Dataset Information

Effect of Vagus Nerve Stimulation on the GASH/Sal Audiogenic-Seizure-Prone Hamster.

ABSTRACT: Vagus nerve stimulation (VNS) is an adjuvant neuromodulation therapy for the treatment of refractory epilepsy. However, the mechanisms behind its effectiveness are not fully understood. Our aim was to develop a VNS protocol for the Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal) in order to evaluate the mechanisms of action of the therapy. The rodents were subject to VNS for 14 days using clinical stimulation parameters by implanting a clinically available neurostimulation device or our own prototype for laboratory animals. The neuroethological assessment of seizures and general behavior were performed before surgery, and after 7, 10, and 14 days of VNS. Moreover, potential side effects were examined. Finally, the expression of 23 inflammatory markers in plasma and the left-brain hemisphere was evaluated. VNS significantly reduced seizure severity in GASH/Sal without side effects. No differences were observed between the neurostimulation devices. GASH/Sal treated with VNS showed statistically significant reduced levels of interleukin IL-1β, monocyte chemoattractant protein MCP-1, matrix metalloproteinases (MMP-2, MMP-3), and tumor necrosis factor TNF-α in the brain. The described experimental design allows for the study of VNS effects and mechanisms of action using an implantable device. This was achieved in a model of convulsive seizures in which VNS is effective and shows an anti-inflammatory effect.

SUBMITTER: Goncalves-Sanchez J

PROVIDER: S-EPMC10778912 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Effect of Vagus Nerve Stimulation on the GASH/Sal Audiogenic-Seizure-Prone Hamster.

Gonçalves-Sánchez Jaime J Sancho Consuelo C López Dolores E DE Castellano Orlando O García-Cenador Begoña B Servilha-Menezes Gabriel G Corchado Juan M JM García-Cairasco Norberto N Gonçalves-Estella Jesús M JM

International journal of molecular sciences 20231220 1

Vagus nerve stimulation (VNS) is an adjuvant neuromodulation therapy for the treatment of refractory epilepsy. However, the mechanisms behind its effectiveness are not fully understood. Our aim was to develop a VNS protocol for the Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal) in order to evaluate the mechanisms of action of the therapy. The rodents were subject to VNS for 14 days using clinical stimulation parameters by implanting a clinically available neurostimulation device or ...[more]

PMID: 38203262

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Project description:Epilepsy is a multifaceted neurological disorder characterized by recurrent seizures and associated with molecular and immune alterations in key brain regions. The GASH/Sal (Genetic Audiogenic Seizure Hamster, Salamanca), a genetic model for audiogenic epilepsy, provides a powerful tool to study seizure mechanisms and resistance in predisposed individuals. This study investigates the proteomic and immune responses triggered by audiogenic kindling in the inferior colliculus, comparing non-responder animals exhibiting reduced seizure severity following repeated stimulation versus GASH/Sal naïve hamsters. To assess auditory pathway functionality, Auditory Brainstem Responses (ABRs) were recorded, revealing reduced neuronal activity in the auditory nerve of non-responders, while central auditory processing remained unaffected. Cytokine profiling demonstrated increased levels of proinflammatory markers, including IL-1 alpha (Interleukin-1 alpha), IL-10 (Interleukin-10), and TGF-beta (Transforming Growth Factor beta), alongside decreased IGF-1 (Insulin-like Growth Factor 1) levels, highlighting systemic inflammation and its interplay with neuroprotection. Building on these findings, a proteomic analysis identified 159 differentially expressed proteins (DEPs). Additionally, bioinformatic approaches, including Gene Set Enrichment Analysis (GSEA) and Weighted Gene Co-expression Network Analysis (WGCNA), revealed disrupted pathways related to metabolic and inflammatory epileptic processes and a module potentially linked to a rise in the threshold of seizures, respectively. Differentially expressed genes, identified through bioinformatic and statistical analyses, were validated by RT-qPCR. This confirmed the upregulation of six genes (Gpc1-Glypican-1; Sdc3-Syndecan-3; Vgf-Nerve Growth Factor Inducible; Cpne5-Copine 5; Agap2-Arf-GAP with GTPase domain, ANK repeat, and PH domain-containing protein 2; and Dpp8-Dipeptidyl Peptidase 8) and the downregulation of two (Ralb-RAS-like proto-oncogene B-and S100b-S100 calcium-binding protein B), aligning with reduced seizure severity. This study may uncover key proteomic and immune mechanisms underlying seizure susceptibility, providing possible novel therapeutic targets for refractory epilepsy.

Project description:Despite evidence that supports cannabidiol (CBD) as an anticonvulsant agent, there remains controversy over the antiseizure efficacy, possible adverse effects, and synergistic interactions with classic antiepileptics such as valproate (VPA). The genetic audiogenic seizure hamster from the University of Salamanca (GASH/Sal) is a reliable experimental model of generalized tonic-clonic seizures in response to intense sound stimulation. The present study examines the behavioral and molecular effects of acute and chronic intraperitoneal administrations of VPA (300 mg/kg) and CBD (100 mg/kg) on the GASH/Sal audiogenic seizures, as well as the coadministration of both drugs. The GASH/Sal animals were examined prior to and after the corresponding treatment at 45 min, 7 days, and 14 days for seizure severity and neuroethology, open-field behaviors, body weight variations, and various hematological and biochemical parameters. Furthermore, the brain tissue containing the inferior colliculus (so-called epileptogenic nucleus) was processed for reverse transcription-quantitative polymerase chain reaction analysis to determine the treatment effects on the gene expression of neuronal receptors associated with drug actions and ictogenesis. Our results indicated that single dose of VPA helps prevent the animals from getting convulsions, showing complete elimination of seizures, whereas 7 days of chronic VPA treatment had few effects in seizure behaviors. Acute CBD administration showed subtle attenuation of seizure behaviors, increasing seizure latency and decreasing the duration of the convulsion phase, but without entirely seizure abolition. Chronic CBD treatments had no significant effects on sound-induced seizures, although some animals slightly improved seizure severity. Acute and chronic CBD treatments have no significant adverse effects on body weight, hematological parameters, and liver function, although locomotor activity was reduced. The combination of VPA and CBD did not alter the therapeutic outcome of the VPA monotherapy, showing no apparent synergistic effects. As compared to sham animals, chronic treatments with CBD caused abnormal mRNA expression levels for Trpv1, Adora1, Slc29a1, and Cnr1 genes, whereas no differences in gene expression were found for Htr1a and Sigmar1. Our study shed light on the behavioral and molecular effects of CBD and VPA on the GASH/Sal model and constituted the basis to develop further studies on the pharmacological effects of CBD and its interactions with other anticonvulsants.

Project description:The Wistar Audiogenic Rat (WAR) and the Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal) strains are audiogenic epilepsy models, in which seizures are triggered by acoustic stimulation. These strains were developed by selective reproduction and have a genetic background with minimal or no variation. In the current study, we evaluated the transcriptome of the inferior colliculus, the epileptogenic nucleus, of both audiogenic models, in order to get insights into common molecular aspects associated to their epileptic phenotype. Based on GASH/Sal RNA-Seq and WAR microarray data, we performed a comparative analysis that includes selection and functional annotation of differentially regulated genes in each model, transcriptional evaluation by quantitative reverse transcription PCR of common genes identified in both transcriptomes and immunohistochemistry. The microarray data revealed 71 genes with differential expression in WAR, and the RNA-Seq data revealed 64 genes in GASH/Sal, showing common genes in both models. Analysis of transcripts showed that Egr3 was overexpressed in WAR and GASH/Sal after audiogenic seizures. The Npy, Rgs2, Ttr, and Abcb1a genes presented the same transcriptional profile in the WAR, being overexpressed in the naïve and stimulated WAR in relation to their controls. Npy appeared overexpressed only in the naïve GASH/Sal compared to its control, while Rgs2 and Ttr genes appeared overexpressed in naïve GASH/Sal and overexpressed after audiogenic seizure. No statistical difference was observed in the expression of Abcb1a in the GASH/Sal model. Compared to control animals, the immunohistochemical analysis of the inferior colliculus showed an increased immunoreactivity for NPY, RGS2, and TTR in both audiogenic models. Our data suggest that WAR and GASH/Sal strains have a difference in the timing of gene expression after seizure, in which GASH/Sal seems to respond more quickly. The transcriptional profile of the Npy, Rgs2, and Ttr genes under free-seizure conditions in both audiogenic models indicates an intrinsic expression already established in the strains. Our findings suggest that these genes may be causing small changes in different biological processes involved in seizure occurrence and response, and indirectly contributing to the susceptibility of the WAR and GASH/Sal models to audiogenic seizures.

Project description:BackgroundAutonomic nerve stimulation is used as a treatment for a growing number of diseases. We have previously demonstrated that application of efferent vagus nerve stimulation (eVNS) has promising glucose lowering effects in a rat model of type 2 diabetes. This paradigm combines high frequency pulsatile stimulation to block nerve activation in the afferent direction with low frequency stimulation to activate the efferent nerve section. In this study we explored the effects of the parameters for nerve blocking on the ability to inhibit nerve activation in the afferent direction. The overarching aim is to establish a blocking stimulation strategy that could be applied using commercially available implantable pulse generators used in the clinic.MethodsMale rats (n = 20) had the anterior abdominal vagus nerve implanted with a multi-electrode cuff. Evoked compound action potentials (ECAP) were recorded at the proximal end of the electrode cuff. The efficacy of high frequency stimulation to block the afferent ECAP was assessed by changes in the threshold and saturation level of the response. Blocking frequency and duty cycle of the blocking pulses were varied while maintaining a constant 4 mA current amplitude.ResultsDuring application of blocking at lower frequencies (≤ 4 kHz), the ECAP threshold increased (ANOVA, p < 0.001) and saturation level decreased (p < 0.001). Application of higher duty cycles (> 70%) led to an increase in evoked neural response threshold (p < 0.001) and a decrease in saturation level (p < 0.001). During the application of a constant pulse width and frequency (1 or 1.6 kHz, > 70% duty cycle), the charge delivered per pulse had a significant influence on the magnitude of the block (ANOVA, p = 0.003), and was focal (< 2 mm range).ConclusionsThis study has determined the range of frequencies, duty cycles and currents of high frequency stimulation that generate an efficacious, focal axonal block of a predominantly C-fiber tract. These findings could have potential application for the treatment of type 2 diabetes.

Dataset Information

Effect of Vagus Nerve Stimulation on the GASH/Sal Audiogenic-Seizure-Prone Hamster.

Publications

Effect of Vagus Nerve Stimulation on the GASH/Sal Audiogenic-Seizure-Prone Hamster.

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