Animal Models of Drug-Resistant Epilepsy as Tools for Deciphering the Cellular and Molecular Mechanisms of Pharmacoresistance and Discovering More Effective Treatments

Cells, Journal Year: 2023, Volume and Issue: 12(9), P. 1233 - 1233

Published: April 24, 2023

In the last 30 years, over 20 new anti-seizure medicines (ASMs) have been introduced into market for treatment of epilepsy using well-established preclinical seizure and models. Despite this success, approximately 20–30% patients with drug-resistant (DRE). The current approach to ASM discovery DRE relies largely on drug testing in various model systems that display varying degrees resistance. recent attempts made include more etiologically relevant models evaluation a investigational drug. Such played an important role advancing greater understanding at mechanistic level hypothesis as experimental evidence becomes available. This review provides critical discussion pharmacology adult focal allow selection responders nonresponders those pharmacoresistance per se two or ASMs. addition, animal major genetic epilepsies is discussed. Importantly, addition chemical compounds, several discussed here can be used evaluate other potential therapies such neurostimulation, dietary treatments, gene therapy, cell transplantation. also discusses challenges associated identifying novel absence mechanisms contribute DRE. Finally, lessons learned from profile recently approved highly efficacious broad-spectrum cenobamate.

Language: Английский

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Epilepsy and its neurobehavioral comorbidities: Insights gained from animal models

Epilepsia, Journal Year: 2022, Volume and Issue: 64(1), P. 54 - 91

Published: Oct. 5, 2022

It is well established that epilepsy associated with numerous neurobehavioral comorbidities, a bidirectional relationship; people have an increased incidence of depression, anxiety, learning and memory difficulties, other psychosocial challenges, the occurrence higher in individuals those comorbidities. Although cause-and-effect relationship uncertain, fuller understanding mechanisms comorbidities within epilepsies could lead to improved therapeutics. Here, we review recent data on its discussing mainly rodent models, which been studied most extensively, emphasize clinically relevant information can be gained from preclinical models. Furthermore, explore potential factors may confound interpretation emerging animal such as specific seizure induction method (e.g., chemical, electrical, traumatic, genetic), role species strain, environmental laboratory environment, handling, epigenetics), behavioral assays are chosen evaluate various aspects neural behavior cognition. Overall, interplay between undoubtedly multifactorial, involving brain structural changes, network-level differences, molecular signaling abnormalities, factors. Animal models poised help dissect shared pathophysiological mechanisms, neurological sequelae, biomarkers

Language: Английский

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Translational veterinary epilepsy: A win-win situation for human and veterinary neurology

The Veterinary Journal, Journal Year: 2023, Volume and Issue: 293, P. 105956 - 105956

Published: Feb. 13, 2023

Epilepsy is a challenging multifactorial disorder with complex genetic background. Our current understanding of the pathophysiology and treatment epilepsy has substantially increased due to animal model studies, including canine but additional basic clinical research required. Drug-resistant an important problem in both dogs humans, since seizure freedom not achieved available antiseizure medications. The evaluation exploration pharmacological particularly non-pharmacological therapeutic options need remain priority research. Combined efforts sharing knowledge expertise between human medical veterinary neurologists are for improving outcomes or even curing dogs. Such interactions could offer exciting approach translate gained from people rodents vice versa. In this article, panel experts discusses similarities gaps epileptology, aim establishing common framework basis future translational

Language: Английский

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Anti-seizure effects of JNJ-54175446 in the intra-amygdala kainic acid model of drug-resistant temporal lobe epilepsy in mice

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 8, 2024

There remains a need for new drug targets treatment-resistant temporal lobe epilepsy. The ATP-gated P2X7 receptor coordinates neuroinflammatory responses to tissue injury. Previous studies in mice reported that the antagonist JNJ-47965567 suppressed spontaneous seizures intraamygdala kainic acid model of epilepsy and reduced attendant gliosis hippocampus. drug-resistance profile this is not fully characterised, however, newer antagonists with superior pharmacokinetic profiles have recently entered clinical trials. Using telemetry-based continuous EEG recordings mice, we demonstrate recurrent are refractory common anti-seizure medicine levetiracetam. In contrast, once-daily dosing JNJ-54175446 (30 mg/kg, intraperitoneal) resulted significant reduction which lasted several days after end administration. combination immunohistochemistry ex vivo radiotracer assay, find JNJ-54175446-treated at display astrogliosis altered microglia process morphology within ipsilateral CA3 subfield hippocampus, but no difference surface expression. present study extends characterisation provides further evidence targeting may therapeutic applications treatment

Language: Английский

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Behavioral comorbidities treatment by fecal microbiota transplantation in canine epilepsy: a pilot study of a novel therapeutic approach

Frontiers in Veterinary Science, Journal Year: 2024, Volume and Issue: 11

Published: June 21, 2024

Introduction Anxiety and cognitive dysfunction are frequent, difficult to treat burdensome comorbidities in human canine epilepsy. Fecal microbiota transplantation (FMT) has been shown modulate behavior rodent models by altering the gastrointestinal (GIM). This study aims investigate beneficial effects of FMT on behavioral a translational model Methods Nine dogs with drug-resistant epilepsy (DRE) were recruited. The fecal donor had unremarkable behavior, which exhibited complete response phenobarbital, resulting it being seizure-free long term. FMTs performed three times, two weeks apart, follow-up visits at six months after FMTs. Comprehensive analysis, including formerly validated questionnaires tests for attention deficit hyperactivity disorder (ADHD)- fear- anxiety-like as well dysfunction, conducted, followed objective computational analysis. Blood samples taken analysis antiseizure drug (ASD) concentrations, hematology, biochemistry. Urine neurotransmitter concentrations measured. subjected using shallow DNA shotgun sequencing, real-time polymerase chain reaction (qPCR)-based Dysbiosis Index (DI) assessment, short-chain fatty acid (SCFA) quantification. Results Following FMT, patients showed improvement ADHD-like quality life. excitatory neurotransmitters aspartate glutamate decreased, while inhibitory gamma-aminobutyric (GABA) GABA/glutamate ratio increased compared baseline. Only minor taxonomic changes observed, decrease Firmicutes Blautia_A species, Ruminococcus species increased. Functional gene SCFA concentration, blood parameters, ASD remained unchanged. Discussion Behavioral IE could be alleviated FMT. highlights FMT’s potential novel approach improving enhancing life

Language: Английский

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Diffusion tensor imaging for detecting biomarkers of idiopathic epilepsy in dogs

Frontiers in Veterinary Science, Journal Year: 2025, Volume and Issue: 11

Published: Jan. 7, 2025

Idiopathic epilepsy (IE) is the most common neurological disease in dogs. Approximately 1/3 of dogs with IE are resistant to anti-seizure medications (ASMs). Because diagnosis largely based on exclusion other diseases, it would be beneficial indicate an biomarker better understand, diagnose, and treat this disease. Diffusion tensor imaging (DTI), a magnetic resonance (MRI) sequence, used human medicine detect microstructural biomarkers epilepsy. Based translational model between people dogs, use DTI should investigated veterinary context determine if viable resource for detecting white matter abnormalities brains IE. As well, there differences microstructure who responsive ASMs ASMs. Using understand neurostructural associated ASM resistance might help refine diagnostic approaches treatment processes medicine.

Language: Английский

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Plasma metabolome reveals altered oxidative stress, inflammation, and amino acid metabolism in dogs with idiopathic epilepsy

Epilepsia, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract Objective Idiopathic epilepsy (IE) is the most common chronic neurological disease in dogs and an established natural animal model for human types with genetic unknown etiology. However, metabolic pathways underlying IE remain largely unknown. Methods Plasma samples of healthy ( n = 39) 49) were metabolically profiled 121 known target metabolites) fingerprinted 1825 untargeted features) using liquid chromatography coupled to mass spectrometry. Dogs classified as mild phenotype (MP; 22) or drug‐resistant (DR; 27). All received same standard adult maintenance diet a minimum 20 days (35 ± 11 days) before sampling. Data analyzed combination univariate (one‐way analysis variance Kruskal–Wallis rank sum test), multivariate limma , orthogonal partial least squares–discriminant analysis), pathway enrichment statistical analysis. Results In both DR MP IE, distinct plasma profile fingerprint compared was observed. Metabolic involved these alterations included oxidative stress, inflammation, amino acid metabolism. Moreover, significantly lower concentrations vitamin B6 found p .001) .005) dogs. Significance Our data provide new insights into dogs, further substantiating its potential humans epilepsy, reflected by related changes stress metabolites B6. Even more, several within uncovered offer promising therapeutic targets management primarily ultimately humans.

Language: Английский

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Comparative Assessment of Faecal Microbiota in Healthy and Epileptic Dogs

Journal of Anatolian Environmental and Animal Sciences, Journal Year: 2025, Volume and Issue: 10(1), P. 79 - 86

Published: Jan. 28, 2025

Idiopathic epilepsy is a neurological condition affecting dogs and cats characterized by repeated seizures for which no cause other than hypothesized genetic predisposition can be identified. The aim of this study was to comparatively evaluate the content mesophilic aerobic bacteria, coliform Escherichia coli, Enterococcus spp., Staphylococcus aureus Lactobacillus spp. in faecal flora healthy diagnosed with epilepsy. Feces 10 were used as material. Selective isolation counts performed inoculating samples on Tryptic Soy Agar MacConkey Eosin Methylene Blue E. Bile Esculin Mannitol Salt S. De Man, Rogosa Sharpe numbers 6.6x106, 2.6x105, 1.4x105, 1.6x105, 3.2x104 4.1 x 104 cfu/mg dogs; 9.0x106, 5.0x105, 2.8x105, 6.4x105, 6.3x104, 1.2x104 epilepsy, respectively. As result, there decrease number compared dogs, while bacteria increased. It concluded that adding probiotic diet epileptic could help regulate gut microbiota reduce severity frequency seizures.

Language: Английский

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One Digital Health - Wearable Technologies bridging the gap between Humans and Pets: A Viewpoint towards Healthcare 5.0 (Preprint)

Published: Feb. 7, 2025

This viewpoint explores the transformative potential of integrating health monitoring between humans and pets through wearable technology, underscoring interconnected nature human-pet health. Wearable technologies mark a transition in healthcare evolution, from paternalistic (Healthcare 1.0) to reactive 2.0), proactive 3.0), data-integrated care 4.0). The next stage, Healthcare 5.0, envisions seamless integration human pet data, fostering more holistic approach disease prevention management. paper examines parallel evolution monitoring, assessing current their enhance both fields. We structure our discussion around five key themes: (i) managing chronic conditions, (ii) physical activity, (iii) behavioral mental health, (iv) early detection, (v) clinical applications. not only improve management but also enable detection zoonotic emerging diseases, contributing public strategies. Additionally, we highlight reusability devices for pets, which can reduce costs accelerate implementation. symbiotic fosters mutual benefits. necessity an integrated, linked platform is emphasized, as it enables real-time data analysis insights, ultimately leading better diagnostic accuracy, optimized treatment plans, enhanced quality life pets. By repurposing advancing contribute collection, patient-centered care, predictive analytics, preventive healthcare—ultimately accelerating realization 5.0.

Language: Английский

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Non-invasive canine electroencephalography (EEG): a systematic review

BMC Veterinary Research, Journal Year: 2025, Volume and Issue: 21(1)

Published: Feb. 18, 2025

The emerging field of canine cognitive neuroscience uses neuroimaging tools such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) to map the processes dogs neural substrates in their brain. Within past decade, non-invasive use EEG has provided real-time, accessible, portable insight into processes. To promote systematization create an overview framings, methods findings for future work, we provide a systematic review studies (N=22), dissecting study makeup, technical setup, analysis frameworks highlighting trends. We further propose new directions development, standardization data structures integrating predictive modeling with descriptive statistical approaches. Our ends by underscoring advances advantages EEG-based potential accessible inform both fundamental sciences well practical applications neuroscience, working dogs, human-canine interactions.

Language: Английский

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