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1.
Theranostics ; 14(14): 5551-5570, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39310099

RESUMEN

Rationale: Epilepsy affects over 70 million people globally, with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) often progressing to a drug-resistant state. Recent research has highlighted the role of reactive astrocytes and glutamate dysregulation in epilepsy pathophysiology. This study aims to investigate the involvement of astrocytic xCT, a glutamate-cystine antiporter, and its regulation by the m6A reader protein YTHDC2 in TLE-HS. Methods: A pilocarpine-induced epilepsy model in mice was used to study the role of xCT in reactive astrocytes. The expression of xCT and its regulation by YTHDC2 were assessed through various molecular and cellular techniques. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to measure mRNA and protein levels of xCT and YTHDC2, respectively; immunofluorescence was utilized to visualize their localization and expression in astrocytes. In vivo glutamate measurements were conducted using microdialysis to monitor extracellular glutamate levels in the hippocampus. RNA immunoprecipitation-qPCR (RIP-qPCR) was performed to investigate the binding of YTHDC2 to SLC7A11 mRNA, while methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) was performed to quantify m6A modifications on SLC7A11 mRNA. A dual-luciferase reporter assay was conducted to assess the effect of m6A modifications on SLC7A11 mRNA translation, and polysome profiling was employed to evaluate the translational efficiency of SLC7A11 mRNA. Inhibition experiments involved shRNA-mediated knockdown of SLC7A11 (commonly known as xCT) and YTHDC2 expression in astrocytes. Video-electroencephalogram (EEG) recordings were used to monitor seizure activity in mice. Results: The xCT transporter in reactive astrocytes significantly contributes to elevated extracellular glutamate levels, enhancing neuronal excitability and seizure activity. Increased xCT expression is influenced by the m6A reader protein YTHDC2, which regulates its expression through m6A methylation. Inhibition of xCT or YTHDC2 in astrocytes reduces glutamate levels and effectively controls seizures in a mouse model. Specifically, mice with SLC7A11- or YTHDC2-knockdown astrocytes showed decreased glutamate concentration in the hippocampus and reduced frequency and duration of epileptic seizures. Conclusions: This study highlights the therapeutic potential of targeting YTHDC2 and xCT in reactive astrocytes to mitigate epilepsy. The findings provide a novel perspective on the mechanisms of glutamate dysregulation and their implications in seizure pathophysiology, suggesting that modulation of YTHDC2 and xCT could be a promising strategy for treating TLE.


Asunto(s)
Sistema de Transporte de Aminoácidos y+ , Astrocitos , Modelos Animales de Enfermedad , Epilepsia del Lóbulo Temporal , Ácido Glutámico , Animales , Astrocitos/metabolismo , Epilepsia del Lóbulo Temporal/metabolismo , Epilepsia del Lóbulo Temporal/genética , Epilepsia del Lóbulo Temporal/fisiopatología , Ratones , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Ácido Glutámico/metabolismo , Masculino , Hipocampo/metabolismo , Pilocarpina , Ratones Endogámicos C57BL , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Humanos
2.
Epilepsy Behav ; 159: 110027, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39217756

RESUMEN

Cell replacement therapies using medial ganglionic eminence (MGE)-derived GABAergic precursors reduce seizures by restoring inhibition in animal models of epilepsy. However, how MGE-derived cells affect abnormal neuronal networks and consequently brain oscillations to reduce ictogenesis is still under investigation. We performed quantitative analysis of pre-ictal local field potentials (LFP) of cortical and hippocampal CA1 areas recorded in vivo in the pilocarpine rat model of epilepsy, with or without intrahippocampal MGE-precursor grafts (PILO and PILO+MGE groups, respectively). The PILO+MGE animals had a significant reduction in the number of seizures. The quantitative analysis of pre-ictal LFP showed decreased power of cortical and hippocampal delta, theta and beta oscillations from the 5 min. interictal baseline to the 20 s. pre-ictal period in both groups. However, PILO+MGE animals had higher power of slow and fast oscillations in the cortex and lower power of slow and fast oscillations in the hippocampus compared to the PILO group. Additionally, PILO+MGE animals exhibited decreased cortico-hippocampal synchrony for theta and gamma oscillations at seizure onset and lower hippocampal CA1 synchrony between delta and theta with slow gamma oscillations compared to PILO animals. These findings suggest that MGE-derived cell integration into the abnormally rewired network may help control ictogenesis.


Asunto(s)
Corteza Cerebral , Modelos Animales de Enfermedad , Epilepsia , Hipocampo , Pilocarpina , Animales , Pilocarpina/toxicidad , Hipocampo/fisiopatología , Masculino , Corteza Cerebral/fisiopatología , Epilepsia/inducido químicamente , Epilepsia/fisiopatología , Ratas , Ondas Encefálicas/fisiología , Ratas Wistar , Electroencefalografía , Eminencia Ganglionar
3.
Epilepsy Behav ; 159: 110028, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39217758

RESUMEN

BACKGROUND: Aprepitant (APR), a neurokinin 1 receptor antagonist, is an approved drug for treating chemotherapy-induced nausea and vomiting. OBJECTIVES: Investigate the beneficial roles of APR alone or in combination with sodium valproate (VPA) against lithium pilocarpine [li-pilo]-induced seizures, behavioral changes, and cognitive deficits. METHODS: Thirty male mice were divided into five groups, each containing 6. "Vehicle Group I," "Control Group II "li-pilo, " Valproate (VPA) group III (400 mg/kg/i.p.), "APR group IV, " and "Combination Group V." Videos of mice were recorded, and they were watched for episodes of spontaneous recurring seizures (SRS). Behavioral Tests were performed. At the end of the study, animal brains were taken for biochemical assays and gene expression studies. RESULTS: APR partially protected against SRS with partial restoration of average behavioral and standard cognitive skills associated with a significant increase in brain SOD activity and a significant decrease in MDA, IL-1ß, NF-КB, and SP-3 levels in relation to the control group. Interestingly, a combination of APR with VPA in epileptic mice showed complete protection against li-pilo-induced behavioral changes and cognitive deficits, a significant increase in brain SOD activity, and a considerable decrease in MDA, IL-1ß, NF-ΚB, and SP levels to normal. CONCLUSION: Using APR as an adjuvant to VPA is more effective in protecting against li-pilo-induced seizures, behavioral changes, and cognitive deficits due to its antioxidant, anti-inflammatory, and NK1 antagonist effects than using APR alone as drug therapy.


Asunto(s)
Anticonvulsivantes , Aprepitant , Modelos Animales de Enfermedad , Epilepsia , Pilocarpina , Convulsiones , Ácido Valproico , Animales , Masculino , Aprepitant/farmacología , Ratones , Ácido Valproico/farmacología , Anticonvulsivantes/farmacología , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Epilepsia/tratamiento farmacológico , Epilepsia/inducido químicamente , Pilocarpina/toxicidad , Morfolinas/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Aprendizaje por Laberinto/efectos de los fármacos , Superóxido Dismutasa/metabolismo
4.
Synapse ; 78(5): e22309, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39285628

RESUMEN

After seizures, the hyperactivation of extracellular signal-regulated kinases (ERK1/2) causes mitochondrial dysfunction. Through the guidance of dynamin-related protein 1 (DRP1), ERK1/2 plays a role in the pathogenesis of several illnesses. Herein, we speculate that ERK1/2 affects mitochondrial division and participates in the pathogenesis of epilepsy by regulating the activity of DRP1. LiCl-Pilocarpine was injected intraperitoneally to establish a rat model of status epilepticus (SE) for this study. Before SE induction, PD98059 and Mdivi-1 were injected intraperitoneally. The number of seizures and the latency period before the onset of the first seizure were then monitored. The analysis of Western blot was also used to measure the phosphorylated and total ERK1/2 and DRP1 protein expression levels in the rat hippocampus. In addition, immunohistochemistry revealed the distribution of ERK1/2 and DRP1 in neurons of hippocampal CA1 and CA3. Both PD98059 and Mdivi-1 reduced the susceptibility of rats to epileptic seizures, according to behavioral findings. By inhibiting ERK1/2 phosphorylation, the Western blot revealed that PD98059 indirectly reduced the phosphorylation of DRP1 at Ser616 (p-DRP1-Ser616). Eventually, the ERK1/2 and DRP1 were distributed in the cytoplasm of neurons by immunohistochemistry. Inhibition of ERK1/2 signaling pathways downregulates p-DRP1-Ser616 expression, which could inhibit DRP1-mediated excessive mitochondrial fission and then regulate the pathogenesis of epilepsy.


Asunto(s)
Dinaminas , Flavonoides , Dinámicas Mitocondriales , Pilocarpina , Quinazolinonas , Ratas Sprague-Dawley , Estado Epiléptico , Animales , Dinaminas/metabolismo , Dinaminas/genética , Dinámicas Mitocondriales/fisiología , Dinámicas Mitocondriales/efectos de los fármacos , Masculino , Pilocarpina/toxicidad , Estado Epiléptico/metabolismo , Estado Epiléptico/inducido químicamente , Flavonoides/farmacología , Quinazolinonas/farmacología , Sistema de Señalización de MAP Quinasas/fisiología , Ratas , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Convulsiones/metabolismo , Cloruro de Litio/farmacología , Modelos Animales de Enfermedad , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Fosforilación
5.
BMJ Case Rep ; 17(8)2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39214584

RESUMEN

A woman in her mid-60s who is a high hypermetrope presented with bilateral eye pain and headache approximately 1 hour after taking a single dose of a widely available decongestant containing paracetamol, guaifenesin and phenylephrine hydrochloride for coryzal symptoms. She had previous successful bilateral peripheral iridotomies performed for narrow angles. At presentation, her intraocular pressures (IOPs) were significantly raised at 72 mm Hg and 66 mm Hg in the right and left eye, respectively, with bilateral corneal oedema. Her IOP was normalised with urgent treatment using 500 mg intravenous acetazolamide, pilocarpine 2%, dexamethasone 0.1% and IOP-lowering drops. She was listed for cataract surgery and was advised to avoid the precipitating agent and other over-the-counter decongestants. This is the first reported case of bilateral angle closure triggered by a decongestant with such a combination of ingredients. Clinicians should be aware of this rare side effect for prompt diagnosis and management.


Asunto(s)
Acetaminofén , Acetazolamida , Glaucoma de Ángulo Cerrado , Humanos , Glaucoma de Ángulo Cerrado/inducido químicamente , Glaucoma de Ángulo Cerrado/tratamiento farmacológico , Femenino , Persona de Mediana Edad , Acetazolamida/uso terapéutico , Acetazolamida/administración & dosificación , Acetaminofén/efectos adversos , Acetaminofén/administración & dosificación , Acetaminofén/uso terapéutico , Fenilefrina/efectos adversos , Fenilefrina/administración & dosificación , Fenilefrina/uso terapéutico , Medicamentos sin Prescripción/efectos adversos , Medicamentos sin Prescripción/administración & dosificación , Guaifenesina/efectos adversos , Guaifenesina/administración & dosificación , Guaifenesina/uso terapéutico , Descongestionantes Nasales/efectos adversos , Descongestionantes Nasales/administración & dosificación , Presión Intraocular/efectos de los fármacos , Medicamentos Compuestos contra Resfriado, Gripe y Alergia/efectos adversos , Pilocarpina/uso terapéutico , Pilocarpina/administración & dosificación , Pilocarpina/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Dexametasona/efectos adversos , Dolor Ocular/inducido químicamente , Dolor Ocular/etiología , Enfermedad Aguda
6.
Mol Cell Neurosci ; 130: 103958, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39151841

RESUMEN

Increasing evidence suggests that cannabinoid receptor 2 (CB2R) serves as a promising anti-inflammatory target. While inflammation is known to play crucial roles in the pathogenesis of epilepsy, the involvement of CB2R in epilepsy remains unclear. This study aimed to investigate the effects of a CB2R agonist, AM1241, on epileptic seizures and depressive-like behaviors in a mouse model of chronic epilepsy induced by pilocarpine. A chronic epilepsy mouse model was established by intraperitoneal administration of pilocarpine. The endogenous cannabinoid system (eCBs) in the hippocampus was examined after status epilepticus (SE). Animals were then treated with AM1241 and compared with a vehicle-treated control group. Additionally, the role of the AMPK/NLRP3 signaling pathway was explored using the selective AMPK inhibitor dorsomorphin. Following SE, CB2R expression increased significantly in hippocampal microglia. Administration of AM1241 significantly reduced seizure frequency, immobility time in the tail suspension test, and neuronal loss in the hippocampus. In addition, AM1241 treatment attenuated microglial activation, inhibited pro-inflammatory polarization of microglia, and suppressed NLRP3 inflammasome activation in the hippocampus after SE. Further, the therapeutic effects of AM1241 were abolished by the AMPK inhibitor dorsomorphin. Our findings suggest that CB2R agonist AM1241 may alleviate epileptic seizures and its associated depression by inhibiting neuroinflammation through the AMPK/NLRP3 signaling pathway. These results provide insight into a novel therapeutic approach for epilepsy.


Asunto(s)
Depresión , Modelos Animales de Enfermedad , Hipocampo , Pilocarpina , Receptor Cannabinoide CB2 , Convulsiones , Animales , Masculino , Ratones , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Depresión/etiología , Depresión/tratamiento farmacológico , Depresión/metabolismo , Epilepsia/metabolismo , Epilepsia/tratamiento farmacológico , Epilepsia/inducido químicamente , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones Endogámicos C57BL , Microglía/metabolismo , Microglía/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/metabolismo , Convulsiones/metabolismo , Convulsiones/tratamiento farmacológico
7.
Toxins (Basel) ; 16(8)2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-39195752

RESUMEN

Epilepsy, a neurological disorder characterized by excessive neuronal activity and synchronized electrical discharges, ranks among the most prevalent global neurological conditions. Despite common use, antiepileptic drugs often result in adverse effects and lack effectiveness in controlling seizures in temporal lobe epilepsy (TLE) patients. Recent research explored the potential of occidentalin-1202, a peptide inspired by Polybia occidentalis venom, in safeguarding Wistar rats from chemically induced seizures. The present study evaluated the new analog from occidentalin-1202 named NOR-1202 using acute and chronic pilocarpine-induced models and an acute kainic acid (KA) male mice model. NOR-1202 was administered through the intracerebroventricular (i.c.v.), subcutaneous, or intraperitoneal routes, with stereotaxic procedures for the i.c.v. injection. In the acute pilocarpine-induced model, NOR-1202 (i.c.v.) protected against generalized seizures and mortality but lacked systemic antiepileptic activity. In the KA model, it did not prevent generalized seizures but improved survival. In the chronic TLE model, NOR-1202's ED50 did not differ significantly from the epileptic or healthy groups regarding time spent in spontaneous recurrent seizures during the five-day treatment. However, the NOR-1202 group exhibited more seizures than the healthy group on the second day of treatment. In summary, NOR-1202 exhibits antiepileptic effects against chemoconvulsant-induced seizures, but no effect was observed when administered systemically.


Asunto(s)
Anticonvulsivantes , Modelos Animales de Enfermedad , Convulsiones , Animales , Masculino , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Ratones , Convulsiones/tratamiento farmacológico , Convulsiones/inducido químicamente , Pilocarpina , Ácido Kaínico/análogos & derivados , Péptidos/farmacología , Péptidos/uso terapéutico , Péptidos/administración & dosificación , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/inducido químicamente
8.
Mol Biol Rep ; 51(1): 929, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39172288

RESUMEN

Epilepsy is a common neurological disease. Increasing evidence has highlighted the role of miRNAs in the molecular mechanisms underlying the development of neurological diseases such as epilepsy. In this study, we established a lithium chloride-pilocarpine epilepsy mouse model, performed miRNA sequencing of hippocampal tissue samples, and compared the obtained miRNA expression profile with that of normal control mice to determine differences in expression levels. We found that 55 miRNAs were differentially expressed in status epilepticus mice compared with normal control mice, with 38 upregulated and 17 downregulated miRNAs. Through subsequent analysis of the five downregulated miRNAs (mmu-let-7a-1-3p, mmu-let-7a-2-3p, mmu-let-7c-5p, mmu-let-7d-5p, and mmu-let-7e-5p) with the most significant differences in expression, the key pathways involved included the MAPK signaling pathway and focal adhesion, among others. Therefore, we believe that let-7 family miRNAs may be potential therapeutic targets for epilepsy.


Asunto(s)
Modelos Animales de Enfermedad , Epilepsia , Hipocampo , MicroARNs , Animales , MicroARNs/genética , MicroARNs/metabolismo , Hipocampo/metabolismo , Ratones , Epilepsia/genética , Epilepsia/metabolismo , Perfilación de la Expresión Génica/métodos , Masculino , Pilocarpina , Regulación de la Expresión Génica , Estado Epiléptico/genética , Estado Epiléptico/metabolismo , Estado Epiléptico/inducido químicamente , Cloruro de Litio/farmacología
9.
J Ethnopharmacol ; 335: 118697, 2024 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-39154669

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia divinorum (Epling and Játiva) is a psychoactive plant traditionally used by the Latinos for various medicinal purposes. Salvinorin A (Sal A), the main bioactive constituent of S. divinorum, is a natural highly selective kappa opioid receptor (KOR) agonist. Considering the anti-inflammatory effect of S. divinorum and endogenous hippocampal dynorphin/kappa opioid receptor (KOR) system playing an anticonvulsant function, we hypothesis that Sal A can be a potential candidate to treat epilepsy. Here, we identified whether Sal A ameliorated epileptic seizures and neuronal damages in animal model and in vitro model and investigated its underlying mechanisms. MATERIALS AND METHODS: Mice epilepsy model was induced by pilocarpine following seizures assessed by Racine classification. Hippocampus tissues were obtained for genetic, protein, and histological investigation. Furthermore, lipopolysaccharide (LPS)-activated BV2 microglial cells were utilized to validate the anti-inflammatory and microglia polarization regulation effects of Sal A. RESULTS: Sal A treatment significantly prolonged the latency to status epileptics (SE) and shortened the duration of SE in the pilocarpine-induced model. It also alleviated neuronal damages via activation of the AMPK/JNK/p-38 MAPK pathway and inhibition of apoptosis-related protein in hippocampus tissues. Furthermore, Sal A dose-dependently reduced microglia-mediated expression of pro-inflammatory cytokines and increased anti-inflammatory factors levels in SE mice and LPS-activated BV2 microglial cells by regulating microglia polarization. In addition, the effect of Sal A in vitro was totally blocked by KOR antagonist nor-BNI. CONCLUSION: Sal A treatment protects against epileptic seizures and neuronal damages in pilocarpine-induced models by suppressing the inflammation response through regulating microglial M1/M2 polarization. This study might serve as a theoretical basis for clinical applications of Sal A and its analogs and provide a new insight into the development of anti-seizure drugs.


Asunto(s)
Diterpenos de Tipo Clerodano , Hipocampo , Microglía , Pilocarpina , Convulsiones , Animales , Microglía/efectos de los fármacos , Microglía/metabolismo , Pilocarpina/toxicidad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Diterpenos de Tipo Clerodano/farmacología , Diterpenos de Tipo Clerodano/uso terapéutico , Masculino , Ratones , Convulsiones/tratamiento farmacológico , Convulsiones/inducido químicamente , Anticonvulsivantes/farmacología , Línea Celular , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/aislamiento & purificación
10.
Eur J Pharmacol ; 981: 176903, 2024 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-39154823

RESUMEN

BACKGROUND: Epilepsy is a prevalent disorder of the central nervous system. Approximately, one-third of patients show resistance to pharmacological interventions. The pathogenesis of epilepsy is complex, and neuronal apoptosis plays a critical role. Aberrantly reactive astrocytes, induced by cytokine release from activated microglia, may lead to neuronal apoptosis. This study investigated the role of glucagon-like peptide 1 receptor (GLP1R) in microglial activation in epilepsy and its impact on astrocyte-mediated neurotoxicity. METHODS: We used human hippocampal tissue from patients with temporal lobe epilepsy and a pilocarpine-induced epileptic mouse model to assess neurobiological changes in epilepsy. BV2 microglial cells and primary astrocytes were used to evaluate cytokine release and astrocyte activation in vitro. The involvement of GLP1R was explored using the GLP1R agonist, Exendin-4 (Ex-4). RESULTS: Our findings indicated that reduced GLP1R expression in hippocampal microglia in both epileptic mouse models and human patients, correlated with increased cytokine release and astrocyte activation. Ex-4 treatment restored microglial homeostasis, decreased cytokine secretion, and reduced astrocyte activation, particularly of the A1 phenotype. These changes were associated with a reduction in neuronal apoptosis. In addition, Ex-4 treatment significantly decreased the frequency and duration of seizures in epileptic mice. CONCLUSIONS: This study highlights the crucial role of microglial GLP1R in epilepsy pathophysiology. GLP1R downregulation contributes to microglial- and astrocyte-mediated neurotoxicity, exacerbating neuronal death and seizures. Activation of GLP1R with Ex-4 has emerged as a promising therapeutic strategy to reduce neuroinflammation, protect neuronal cells, and control seizures in epilepsy. This study provides a foundation for developing novel antiepileptic therapies targeting microglial GLP1R, with the potential to improve outcomes in patients with epilepsy.


Asunto(s)
Apoptosis , Receptor del Péptido 1 Similar al Glucagón , Hipocampo , Microglía , Neuronas , Animales , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Apoptosis/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Humanos , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Ratones , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Exenatida/farmacología , Exenatida/uso terapéutico , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/patología , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Epilepsia/inducido químicamente , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Femenino , Adulto , Pilocarpina , Modelos Animales de Enfermedad , Citocinas/metabolismo , Ratones Endogámicos C57BL , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/metabolismo , Epilepsia del Lóbulo Temporal/patología , Persona de Mediana Edad
11.
BMC Oral Health ; 24(1): 881, 2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-39095752

RESUMEN

BACKGROUND: Hyposalivation is treated using oral cholinergic drugs; however, systemic side effects occasionally lead to discontinuation of treatment. We aimed to investigate the effects of transdermal pilocarpine on the salivary gland skin on saliva secretion and safety in rats. METHODS: Pilocarpine was administered to rats orally (0.5 mg/kg) or topically on the salivary gland skin (5 mg/body). Saliva volume, the number of sweat dots, and fecal weight were measured along with pilocarpine concentration in plasma and submandibular gland tissues. RESULTS: Saliva volume significantly increased 0.5 h after oral administration and 0.5, 3, and 12 h after topical administration. Fecal weight and sweat dots increased significantly 1 h after oral administration; however, no changes were observed after topical application. The pilocarpine concentration in the submandibular gland tissues of the topical group was higher than that in the oral group at 0.5, 3, and 12 h of administration. CONCLUSIONS: Pilocarpine application to salivary gland skin persistently increased salivary volume in rats without inducing sweating or diarrhea. Transdermal pilocarpine applied to the skin over the salivary glands may be an effective and safe treatment option for hyposalivation.


Asunto(s)
Administración Cutánea , Pilocarpina , Glándulas Salivales , Salivación , Xerostomía , Pilocarpina/administración & dosificación , Pilocarpina/farmacología , Animales , Salivación/efectos de los fármacos , Ratas , Masculino , Glándulas Salivales/efectos de los fármacos , Glándulas Salivales/metabolismo , Xerostomía/inducido químicamente , Xerostomía/tratamiento farmacológico , Agonistas Muscarínicos/administración & dosificación , Agonistas Muscarínicos/farmacología , Saliva/metabolismo , Saliva/química , Administración Oral , Glándula Submandibular/efectos de los fármacos , Glándula Submandibular/metabolismo , Ratas Sprague-Dawley
12.
Neural Plast ; 2024: 9946769, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39104708

RESUMEN

Although several adult rat models of medial temporal lobe epilepsy (mTLE) have been described in detail, our knowledge of mTLE epileptogenesis in infant rats is limited. Here, we present a novel infant rat model of mTLE (InfRPil-mTLE) based on a repetitive, triphasic injection regimen consisting of low-dose pilocarpine administrations (180 mg/kg. i.p.) on days 9, 11, and 15 post partum (pp). The model had a survival rate of >80% and exhibited characteristic spontaneous recurrent electrographic seizures (SRES) in both the hippocampus and cortex that persisted into adulthood. Using implantable video-EEG radiotelemetry, we quantified a complex set of seizure parameters that demonstrated the induction of chronic electroencephalographic seizure activity in our InfRPil-mTLE model, which predominated during the dark cycle. We further analyzed selected candidate genes potentially relevant to epileptogenesis using a RT-qPCR approach. Several candidates, such as the low-voltage-activated Ca2+ channel Cav3.2 and the auxiliary subunits ß 1 and ß 2, which were previously reported to be upregulated in the hippocampus of the adult pilocarpine mTLE model, were found to be downregulated (together with Cav2.1, Cav2.3, M1, and M3) in the hippocampus and cortex of our InfRPil-mTLE model. From a translational point of view, our model could serve as a blueprint for childhood epileptic disorders and further contribute to antiepileptic drug research and development in the future.


Asunto(s)
Modelos Animales de Enfermedad , Epilepsia del Lóbulo Temporal , Pilocarpina , Animales , Epilepsia del Lóbulo Temporal/fisiopatología , Epilepsia del Lóbulo Temporal/genética , Epilepsia del Lóbulo Temporal/metabolismo , Epilepsia del Lóbulo Temporal/inducido químicamente , Ratas , Electroencefalografía , Hipocampo/metabolismo , Animales Recién Nacidos , Encéfalo/metabolismo , Ratas Sprague-Dawley , Masculino , Femenino
13.
FASEB J ; 38(15): e23878, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-39120551

RESUMEN

The ciliary muscle constitutes a crucial element in refractive regulation. Investigating the pathophysiological mechanisms within the ciliary muscle during excessive contraction holds significance in treating ciliary muscle dysfunction. A guinea pig model of excessive contraction of the ciliary muscle induced by drops pilocarpine was employed, alongside the primary ciliary muscle cells was employed in in vitro experiments. The results of the ophthalmic examination showed that pilocarpine did not significantly change refraction and axial length during the experiment, but had adverse effects on the regulatory power of the ciliary muscle. The current data reveal notable alterations in the expression profiles of hypoxia inducible factor 1 (HIF-1α), ATP2A2, P53, α-SMA, Caspase-3, and BAX within the ciliary muscle of animals subjected to pilocarpine exposure, alongside corresponding changes observed in cultured cells treated with pilocarpine. Augmented levels of ROS were detected in both tissue specimens and cells, culminating in a significant increase in cell apoptosis in in vivo and in vitro experiments. Further examination revealed that pilocarpine induced an increase in intracellular Ca2+ levels and disrupted MMP, as evidenced by mitochondrial swelling and diminished cristae density compared to control conditions, concomitant with a noteworthy decline in antioxidant enzyme activity. However, subsequent blockade of Ca2+ channels in cells resulted in downregulation of HIF-1α, ATP2A2, P53, α-SMA, Caspase-3, and BAX expression, alongside ameliorated mitochondrial function and morphology. The inhibition of Ca2+ channels presents a viable approach to mitigate ciliary cells damage and sustain proper ciliary muscle function by curtailing the mitochondrial damage induced by excessive contractions.


Asunto(s)
Apoptosis , Calcio , Senescencia Celular , Pilocarpina , Animales , Pilocarpina/farmacología , Cobayas , Apoptosis/efectos de los fármacos , Calcio/metabolismo , Senescencia Celular/efectos de los fármacos , Cuerpo Ciliar/metabolismo , Masculino , Células Cultivadas , Especies Reactivas de Oxígeno/metabolismo
14.
Synapse ; 78(5): e22307, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39171546

RESUMEN

To present the expression of calsyntenin-1 (Clstn1) in the brain and investigate the potential mechanism of Clstn1 in lithium-pilocarpine rat seizure models. Thirty-five male SD adult rats were induced to have seizures by intraperitoneal injection of lithium chloride pilocarpine. Rats exhibiting spontaneous seizures were divided into the epilepsy (EP) group (n = 15), whereas those without seizures were divided into the control group (n = 14). Evaluate the expression of Clstn1 in the temporal lobe of two groups using Western blotting, immunohistochemistry, and immunofluorescence. Additionally, 55 male SD rats were subjected to status epilepticus (SE) using the same induction method. Rats experiencing seizures exceeding Racine's level 4 (n = 48) were randomly divided into three groups: SE, SE + control lentivirus (lentiviral vector expressing green fluorescent protein [LV-GFP]), and SE + Clstn1-targeted RNA interference lentivirus (LV-Clstn1-RNAi). The LV-GFP group served as a control for the lentiviral vector, whereas the LV-Clstn1-RNAi group received a lentivirus designed to silence Clstn1 expression. These lentiviral treatments were administered via hippocampal stereotactic injection 2 days after SE induction. Seven days after SE, Western blot analysis was performed to evaluate the expression of Clstn1 in the hippocampus and temporal lobe. Meanwhile, we observed the latency of spontaneous seizures and the frequency of spontaneous seizures within 8 weeks among the three groups. The expression of Clstn1 in the cortex and hippocampus of the EP group was significantly increased compared to the control group (p < .05). Immunohistochemistry and immunofluorescence showed that Clstn1 was widely distributed in the cerebral cortex and hippocampus of rats, and colocalization analysis revealed that it was mainly co expressed with neurons in the cytoplasm. Compared with the SE group (11.80 ± 2.17 days) and the SE + GFP group (12.40 ± 1.67 days), there was a statistically significant difference (p < .05) in the latency period of spontaneous seizures (15.14 ± 2.41 days) in the SE + Clstn1 + RNAi group rats. Compared with the SE group (4.60 ± 1.67 times) and the SE + GFP group (4.80 ± 2.05 times), the SE + Clstn1 + RNAi group (2.0 ± .89 times) showed a significant reduction in the frequency of spontaneous seizures within 2 weeks of chronic phase in rats (p < .05). Elevated Clstn1 expression in EP group suggests its role in EP onset. Targeting Clstn1 may be a potential therapeutic approach for EP management.


Asunto(s)
Modelos Animales de Enfermedad , Pilocarpina , Ratas Sprague-Dawley , Convulsiones , Animales , Masculino , Pilocarpina/toxicidad , Ratas , Convulsiones/metabolismo , Convulsiones/inducido químicamente , Convulsiones/genética , Estado Epiléptico/inducido químicamente , Estado Epiléptico/metabolismo , Neurocalcina/metabolismo , Neurocalcina/genética , Hipocampo/metabolismo , Cloruro de Litio , Lóbulo Temporal/metabolismo , Encéfalo/metabolismo
15.
Brain Res ; 1844: 149138, 2024 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-39134259

RESUMEN

Cognitive impairment is a prevalent co-morbidity associated with epilepsy. Emerging studies indicate that neuroinflammation could be a possible link between epilepsy and its comorbidities, including cognitive impairment. In this context, the roles of glial activation, proinflammatory mediators, and neuronal death have been well studied and correlated with epilepsy-associated cognitive impairment in animal studies. While recent reports have demonstrated the anti-epileptogenic and anti-convulsant actions of metformin, its effect on epilepsy associated cognitive deficit remains unknown. Therefore, the current study investigated the effect of metformin treatment on neuroinflammation, neurodegeneration, and cognitive deficits after inducing status epilepticus (SE) with lithium-pilocarpine in rats. Metformin treatment improved the hippocampal-dependent spatial and recognition memory in Morris water maze and Novel object recognition tasks, respectively. Further, metformin treatment attenuated microglial and astroglial activation, accompanied by reduced IL-1ß, COX-2 and NF-Ä¸ß gene expression. Additionally, metformin conferred neuroprotection by inhibiting the neuronal death as assessed by Nissl staining and transmission electron microscopy. These findings suggest that metformin holds promise as a therapeutic intervention for cognitive impairment associated with epilepsy, possibly through its modulation of glial activation and neuronal survival. Further research is needed to elucidate the precise mechanisms and to assess the long-term effect of metformin in epilepsy-associated cognitive impairment.


Asunto(s)
Disfunción Cognitiva , Modelos Animales de Enfermedad , Epilepsia del Lóbulo Temporal , Gliosis , Metformina , Animales , Metformina/farmacología , Metformina/uso terapéutico , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Ratas , Masculino , Gliosis/tratamiento farmacológico , Pilocarpina , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/patología , Ratas Sprague-Dawley , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo
16.
BMC Ophthalmol ; 24(1): 371, 2024 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-39187764

RESUMEN

BACKGROUND: The present study elucidates a common significant postoperative complication of micropulse transscleral laser treatment (mTLT) and explores its potential management strategies for younger patients with good central vision. CASE PRESENTATION: Three younger Chinese glaucoma patients with good central vision maintained high intraocular pressures (IOPs) (36, 25, and 30 mmHg) on maximally tolerated topical anti-glaucoma medications. All patients were treated with mTLT because of a higher risk of complications with filtering surgery. After the procedure, their best-corrected visual acuities were not significantly changed, IOPs were significantly decreased, and the number of topical anti-glaucoma medicines was gradually decreased. However, all patients complained about reduced near visual acuity (NVA) for 1-5 months. Slit-lamp examination revealed pupillary dilation, and binocular accommodative function examination indicated accommodation loss. After treatment with 2% topical pilocarpine, all patients reported an improvement in NVA. Among them, we could observe pupillary constriction, recovery of accommodation function, and improved NVA, even discontinuation of pilocarpine in Patient 2. CONCLUSION: In younger patients with good central vision, topical pilocarpine might ameliorate accommodation loss and pupillary dilation after mTLT.


Asunto(s)
Acomodación Ocular , Presión Intraocular , Pilocarpina , Humanos , Pilocarpina/uso terapéutico , Pilocarpina/administración & dosificación , Masculino , Femenino , Adulto , Presión Intraocular/fisiología , Acomodación Ocular/fisiología , Agudeza Visual , Mióticos/administración & dosificación , Mióticos/uso terapéutico , Pupila/efectos de los fármacos , Esclerótica/cirugía , Glaucoma/cirugía , Glaucoma/fisiopatología , Terapia por Láser/métodos , Soluciones Oftálmicas , Persona de Mediana Edad , Complicaciones Posoperatorias , Administración Tópica
17.
J Adv Res ; 63: 73-90, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39048074

RESUMEN

INTRODUCTION: Our previous work reveals a critical role of activation of neuronal Alox5 in exacerbating brain injury post seizures. However, whether neuronal Alox5 impacts the pathological process of epilepsy remains unknown. OBJECTIVES: To prove the feasibility of neuron-specific deletion of Alox5 via CRISPR-Cas9 in the blockade of seizure onset and epileptic progression. METHODS: Here, we employed a Clustered regularly interspaced short-palindromic repeat-associated proteins 9 system (CRISPR/Cas9) system delivered by adeno-associated virus (AAV) to specifically delete neuronal Alox5 gene in the hippocampus to explore its therapeutic potential in various epilepsy mouse models and possible mechanisms. RESULTS: Neuronal depletion of Alox5 was successfully achieved in the brain. AAV delivery of single guide RNA of Alox5 in hippocampus resulted in reducing seizure severity, delaying epileptic progression and improving epilepsy-associated neuropsychiatric comorbidities especially anxiety, cognitive deficit and autistic-like behaviors in pilocarpine- and kainic acid-induced temporal lobe epilepsy (TLE) models. In addition, neuronal Alox5 deletion also reversed neuron loss, neurodegeneration, astrogliosis and mossy fiber sprouting in TLE model. Moreover, a battery of tests including analysis of routine blood test, hepatic function, renal function, routine urine test and inflammatory factors demonstrated no noticeable toxic effect, suggesting that Alox5 deletion possesses the satisfactory biosafety. Mechanistically, the anti-epileptic effect of Alox5 deletion might be associated with reduction of glutamate level to restore excitatory/inhibitory balance by reducing CAMKII-mediated phosphorylation of Syn ISer603. CONCLUSION: Our findings showed the translational potential of AAV-mediated delivery of CRISPR-Cas9 system including neuronal Alox5 gene for an alternative promising therapeutic approach to treat epilepsy.


Asunto(s)
Araquidonato 5-Lipooxigenasa , Sistemas CRISPR-Cas , Modelos Animales de Enfermedad , Epilepsia , Hipocampo , Neuronas , Animales , Ratones , Araquidonato 5-Lipooxigenasa/metabolismo , Araquidonato 5-Lipooxigenasa/genética , Neuronas/metabolismo , Hipocampo/metabolismo , Epilepsia/genética , Masculino , Ratones Endogámicos C57BL , Eliminación de Gen , Epilepsia del Lóbulo Temporal/genética , Dependovirus/genética , Pilocarpina
18.
Int J Pharm ; 662: 124497, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-39033941

RESUMEN

The development of an effective transdermal drug delivery protocol to eccrine sweat glands is important for the advancement of research on the human sweating response. We investigated whether microneedle treatment prior to the application of pilocarpine, a hydrophilic and sudorific agent that does not induce sweating due to a limited percutaneous passive diffusion by skin application alone, augments sweat production. We applied three microneedle arrays to forearm skin sites simultaneously (n = 20). Upon removal of the microneedles, 1 % pilocarpine was applied to each site for 5-, 15-, and 30-min for the assessment of sweat gland function. In parallel, pilocarpine was administered by transdermal iontophoresis (5-min) at a separate site. Sweat rate was assessed continuously via the ventilated capsule technique. Pilocarpine augmented sweat rate at the 15- and 30-min periods as compared to the application at 5-min. The sweating responses induced by the 15- and 30-min application of pilocarpine were equivalent to âˆ¼ 80 % of that measured at the iontophoretically treated sites. Notably, we observed a correlation in sweat rate between these two transdermal drug delivery methods. Altogether, our findings show that pre-treatment of microneedle arrays can enhance transdermal delivery efficiency of pilocarpine to human eccrine sweat glands.


Asunto(s)
Administración Cutánea , Iontoforesis , Agujas , Pilocarpina , Sudoración , Pilocarpina/administración & dosificación , Humanos , Sudoración/efectos de los fármacos , Masculino , Adulto , Iontoforesis/métodos , Femenino , Adulto Joven , Sistemas de Liberación de Medicamentos/instrumentación , Agonistas Muscarínicos/administración & dosificación , Sudor , Piel/metabolismo
19.
J Physiol Sci ; 74(1): 38, 2024 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-39075341

RESUMEN

This in vivo mouse model study was conducted to investigate the temporal alteration of the function of CD36 in salivary secretion. CD36 was highly expressed in the parotid gland of BALB/c mice. No significant variations were shown in the CD36 levels in the 8-, 48-, and 72-week-old animals. However, pilocarpine-induced salivary secretion was reduced in an age-dependent manner, showing a significantly low level at the age of 72 weeks. Pilocarpine-induced salivary secretion was significantly reduced by pretreatment with a CD36 inhibitor at 8 and 48 weeks, but not at 72 weeks. In senescence-accelerated mice (SAM), the pilocarpine-induced salivary secretion was significantly reduced at the age of 56 weeks, and a significantly lower amount of CD36 was demonstrated in the parotid gland, compared with the control. These results suggest that the involvement of parotid CD36 in mouse salivary secretion is altered with age.


Asunto(s)
Envejecimiento , Antígenos CD36 , Ratones Endogámicos BALB C , Glándula Parótida , Saliva , Animales , Glándula Parótida/metabolismo , Antígenos CD36/metabolismo , Ratones , Masculino , Saliva/metabolismo , Envejecimiento/metabolismo , Envejecimiento/fisiología , Pilocarpina/farmacología , Salivación/efectos de los fármacos
20.
ACS Chem Neurosci ; 15(15): 2695-2702, 2024 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-38989663

RESUMEN

Status epilepticus (SE) is a medical emergency associated with high mortality and morbidity. Na+, K+-ATPase, is a promising therapeutic target for SE, given its critical role in regulation of neuron excitability and cellular homeostasis. We investigated the effects of a Na+, K+-ATPase-activating antibody (DRRSAb) on short-term electrophysiological and behavioral consequences of pilocarpine-induced SE. Rats were submitted to pilocarpine-induced SE, followed by intranasal administration (2 µg/nostril). The antibody increased EEG activity following SE, namely, EEG power in theta, beta, and gamma frequency bands, assessed by quantitative analysis of EEG power spectra. One week later, DRRSAb-treated animals displayed less behavioral hyperreactivity in pick-up tests and better performance in novel object recognition tests, indicating that the intranasal administration of this Na+, K+-ATPase activator immediately after SE improves behavioral outcomes at a later time point. These results suggest that Na+, K+-ATPase activation warrants further investigation as an adjunctive therapeutic strategy for SE.


Asunto(s)
Administración Intranasal , Electroencefalografía , Pilocarpina , ATPasa Intercambiadora de Sodio-Potasio , Estado Epiléptico , Animales , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológico , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Masculino , Pilocarpina/farmacología , Electroencefalografía/métodos , Electroencefalografía/efectos de los fármacos , Ratas , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Ratas Wistar , Anticuerpos/farmacología , Anticuerpos/administración & dosificación
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