reagent. The results showed that glutamate (20 μmol/L), AMPA (5 μmol/L) or NMDA (10 μmol/L) inhibited the acute hypoxia-induced enhancement of carotid sinus nerve activity, and these inhibitory effects were dose-dependent. In summary, the activation of glutamate ionotropic receptors appears to exert an inhibitory effect on the response to acute hypoxia in carotid body of rats.
Rats ; Animals ; Glutamic Acid/pharmacology* ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology* ; N-Methylaspartate/pharmacology* ; Carotid Body ; Rats, Sprague-Dawley ; Carbon Dioxide ; Receptors, N-Methyl-D-Aspartate ; Receptors, AMPA ; Hypoxia

Post-traumatic stress disorder (PTSD) has been reported to be associated with a higher risk of cardiovascular disease. The amygdala may have an important role in regulating cardiovascular function. This study aims to explore the effect of amygdala glutamate receptors (GluRs) on cardiovascular activity in a rat model of PTSD. A compound stress method combining electrical stimulation and single prolonged stress was used to prepare the PTSD model, and the difference of weight gain before and after modeling and the elevated plus maze were used to assess the PTSD model. In addition, the distribution of retrogradely labeled neurons was observed using the FluoroGold (FG) retrograde tracking technique. Western blot was used to analyze the changes of amygdala GluRs content. To further investigate the effects, artificial cerebrospinal fluid (ACSF), non-selective GluR blocker kynurenic acid (KYN) and AMPA receptor blocker CNQX were microinjected into the central nucleus of the amygdala (CeA) in the PTSD rats, respectively. The changes in various indices following the injection were observed using in vivo multi-channel synchronous recording technology. The results indicated that, compared with the control group, the PTSD group exhibited significantly lower weight gain (P < 0.01) and significantly decreased ratio of open arm time (OT%) (P < 0.05). Retrograde labeling of neurons was observed in the CeA after microinjection of 0.5 µL FG in the rostral ventrolateral medulla (RVLM). The content of AMPA receptor in the PTSD group was lower than that in the control group (P < 0.05), while there was no significant differences in RVLM neuron firing frequency and heart rate (P > 0.05) following ACSF injection. However, increases in RVLM neuron firing frequency and heart rate were observed after the injection of KYN or CNQX into the CeA (P < 0.05) in the PTSD group. These findings suggest that AMPA receptors in the amygdala are engaged in the regulation of cardiovascular activity in PTSD rats, possibly by acting on inhibitory pathways.
Rats ; Animals ; Rats, Sprague-Dawley ; Stress Disorders, Post-Traumatic ; Receptors, AMPA ; 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology* ; Receptors, Glutamate/metabolism* ; Amygdala ; Weight Gain ; Medulla Oblongata/physiology* ; Blood Pressure

Mutations in genes encoding amyloid precursor protein (APP) and presenilins (PSs) cause familial forms of Alzheimer's disease (AD), a neurodegenerative disorder strongly associated with aging. It is currently unknown whether and how AD risks affect early brain development, and to what extent subtle synaptic pathology may occur prior to overt hallmark AD pathology. Transgenic mutant APP/PS1 over-expression mouse lines are key tools for studying the molecular mechanisms of AD pathogenesis. Among these lines, the 5XFAD mice rapidly develop key features of AD pathology and have proven utility in studying amyloid plaque formation and amyloid β (Aβ)-induced neurodegeneration. We reasoned that transgenic mutant APP/PS1 over-expression in 5XFAD mice may lead to neurodevelopmental defects in early cortical neurons, and performed detailed synaptic physiological characterization of layer 5 (L5) neurons from the prefrontal cortex (PFC) of 5XFAD and wild-type littermate controls. L5 PFC neurons from 5XFAD mice show early APP/Aβ immunolabeling. Whole-cell patch-clamp recording at an early post-weaning age (P22-30) revealed functional impairments; although 5XFAD PFC-L5 neurons exhibited similar membrane properties, they were intrinsically less excitable. In addition, these neurons received smaller amplitude and frequency of miniature excitatory synaptic inputs. These functional disturbances were further corroborated by decreased dendritic spine density and spine head volumes that indicated impaired synapse maturation. Slice biotinylation followed by Western blot analysis of PFC-L5 tissue revealed that 5XFAD mice showed reduced synaptic AMPA receptor subunit GluA1 and decreased synaptic NMDA receptor subunit GluN2A. Consistent with this, patch-clamp recording of the evoked L23>L5 synaptic responses revealed a reduced AMPA/NMDA receptor current ratio, and an increased level of AMPAR-lacking silent synapses. These results suggest that transgenic mutant forms of APP/PS1 overexpression in 5XFAD mice leads to early developmental defects of cortical circuits, which could contribute to the age-dependent synaptic pathology and neurodegeneration later in life.
Mice ; Animals ; Alzheimer Disease/pathology* ; Amyloid beta-Peptides/metabolism* ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Amyloid beta-Protein Precursor/metabolism* ; Mice, Transgenic ; Neurons/metabolism* ; Receptors, AMPA/metabolism* ; Disease Models, Animal

CaMKII is essential for long-term potentiation (LTP), a process in which synaptic strength is increased following the acquisition of information. Among the four CaMKII isoforms, γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons (LTP_E→I). However, the molecular mechanism underlying how γCaMKII mediates LTP_E→I remains unclear. Here, we show that γCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10-30 Hz range. Following stimulation, γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95. Knocking down γCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors (AMPARs) in putative inhibitory interneurons, which are restored by overexpression of γCaMKII but not its kinase-dead form. Taken together, these data suggest that γCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.
Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism* ; Hippocampus/metabolism* ; Interneurons/physiology* ; Long-Term Potentiation/physiology* ; N-Methylaspartate/metabolism* ; Receptors, AMPA/physiology* ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Synapses/physiology*

OBJECTIVE: To explore the influence of electroacupuncture (EA) on the expression of AMPA receptor subunit GluR1 in the rats with acute spinal cord injury (SCI) and explore the potential effect mechanism of EA in treatment of acute SCI. METHODS: A total of 80 SD rats were randomly divided into five groups, i.e. a sham-operation group, a model group, an AMPA antagonist (DNQX) group, an EA group and a DNQX+EA group, 16 rats in each group. The modified Allen's impacting method was adopted to prepare the rat model of acute SCI at T RESULTS: Compared to the sham-operation group in 6 h, 24 h and 48 h after modeling, the BBB scores were all significantly decreased in the model group ( CONCLUSION The intervention with EA at "Dazhui" and "Mingmen" promotes the repair of the injured nerve in the spinal anterior horn probably through inhibiting GluR1 expression in the spinal injured area in the rats with acute SCI.
Animals ; Electroacupuncture ; Rats ; Rats, Sprague-Dawley ; Receptors, AMPA/genetics* ; Spinal Cord ; Spinal Cord Injuries/therapy*