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Frontiers in Systems Neuroscience 2022Although neural plasticity is now widely studied, there was a time when the idea of adult plasticity was antithetical to the mainstream. The essential stumbling block...
Although neural plasticity is now widely studied, there was a time when the idea of adult plasticity was antithetical to the mainstream. The essential stumbling block arose from the seminal experiments of Hubel and Wiesel who presented convincing evidence that there existed a critical period for plasticity during development after which the brain lost its ability to change in accordance to shifts in sensory input. Despite the zeitgeist that mature brain is relatively immutable to change, there were a number of examples of adult neural plasticity emerging in the scientific literature. Interestingly, some of the earliest of these studies involved visual plasticity in the adult cat. Even earlier, there were reports of what appeared to be functional reorganization in adult rat somatosensory thalamus after dorsal column lesions, a finding that was confirmed and extended with additional experimentation. To demonstrate that these findings reflected more than a response to central injury, and to gain greater control of the extent of the sensory loss, peripheral nerve injuries were used that eliminated ascending sensory information while leaving central pathways intact. Merzenich, Kaas, and colleagues used peripheral nerve transections to reveal unambiguous reorganization in primate somatosensory cortex. Moreover, these same researchers showed that this plasticity proceeded in no less than two stages, one immediate, and one more protracted. These findings were confirmed and extended to more expansive cortical deprivations, and further extended to the thalamus and brainstem. There then began a series of experiments to reveal the physiological, morphological and neurochemical mechanisms that permitted this plasticity. Ultimately, Mowery and colleagues conducted a series of experiments that carefully tracked the levels of expression of several subunits of glutamate (AMPA and NMDA) and GABA (GABAA and GABAB) receptor complexes in primate somatosensory cortex at several time points after peripheral nerve injury. These receptor subunit mapping experiments revealed that membrane expression levels came to reflect those seen in early phases of critical period development. This suggested that under conditions of prolonged sensory deprivation the adult cells were returning to critical period like plastic states, i.e., developmental recapitulation. Here we outline the heuristics that drive this phenomenon.
PubMed: 36762289
DOI: 10.3389/fnsys.2022.1086680 -
Brain Sciences Feb 2023Brain tumor-related epilepsy (BTRE) is a common comorbidity in patients with brain neoplasms and it may be either the first symptom or develop after the tumor diagnosis.... (Review)
Review
Brain tumor-related epilepsy (BTRE) is a common comorbidity in patients with brain neoplasms and it may be either the first symptom or develop after the tumor diagnosis. Increasing evidence suggests that brain tumors and BTRE share common pathophysiological mechanisms. Glutamatergic mechanisms can play a central role in promoting both primary brain tumor growth and epileptogenesis. Perampanel (PER), which acts as a selective antagonist of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, may play a role both in the reduction in tumor growth and the control of epileptiform activity. This systematic review aimed to summarize the pre-clinical and clinical evidence about the antitumor properties, antiseizure effects and tolerability of PER in BTRE. Eight pre-clinical and eight clinical studies were identified. The currently available evidence suggests that PER can be an effective and generally well-tolerated therapeutic option in patients with BTRE. In vitro studies demonstrated promising antitumor activity of PER, while no role in slowing tumor progression has been demonstrated in rat models; clinical data on the potential antitumor activity of PER are scarce. Additional studies are needed to explore further the effects of PER on tumor progression and fully characterize its potentialities in patients with BTRE.
PubMed: 36831869
DOI: 10.3390/brainsci13020326 -
Seizure Nov 2022Perampanel a third-generation antiseizure medication, belongs to a new promising class of drugs called AMPA receptor antagonists, approved to treat focal-onset seizures... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Perampanel a third-generation antiseizure medication, belongs to a new promising class of drugs called AMPA receptor antagonists, approved to treat focal-onset seizures with or without focal to bilateral tonic clonic seizures and primary generalized tonic-clonic seizures.
METHODS
This review included RCTs on patients with epilepsy exposed to perampanel compared with placebo, or one or more pre-existing antiseizure medications. Four databases and two clinical trial registries were searched from inception to July 2021. Included outcomes were 50% responder rate, seizure-free rate, discontinuation due to treatment-emergent adverse events (TEAE)s, having any TEAEs, and most reported TEAEs. Cochrane risk of bias tool was used to assess the internal validity of the included RCTs.
RESULTS
From 2211 retrieved citations, eight RCTs were included in the meta-analysis. Fifty-percent responder and seizure freedom rates were significantly higher in patients receiving perampanel when compared to placebo (RR 1.57, 95 % CI 1.35 to 1.82, I 15% and RR 2.79, 95% CI 1.58 to 4.93, I 7%, respectively). The 50% responder rates for 8mg and 12 mg, when compared to placebo, were similar. The most-reported TEAEs were dizziness and somnolence with <1% reporting serious psychological outcomes.
CONCLUSION
This systematic review reports significant reduction in seizures and a potential dose-based increase in discontinuations due to TEAE. The most-reported TEAEs were non-threatening, with the possibility of rare but serious adverse psychological outcomes. Further independent RCTs studying the most efficient dose for efficacy and safety are needed.
Topics: Humans; Anticonvulsants; Treatment Outcome; Pyridones; Seizures; Epilepsy; Drug Therapy, Combination; Randomized Controlled Trials as Topic
PubMed: 36206645
DOI: 10.1016/j.seizure.2022.09.020 -
Schizophrenia Research May 2022While altered expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type receptor has been reported in postmortem studies of schizophrenia, these...
BACKGROUND
While altered expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type receptor has been reported in postmortem studies of schizophrenia, these findings are inconsistent. Therefore, we aimed to systematically review postmortem studies that investigated AMPA receptor expressions in schizophrenia.
METHODS
A systematic literature search was conducted for postmortem studies that measured AMPA receptor subunit expressions or receptor bindings in schizophrenia compared to healthy individuals on February 3, 2021, using Medline and Embase.
RESULTS
A total of 39 relevant articles were identified from 1360 initial reports. The dorsolateral prefrontal cortex (DLPFC) was the most investigated region (15 studies), followed by the medial temporal lobe (8 studies). For the DLPFC, 4/15 studies (26.7%) showed increased AMPA receptor binding or subunit expression in patients with schizophrenia compared to that in controls, especially in GRIA1 and GRIA4, 2/15 studies (13.3%) reported a decrease, particularly in GRIA2, and 8/15 studies (56.7%) found no significant differences. A decreased expression or receptor binding was observed in 6/8 studies (75.0%) in the subregions of the hippocampus in patients with schizophrenia compared to that in controls, whereas the other two studies found no significant differences.
CONCLUSION
Published data have reported decreased subunit expression or receptor binding in the hippocampus in schizophrenia. These findings were inconsistent in other brain regions, which might be due to the heterogeneity of this population, various study design, physiological changes after death, and limited number of studies. Future in vivo studies are warranted to examine AMPA receptor expressions in human brains, together with their comprehensive clinical characterization.
Topics: Gene Expression; Hippocampus; Humans; Receptors, AMPA; Schizophrenia; Temporal Lobe
PubMed: 35247795
DOI: 10.1016/j.schres.2022.02.033 -
Epilepsy & Behavior : E&B Mar 2022Status epilepticus (SE) is a neurological emergency necessitating rapid seizure control to prevent long-term consequences. Perampanel (PER) is a novel selective,... (Review)
Review
BACKGROUND
Status epilepticus (SE) is a neurological emergency necessitating rapid seizure control to prevent long-term consequences. Perampanel (PER) is a novel selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor antagonist that demonstrated efficacy and safety in lithium-pilocarpine models of SE; however, data in humans are limited. This systematic review was performed to assess the efficacy and safety of PER in patients with SE, RSE, and SRSE.
METHODS
We searched MEDLINE (accessed through PubMed), Embase, Scopus, Cochrane Library, and ClinicalTrials.gov from inception until May 30, 2021 to identify all human studies on PER for the treatment of SE of any type and etiology. An additional search was performed on DANS Easy Archive, in which OpenGrey data were stored, from inception until January 10, 2022 and conference proceedings by the International League Against Epilepsy from 2011 onward. The GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach was used to assess the overall certainty of the body of evidence.
RESULTS
Twenty-one studies (7 case reports, 9 case series, and 5 retrospective cohort studies) were included with a total of 369 cases of SE in 368 patients aged 11 months to 99 years, of which 56.2% were female. Seizures of the majority were refractory (n = 220), super refractory SE (n = 70), or either (n = 81) with prominent motor symptoms (n = 284) and are associated with a structural etiology (n = 218). The number of antiseizure medications and/or anesthetics used prior to PER ranged from 1 to 13. PER was administered in 324 cases and was initiated at a dose of 2-36 mg between 30 min to 59 days from SE onset. SE cessation ranged from 1 h to 4 weeks from PER initiation. A total of 119 cases (36.6%) were considered PER responders. According to the GRADE approach, there is very low certainty of evidence for all outcomes.
CONCLUSIONS
The real-world data of PER as a possible therapeutic option in SE of any type are increasing. However, there is very low certainty of evidence for its use and this requires further clinical studies to establish the appropriate timing, dosing, and titration that are efficacious and safe for SE cessation.
Topics: Anticonvulsants; Female; Humans; Infant; Nitriles; Pyridones; Retrospective Studies; Status Epilepticus
PubMed: 35151187
DOI: 10.1016/j.yebeh.2022.108583 -
Pharmacology, Biochemistry, and Behavior Feb 2023Approximately two-thirds of patients with major depressive disorder (MDD) fail to respond to conventional antidepressants, suggesting that additional mechanisms are... (Review)
Review
Approximately two-thirds of patients with major depressive disorder (MDD) fail to respond to conventional antidepressants, suggesting that additional mechanisms are involved in the MDD pathophysiology. In this scenario, the glutamatergic system represents a promising therapeutic target for treatment-resistant depression. To our knowledge, this is the first study using semantic approach with systems biology to identify potential targets involved in the fast-acting antidepressant effects of ketamine and its enantiomers as well as identifying specific targets of (R)-ketamine. We performed a systematic review, followed by a semantic analysis and functional gene enrichment to identify the main biological processes involved in the therapeutic effects of these agents. Protein-protein interaction networks were constructed, and the genes exclusively regulated by (R)-ketamine were explored. We found that the regulation of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) receptor and N-methyl-d-aspartate (NMDA) receptor subunits-Postsynaptic Protein 95 (PSD-95), Brain Derived Neurotrophic Factor (BDNF), and Tyrosine Receptor Kinase B (TrkB) are shared by the three-antidepressant agents, reinforcing the central role of the glutamatergic system and neurogenesis on its therapeutic effects. Differential regulation of Transforming Growth Factor Beta 1 (TGF-β1) receptors-Mitogen-Activated Protein Kinases (MAPK's), Receptor Activator of Nuclear Factor-Kappa Beta Ligand (RANKL), and Serotonin Transporter (SERT) seems to be particularly involved in (R)-ketamine antidepressant effects. Our data helps further studies investigating the relationship between these targets and the mechanisms of (R)-ketamine and searching for other therapeutic compounds that share the regulation of these specific biomolecules. Ultimately, this study could contribute to improve the fast management of depressive-like symptoms with less detrimental side effects than ketamine and (S)-ketamine.
Topics: Humans; Ketamine; Depression; Depressive Disorder, Major; Systems Biology; Antidepressive Agents; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate
PubMed: 36731751
DOI: 10.1016/j.pbb.2023.173523 -
Neuropsychopharmacology Reports Sep 2019Altered trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors has been reported in postmortem studies and suggested the involvement of...
BACKGROUND AND OBJECTIVES
Altered trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors has been reported in postmortem studies and suggested the involvement of AMPA receptors in the pathophysiology underpinning addictive disorders. However, these findings seemed mixed.
METHODS
A systematic literature search was conducted, using PubMed and Embase (last search, August 2018), to identify human postmortem studies that examined the expression of proteins and mRNA of AMPA receptor subunits in patients with addictive disorders in comparison with healthy controls.
RESULTS
Twelve (18 studies) out of 954 articles were identified to be relevant. Eight studies included alcohol use disorders, and four studies included heroin/cocaine abusers. The most frequently investigated regions were the hippocampus (three studies), amygdala (three studies), and putamen (three studies). In summary, two out of the three studies showed an increase in the expression of AMPA receptors in the hippocampus, while the other study found no change. Two studies to examine the amygdala demonstrated either a decreased or no change in receptor expression or binding. Concerning putamen, two studies showed no significant change whereas an overexpression of receptors was observed in the other.
CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE
The hippocampus and amygdala may be pertinent to addictive disorders through their functions on learning and memory, whereas findings in other regions were inconsistent across the studies. Human postmortem studies are prone to degenerative changes after death. Moreover, only qualitative assessment was conducted because of the limited, heterogenous data. These limitations emphasize the need to investigate AMPA receptors in the living human brains.
Topics: Adult; Aged; Amygdala; Autopsy; Female; Hippocampus; Humans; Male; Middle Aged; Protein Binding; Protein Subunits; Putamen; RNA, Messenger; Receptors, AMPA; Substance-Related Disorders
PubMed: 31070872
DOI: 10.1002/npr2.12058 -
Epileptic Disorders : International... Aug 2022Epileptic myoclonus or myoclonic seizures can occur in idiopathic generalized epilepsy (IGE) and progressive myoclonus epilepsy (PME). However, symptomatic myoclonus... (Review)
Review
Epileptic myoclonus or myoclonic seizures can occur in idiopathic generalized epilepsy (IGE) and progressive myoclonus epilepsy (PME). However, symptomatic myoclonus which is stimulus-sensitive and provoked by movement is typically seen in PME and Lance-Adams syndrome. Symptomatic myoclonus is not always associated with epileptiform discharges on the electroencephalogram. Therapeutic interventions such as anti-seizure medications (ASMs), the ketogenic diet and vagus nerve stimulation are not always effective. There is emerging evidence that perampanel (PER), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, may be effective for the treatment of myoclonic seizures and symptomatic myoclonus. We performed a systematic review of the literature to assess the efficacy of PER as treatment for myoclonic seizures and symptomatic myoclonus. Twenty-seven studies with a total sample size of 260 patients were included. The efficacy of PER was analysed separately for myoclonic seizures and symptomatic myoclonus. In the group with myoclonic seizures, 50% responder, 75% responder and seizure freedom rates were reported as 74.3% (101/ 136), 60.3% (82/136) and 57.4% (78/136), respectively, with a follow-up duration of 6-12 months. However, in one post-hoc analysis of data from patients with IGE, the efficacy of PER as treatment for myoclonic seizures during the double-blind phase showed no significant difference compared to placebo. The efficacy of PER for symptomatic myoclonus was reported in a total of 119 patients. Four studies (n=88 patients) reported the efficacy of PER as a decrease in myoclonus score/scale. In the remaining 31 patients, symptomatic myoclonus resolved in three patients, decreased in 21 patients and seven patients showed no improvement. We also analysed the number of patients who were already on levetiracetam (LEV) or valproic acid (VPA) at the time of PER initiation; these data were available for 153 patients. Of these, 56.8% were on LEV and 75.1% were on VPA when PER was initiated. This systematic review suggests that PER maybe effective as treatment for drug-resistant myoclonic seizures and symptomatic myoclonus. It may also be effective in patients who have already failed to respond to LEV and VPA. These findings are preliminary yet encouraging. This study has several limitations, particularly given the scarcity of high-quality randomized controlled trials and marked heterogeneity regarding the type and results of the studies. Hence, the findings of this review should be viewed with considerable reservation.
Topics: Anticonvulsants; Epilepsies, Myoclonic; Epilepsy, Generalized; Humans; Immunoglobulin E; Levetiracetam; Myoclonic Epilepsies, Progressive; Myoclonus; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome; Valproic Acid
PubMed: 35770766
DOI: 10.1684/epd.2022.1439 -
Biomedicines Feb 2023(1) Background: Epilepsy is a frequent comorbidity in patients with brain tumors, in whom seizures are often drug-resistant. Current evidence suggests that excess of... (Review)
Review
(1) Background: Epilepsy is a frequent comorbidity in patients with brain tumors, in whom seizures are often drug-resistant. Current evidence suggests that excess of glutamatergic activity in the tumor microenvironment may favor epileptogenesis, but also tumor growth and invasiveness. The selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel (PER) was demonstrated to be efficacious and well-tolerated in patients with focal seizures. Moreover, preclinical in vitro studies suggested a potential anti-tumor activity of this drug. In this systematic review, the clinical evidence on the efficacy and tolerability of PER in brain tumor-related epilepsy (BTRE) is summarized. (2) Methods: Five databases and two clinical trial registries were searched from inception to December 2022. (3) Results: Seven studies and six clinical trials were included. Sample size ranged from 8 to 36 patients, who received add-on PER (mean dosage from 4 to 7 mg/day) for BTRE. After a 6-12 month follow-up, the responder rate (% of patients achieving seizure freedom or reduction ≥ 50% of seizure frequency) ranged from 75% to 95%, with a seizure freedom rate of up to 94%. Regarding tolerability, 11-52% of patients experienced non-severe adverse effects (most frequent: dizziness, vertigo, anxiety, irritability). The retention rate ranged from 56% to 83%. However, only up to 12.5% of patients discontinued the drug because of the adverse events. (4) Conclusions: PER seems to be efficacious, safe, and well-tolerated in patients with BTRE. Further randomized studies should be conducted in more homogeneous and larger populations, also evaluating the effect of PER on tumor progression, overall survival, and progression-free survival.
PubMed: 36979629
DOI: 10.3390/biomedicines11030651 -
European Neurology 2021Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antibody-related diseases are very rare in autoimmune neurological diseases. We collected and...
Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antibody-related diseases are very rare in autoimmune neurological diseases. We collected and analyzed the data of 3 patients with peculiar clinical manifestation positive for AMPA2-R antibody in the Department of Neurology, Xuanwu Hospital, Capital Medical University. In our reported case series, 2 patients were male and 1 was female. The initial clinical features of 3 patients were all consistent with an encephalopathy predominantly involving the limbic system. Interestingly, as the disease continues to advance, case 1 presented with limb paralysis, case 2 developed typical cerebellar ataxia, and case 3 had symptoms of autonomic instability. These 3 types of clinical features were very rare in patients with AMPAR-Ab. After immunotherapy, cases 1 and 3 responded well and case 2 was not responsive. During the follow-up, residual memory loss of cases 1 and 3 improved gradually, and they returned to work. To eliminate the influence of the presence of other pathogenic antibodies, we analyzed the available individual clinical information of 37 patients with the single AMPAR-Ab by systematic literature review. A majority of patients had sudden short-term memory loss as the initial symptom and developed limbic encephalitis. Residual memory deficit was the most common symptom after discharge. The combination of at least 2 types of immunotherapy was recommended as the first-line treatment, and patients would benefit from the tumor screening. In addition, compared with the patients positive for single AMPAR-Ab, the patients with both AMPAR-Ab and other antibodies had a higher risk of malignant tumor and might have a poor therapeutic response, which led to a poor prognosis.
Topics: Autoantibodies; Female; Humans; Limbic Encephalitis; Male; Receptors, AMPA; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
PubMed: 33857949
DOI: 10.1159/000515592