In vitro and in vivo experimental models employed in the discovery and development of antiepileptic drugs for pharmacoresistant epilepsy

Campos, Gonçalo; Fortuna, Ana; Alves, Gilberto

doi:10.1016/j.eplepsyres.2018.07.008

Cited by 41 publications

(30 citation statements)

References 201 publications

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“…Although it is estimated that one in 26 people develop epilepsy within their lifetime, current AEDs are not effective for a third of affected patients . This unmet need has led to the development of 17 clinically approved AEDs in the last 30 years . The rise in the number of clinically available AEDs resulted in the use of polytherapy to address drug‐resistant epilepsies.…”

Section: Discussionmentioning

confidence: 99%

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Sulfasalazine decreases mouse cortical hyperexcitability

et al. 2019

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Objective Currently prescribed antiepileptic drugs (AEDs) are ineffective in treating approximately 30% of epilepsy patients. Sulfasalazine (SAS) is an US Food and Drug Administration (FDA)–approved drug for the treatment of Crohn disease that has been shown to inhibit the cystine/glutamate antiporter system xc‐ (SXC) and decrease tumor‐associated seizures. This study evaluates the effect of SAS on distinct pharmacologically induced network excitability and determines whether it can further decrease hyperexcitability when administered with currently prescribed AEDs. Methods Using in vitro cortical mouse brain slices, whole‐cell patch‐clamp recordings were made from layer 2/3 pyramidal neurons. Epileptiform activity was induced with bicuculline (bic), 4‐aminopyridine (4‐AP) and magnesium‐free (Mg2+‐free) solution to determine the effect of SAS on epileptiform events. In addition, voltage‐sensitive dye (VSD) recordings were performed to characterize the effect of SAS on the spatiotemporal spread of hyperexcitable network activity and compared to currently prescribed AEDs. Results SAS decreased evoked excitatory postsynaptic currents (eEPSCs) and increased the decay kinetics of evoked inhibitory postsynaptic currents (eIPSCs) in layer 2/3 pyramidal neurons. Although application of SAS to bic and Mg2+‐free–induced epileptiform activity caused a decrease in the duration of epileptiform events, SAS completely blocked 4‐AP–induced epileptiform events. In VSD recordings, SAS decreased VSD optical signals induced by 4‐AP. Co‐application of SAS with the AED topiramate (TPM) caused a significantly further decrease in the spatiotemporal spread of VSD optical signals. Significance Taken together this study provides evidence that inhibition of SXC by SAS can decrease network hyperexcitability induced by three distinct pharmacologic agents in the superficial layers of the cortex. Furthermore, SAS provided additional suppression of 4‐AP–induced network activity when administered with the currently prescribed AED TPM. These findings may serve as a foundation to assess the potential for SAS or other compounds that selectively target SXC as an adjuvant treatment for epilepsy.

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Section: Discussionmentioning

confidence: 99%

“…24 This unmet need has led to the development of 17 clinically approved AEDs in the last 30 years. 25 The rise in the number of clinically available AEDs resulted in the use of polytherapy to address drug-resistant epilepsies. However, the efficacy of polytherapy has been debated as different studies have demonstrated mixed results.…”

Section: Discussionmentioning

confidence: 99%

Sulfasalazine decreases mouse cortical hyperexcitability

et al. 2019

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“…Besides, the prototype needs to display multiple neuropathological features of chronic TLE, including the loss of GABA-ergic interneurons, persistently waned and abnormal neurogenesis, chronic neuroinflammation, and aberrant mossy fiber sprouting. Numerous studies on SE and TLE have utilized a variety of mouse and rat models exhibiting different frequencies of SRS, behavioral comorbidities and variable levels of neuropathology in the hippocampus and/or other regions of the limbic system [73][74][75][76][77][78]. Nonetheless, the epilepsy field is yet to identify a prototype that presents robust and consistent SRS over days, weeks, and months in the chronic phase of TLE.…”

Section: Discussionmentioning

confidence: 99%

A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology

Upadhya¹,

Kodali²,

Gitaí³

et al. 2019

Aging and disease

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Many animal prototypes illustrating the various attributes of human temporal lobe epilepsy (TLE) are available. These models have been invaluable for comprehending multiple epileptogenic processes, modifications in electrophysiological properties, neuronal hyperexcitability, neurodegeneration, neural plasticity, and chronic neuroinflammation in TLE. Some models have also uncovered the efficacy of new antiepileptic drugs or biologics for alleviating epileptogenesis, cognitive impairments, or spontaneous recurrent seizures (SRS). Nonetheless, the suitability of these models for testing candidate therapeutics in conditions such as chronic TLE is debatable because of a lower frequency of SRS and an inconsistent pattern of SRS activity over days, weeks or months. An ideal prototype of chronic TLE for investigating novel therapeutics would need to display a large number of SRS with a dependable frequency and severity and related co-morbidities. This study presents a new kainic acid (KA) model of chronic TLE generated through induction of status epilepticus (SE) in 6-8 weeks old male F344 rats. A rigorous characterization in the chronic epilepsy period validated that the animal prototype mimicked the most salient features of robust chronic TLE. Animals displayed a constant frequency and intensity of SRS across weeks and months in the 5th and 6th month after SE, as well as cognitive and mood impairments. Moreover, SRS frequency displayed a rhythmic pattern with 24-hour periodicity and a consistently higher number of SRS in the daylight period. Besides, the model showed many neuropathological features of chronic TLE, which include a partial loss of inhibitory interneurons, reduced neurogenesis with persistent aberrant migration of newly born neurons, chronic neuroinflammation typified by hypertrophied astrocytes and rod-shaped microglia, and a significant aberrant mossy fiber sprouting in the hippocampus. This consistent chronic seizure model is ideal for investigating the efficacy of various antiepileptic drugs and biologics as well as understanding multiple pathophysiological mechanisms underlying chronic epilepsy.

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“…Laboratory animals represent a valuable tool for mimicking physiological conditions in humans and are, therefore, still widely used for biomedical research in the pursuit of understanding the pathophysiology of a disease and exploring novel treatments 1,2 . On the other hand, improving animal welfare is important in order to alleviate the suffering of animals.…”

Section: Introductionmentioning

confidence: 99%

A novel multi-parametric analysis of non-invasive methods to assess animal distress during chronic pancreatitis

Abdelrahman

Kumstel

Zhang

et al. 2019

Sci Rep

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ethical responsibility, legal requirements and the need to improve the quality of research create a growing interest in the welfare of laboratory animals. Judging the welfare of animals requires readout parameters, which are valid and sensitive as well as specific to assess distress after different interventions. In the present study, we evaluated the sensitivity and specificity of different non-invasive parameters (body weight change, faecal corticosterone metabolites concentration, burrowing and nesting activity) by receiver operating characteristic curves and judged the merit of a multi-parametric analysis by logistic regression. Chronic pancreatitis as well as laparotomy caused significant changes in all parameters. However, the accuracy of these parameters was different between the two animal models. in both animal models, the multi-parametric analysis relying on all the readout parameters had the highest accuracy when predicting distress. this multi-parametric analysis revealed that C57BL/6 mice during the course of chronic pancreatitis often experienced less distress than mice after laparotomy. interestingly these data also suggest that distress does not steadily increase during chronic pancreatitis. in conclusion, combining these non-invasive methods for severity assessment represents a reliable approach to evaluate animal distress in models such as chronic pancreatitis.

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In vitro and in vivo experimental models employed in the discovery and development of antiepileptic drugs for pharmacoresistant epilepsy

Cited by 41 publications

References 201 publications

Sulfasalazine decreases mouse cortical hyperexcitability

Sulfasalazine decreases mouse cortical hyperexcitability

A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology

A novel multi-parametric analysis of non-invasive methods to assess animal distress during chronic pancreatitis

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