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1.
Epilepsia Open ; 8 Suppl 1: S35-S65, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36861477

RESUMO

Status epilepticus (SE) remains a significant cause of morbidity and mortality and often is refractory to standard first-line treatments. A rapid loss of synaptic inhibition and development of pharmacoresistance to benzodiazepines (BZDs) occurs early during SE, while NMDA and AMPA receptor antagonists remain effective treatments after BZDs have failed. Multimodal and subunit-selective receptor trafficking within minutes to an hour of SE involves GABA-A, NMDA, and AMPA receptors and contributes to shifts in the number and subunit composition of surface receptors with differential impacts on the physiology, pharmacology, and strength of GABAergic and glutamatergic currents at synaptic and extrasynaptic sites. During the first hour of SE, synaptic GABA-A receptors containing γ2 subunits move to the cell interior while extrasynaptic GABA-A receptors with δ subunits are preserved. Conversely, NMDA receptors containing N2B subunits are increased at synaptic and extrasynaptic sites, and homomeric GluA1 ("GluA2-lacking") calcium permeant AMPA receptor surface expression also is increased. Molecular mechanisms, largely driven by NMDA receptor or calcium permeant AMPA receptor activation early during circuit hyperactivity, regulate subunit-specific interactions with proteins involved with synaptic scaffolding, adaptin-AP2/clathrin-dependent endocytosis, endoplasmic reticulum (ER) retention, and endosomal recycling. Reviewed here is how SE-induced shifts in receptor subunit composition and surface representation increase the excitatory to inhibitory imbalance that sustains seizures and fuels excitotoxicity contributing to chronic sequela such as "spontaneous recurrent seizures" (SRS). A role for early multimodal therapy is suggested both for treatment of SE and for prevention of long-term comorbidities.


Assuntos
Receptores de GABA-A , Estado Epiléptico , Humanos , Receptores de GABA-A/metabolismo , N-Metilaspartato/efeitos adversos , Receptores de AMPA , Estado Epiléptico/tratamento farmacológico , Convulsões/tratamento farmacológico , Benzodiazepinas/efeitos adversos , Receptores de N-Metil-D-Aspartato/fisiologia , Receptores de N-Metil-D-Aspartato/uso terapêutico
3.
Mol Genet Metab ; 116(1-2): 69-74, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26260077

RESUMO

Enzyme replacement therapy with laronidase (recombinant human alpha-l-iduronidase) is successfully used to treat patients with mucopolysaccharidosis type I (MPS I). However, the intravenously-administered enzyme is not expected to treat or prevent neurological deterioration. As MPS I patients suffer from spinal cord compression due in part to thickened spinal meninges, we undertook a phase I clinical trial of lumbar intrathecal laronidase in MPS I subjects age 8 years and older with symptomatic (primarily cervical) spinal cord compression. The study faced significant challenges, including a heterogeneous patient population, difficulty recruiting subjects despite an international collaborative effort, and an inability to include a placebo-controlled design due to ethical concerns. Nine serious adverse events occurred in the subjects. All subjects reported improvement in symptomatology and showed improved neurological examinations, but objective outcome measures did not demonstrate change. Despite limitations, we demonstrated the safety of this approach to treating neurological disease due to MPS I.


Assuntos
Colo do Útero/patologia , Constrição Patológica/tratamento farmacológico , Iduronidase/efeitos adversos , Mucopolissacaridose I/tratamento farmacológico , Adolescente , Adulto , Colo do Útero/efeitos dos fármacos , Criança , Constrição Patológica/patologia , Feminino , Humanos , Iduronidase/administração & dosagem , Iduronidase/uso terapêutico , Masculino , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Canal Medular/efeitos dos fármacos , Adulto Jovem
4.
Epileptic Disord ; 16 Spec No 1: S69-83, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25323468

RESUMO

Several clinical trials have shown improved seizure control and outcome by early initiation of treatment with benzodiazepines, before arrival in the emergency department and before intravenous access can be established. Here, evidence is provided and reviewed for rapid treatment of acute seizures in order to avoid the development of benzodiazepine pharmacoresistance and the emergence of self-sustaining status epilepticus. Alterations in the physiology, pharmacology, and postsynaptic level of GABA-A receptors can develop within minutes to an hour and hinder the ability of synaptic inhibition to stop seizures while also impairing the efficacy of GABAergic agents, such as benzodiazepines, to boost impaired inhibition. In addition, heightened excitatory transmission further exacerbates the inhibitory/excitatory balance and makes seizure control even more resistant to treatment. The acute increase in the surface expression of NMDA receptors during prolonged seizures also may cause excitotoxic injury, cell death, and other pathological expressions and re-arrangements of receptor subunits that all contribute to long-term sequelae such as cognitive impairment and chronic epilepsy. In conclusion, a short window of opportunity exists when seizures are maximally controlled by first-line benzodiazepine treatment. After that, multiple pathological mechanisms quickly become engaged that make seizures increasingly more difficult to control with high risk for long-term harm.


Assuntos
Anticonvulsivantes/uso terapêutico , Benzodiazepinas/uso terapêutico , Convulsões/tratamento farmacológico , Doença Aguda , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Humanos , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/fisiologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Convulsões/fisiopatologia , Estado Epiléptico/tratamento farmacológico , Fatores de Tempo , Resultado do Tratamento
5.
Epilepsia ; 54 Suppl 6: 78-80, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24001081

RESUMO

We used two models of status epilepticus (SE) to study trafficking of N-methyl-d-aspartate (NMDA) receptors. SE is associated with increased surface expression of NR1 subunits of NMDA receptors, and with an increase of NMDA synaptic and extrasynaptic currents suggesting an increase in number of functional NMDA receptors on dentate granule cells. The therapeutic implications of these results are discussed.


Assuntos
N-Metilaspartato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Estado Epiléptico/terapia , Animais , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Neurônios/metabolismo , Ratos , Estado Epiléptico/metabolismo , Estado Epiléptico/fisiopatologia
6.
Neurobiol Dis ; 54: 225-38, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23313318

RESUMO

After 1h of lithium-pilocarpine status epilepticus (SE), immunocytochemical labeling of NMDA receptor NR1 subunits reveals relocation of subunits from the interior to the cell surface of dentate gyrus granule cells and CA3 pyramidal cells. Simultaneously, an increase in NMDA-miniature excitatory postsynaptic currents (mEPSC) as well as an increase in NMDA receptor-mediated tonic currents is observed in hippocampal slices after SE. Mean-variance analysis of NMDA-mEPSCs estimates that the number of functional postsynaptic NMDA receptors per synapse increases 38% during SE, and antagonism by ifenprodil suggests that an increase in the surface representation of NR2B-containing NMDA receptors is responsible for the augmentation of both the phasic and tonic excitatory currents with SE. These results provide a potential mechanism for an enhancement of glutamatergic excitation that maintains SE and may contribute to excitotoxic injury during SE. Therapies that directly antagonize NMDA receptors may be a useful therapeutic strategy during refractory SE.


Assuntos
Potenciais Pós-Sinápticos Excitadores/fisiologia , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Estado Epiléptico/metabolismo , Animais , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Técnicas de Patch-Clamp , Transporte Proteico , Ratos , Ratos Wistar , Sinapses/metabolismo
7.
Epilepsia ; 52 Suppl 8: 70-1, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21967369

RESUMO

We used a model of severe cholinergic status epilepticus (SE) to study polytherapy aimed at reversing the effects of seizure-induced loss of synaptic GABA(A) receptors and seizure-induced gain of synaptic NMDA receptors. Combinations of a benzodiazepine with ketamine and valproate, or with ketamine and brivaracetam, were more effective and less toxic than benzodiazepine monotherapy in this model of SE.


Assuntos
Anticonvulsivantes/uso terapêutico , Quimioterapia Combinada/métodos , Convulsões/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico , Animais , Modelos Animais de Doenças , Humanos
8.
Epilepsia ; 51 Suppl 3: 106-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20618413

RESUMO

Seizures rapidly become self-sustaining and pharmacoresistant to benzodiazepines during status epilepticus (SE). A decrease in the number of postsynaptic gamma-aminobutyric acid (GABA)(A) receptors with SE causes a loss of synaptic inhibition, whereas increases in postsynaptic glutamatergic receptors further upset the balance between excitation and inhibition. Although extracellular GABA levels may increase during SE and contribute to postsynaptic GABA(A) receptor desensitization, other pathways involving glutamatergic activation ultimately may be responsible for the persistent down-regulation of postsynaptic GABA(A) receptors and erosion of synaptic inhibition.


Assuntos
Ácido Glutâmico/fisiologia , Estado Epiléptico/fisiopatologia , Ácido gama-Aminobutírico/fisiologia , Animais , Modelos Animais de Doenças , Receptores de GABA-A/fisiologia , Receptores de Glutamato/fisiologia , Estado Epiléptico/etiologia , Transmissão Sináptica/fisiologia
10.
J Neurosci ; 25(34): 7724-33, 2005 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-16120773

RESUMO

During status epilepticus (SE), GABAergic mechanisms fail and seizures become self-sustaining and pharmacoresistant. During lithiumpilocarpine-induced SE, our studies of postsynaptic GABA(A) receptors in dentate gyrus granule cells show a reduction in the amplitude of miniature IPSCs (mIPSCs). Anatomical studies show a reduction in the colocalization of the beta2/beta3 and gamma2 subunits of GABA(A) receptors with the presynaptic marker synaptophysin and an increase in the proportion of those subunits in the interior of dentate granule cells and other hippocampal neurons with SE. Unlike synaptic mIPSCs, the amplitude of extrasynaptic GABA(A) tonic currents is augmented during SE. Mathematical modeling suggests that the change of mIPSCs with SE reflects a decrease in the number of functional postsynaptic GABA(A) receptors. It also suggests that increases in extracellular [GABA] during SE can account for the tonic current changes and can affect postsynaptic receptor kinetics with a loss of paired-pulse inhibition. GABA exposure mimics the effects of SE on mIPSC and tonic GABA(A) current amplitudes in granule cells, consistent with the model predictions. These results provide a potential mechanism for the inhibitory loss that characterizes initiation of SE and for the pharmacoresistance to benzodiazepines, as a reduction of available functional GABA(A) postsynaptic receptors. Novel therapies for SE might be directed toward prevention or reversal of these losses.


Assuntos
Inibição Neural/fisiologia , Receptores de GABA-A/metabolismo , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/metabolismo , Animais , Resistência a Medicamentos/fisiologia , Antagonistas GABAérgicos/metabolismo , Antagonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/uso terapêutico , Agonistas de Receptores de GABA-A , Antagonistas de Receptores de GABA-A , Masculino , Inibição Neural/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/fisiologia , Ratos , Ratos Wistar , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologia
11.
Epilepsia ; 46 Suppl 5: 142-7, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15987269

RESUMO

PURPOSE: To study the pharmacologic and synaptic basis for the early loss of paired-pulse inhibition that occurs in the perforant-path stimulation model of status epilepticus. METHODS: Hippocampal slices were prepared from male Wistar rats. Test paired pulses (20- to 50-ms interstimulus interval) of the perforant path were used before and after an abbreviated period of perforant-path stimulation (1-5 min; 2-Hz continuous with 20 Hz of 10 s/min pulses) while either recording field potentials from the dentate gyrus granule cell layer or directly measuring whole-cell patch-clamp currents from granule cells. Paired-pulse field recordings also were obtained during perfusion of the gamma-aminobutyric acid (GABA)(A) antagonist bicuculline. RESULTS: Prolonged loss of paired-pulse inhibition occurs after brief (< 5 min) perforant-path stimulation in vitro (similar to results in vivo) with the paired-pulse population spike amplitude ratio (P2/P1) increasing from a baseline of 0.53 +/- 0.29 to 1.17 +/- 0.09 after perforant-path stimulation (p < 0.05). After perfusion with the GABA(A) antagonist, bicuculline, the P2/P1 ratio also increased from a baseline of 0.52 +/- 0.16 to 1.15 +/- 0.26 (p < 0.05). After 1-2 min of perforant-path stimulation, a 22 +/- 6% (p < 0.05) decrease occurred in the P2/P1 amplitude ratio of paired-pulse evoked inhibitory postsynaptic currents. CONCLUSIONS: Similar to in vivo, loss of paired-pulse inhibition occurs with brief perforant-path stimulation in vitro. GABA(A) antagonism causes a similar loss of paired-pulse inhibition, and the effects of perforant-path stimulation on postsynaptic inhibitory currents also are consistent with the involvement of GABA(A) synaptic receptors. The findings suggest that loss of inhibition at GABA synapses may be an important early event in the initiation of status epilepticus.


Assuntos
Giro Denteado/fisiologia , Inibição Neural/fisiologia , Via Perfurante/fisiologia , Estado Epiléptico/fisiopatologia , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Bicuculina/farmacologia , Giro Denteado/citologia , Modelos Animais de Doenças , Estimulação Elétrica , Antagonistas GABAérgicos/farmacologia , Técnicas In Vitro , Masculino , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/fisiologia , Estado Epiléptico/induzido quimicamente , Transmissão Sináptica/efeitos dos fármacos
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