Modeling poststroke epilepsy and preclinical development of drugs for poststroke epilepsy

Leo, Antonio; De, Carmen; Nesci, Valentina; Tallarico, Martina; Sarro, Giovambattista De; Russo, Emilio; Citraro, Rita

doi:10.1016/j.yebeh.2019.106472

Cited by 8 publications

(6 citation statements)

References 116 publications

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“…In contrast, we also demonstrated that the photothrombotic (or PT) stroke model used in our study showed nonconvulsive seizures of shorter duration than pMCAO seizures 36 . This photothrombotic ischemic model also generated variations in ictal activity, with sharp waves followed by hypersynchronous polyspike discharges, in contrast with the classical spike‐and‐wave morphology of the pMCAO seizure model 14,42,43 . However, our results with the PT model demonstrated that early poststroke seizures were restricted primarily to large cortical lesions, whereas smaller photothrombotic lesions did not induce seizures.…”

Section: Discussioncontrasting

confidence: 45%

“…36 This photothrombotic ischemic model also generated variations in ictal activity, with sharp waves followed by hypersynchronous polyspike discharges, in contrast with the classical spike-and-wave morphology of the pMCAO seizure model. 14,42,43 However, our results with the PT model demonstrated that early poststroke seizures were restricted primarily to large cortical lesions, whereas smaller photothrombotic lesions did not induce seizures. This observation supports previous clinical data in which the probability of early seizures was higher in patients with stroke with larger lesions.…”

Section: F I G U R E 4 Intracranial Electroencephalography (Ieeg) Cha...mentioning

confidence: 50%

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Preclinical examination of early‐onset thalamic‐cortical seizures after hemispheric stroke

García‐Peña,

Ramos,

López

et al. 2023

Epilepsia

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ObjectiveIschemic stroke is one of the main causes of death and disability worldwide and currently has limited treatment options. Electroencephalography (EEG) signals are significantly affected in stroke patients during the acute stage. In this study, we preclinically characterized the brain electrical rhythms and seizure activity during the hyperacute and late acute phases in a hemispheric stroke model with no reperfusion.MethodsEEG signals and seizures were studied in a model of hemispheric infarction induced by permanent occlusion of the middle cerebral artery (pMCAO), which mimics the clinical condition of stroke patients with permanent ischemia. Electrical brain activity was also examined using a photothrombotic (PT) stroke model. In the PT model, we induced a similar (PT group‐1) or smaller (PT group‐2) cortical lesion than in the pMCAO model. For all models, we used a nonconsanguineous mouse strain that mimics human diversity and genetic variation.ResultsThe pMCAO hemispheric stroke model exhibited thalamic‐origin nonconvulsive seizures during the hyperacute stage that propagated to the thalamus and cortex. The seizures were also accompanied by progressive slowing of the EEG signal during the acute phase, with elevated delta/theta, delta/alpha, and delta/beta ratios. Cortical seizures were also confirmed in the PT stroke model of similar lesions as in the pMCAO model, but not in the PT model of smaller injuries.SignificanceIn the clinically relevant pMCAO model, poststroke seizures and EEG abnormalities were inferred from recordings of the contralateral hemisphere (noninfarcted hemisphere), emphasizing the reciprocity of interhemispheric connections and that injuries affecting one hemisphere had consequences for the other. Our results recapitulate many of the EEG signal hallmarks seen in stroke patients, thereby validating this specific mouse model for the examination of the mechanistic aspects of brain function and for the exploration of the reversion or suppression of EEG abnormalities in response to neuroprotective and anti‐epileptic therapies.

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Section: Discussioncontrasting

confidence: 45%

Section: F I G U R E 4 Intracranial Electroencephalography (Ieeg) Cha...mentioning

confidence: 50%

Preclinical examination of early‐onset thalamic‐cortical seizures after hemispheric stroke

García‐Peña,

Ramos,

López

et al. 2023

Epilepsia

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“…In analogy to rodent models of stroke and hypoxiainduced epilepsies via middle cerebral artery occlusion and cortical photothrombosis [53], zebrafish with their well-described cerebrovascular system [54,55] and accessible brains also presents a great potential for developing stroke-induced epilepsy models. In fact, there are currently several zebrafish stroke models readily available via genetic interventions [56], reduced oxygen levels [57], and photochemical thrombosis [58].…”

Section: Causes Of Epilepsymentioning

confidence: 99%

Past, present and future of zebrafish in epilepsy research

et al. 2021

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Animal models contribute greatly to our understanding of brain development and function as well as its dysfunction in neurological diseases. Epilepsy research is a very good example of how animal models can provide us with a mechanistic understanding of the genes, molecules, and pathophysiological processes involved in disease. Over the course of the last two decades, zebrafish came in as a new player in epilepsy research, with an expanding number of laboratories using this animal to understand epilepsy and to discover new strategies for preventing seizures. Yet, zebrafish as a model offers a lot more for epilepsy research. In this viewpoint, we aim to highlight some key contributions of zebrafish to epilepsy research, and we want to emphasize the great untapped potential of this animal model for expanding these contributions. We hope that our suggestions will trigger further discussions between clinicians and researchers with a common goal to understand and cure epilepsy.

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“…Interestingly, some clinical and preclinical studies reported that hyperglycemia and/or obesity, which represent risk factors for T2DM, can precipitate seizures, particularly those of focal onset [5][6][7][8][9]. Furthermore, it has been well-established that several diseases associated with MetS and/or T2DM such as hypertension and stroke are also predisposing factors to epilepsy [10][11][12], whereas others such as cognitive impairment, anxiety and depression are well-documented comorbidities of both conditions [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Alterations Predispose to Seizure Development in High-Fat Diet-Treated Mice: the Role of Metformin

et al. 2020

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The link between epilepsy and type 2 diabetes (T2DM) and/or metabolic syndrome (MetS) has been poorly investigated. Therefore, we tested whether a high fat diet (HFD), inducing insulinresistant diabetes and obesity in mice, would increase susceptibility to develop generalized seizures induced by pentylentetrazole (PTZ) kindling. Furthermore, molecular mechanisms linked to glucose brain transport and the effects of the T2DM antidiabetic drug metformin were also studied along with neuropsychiatric comorbidities. To this aim, two sets of experiments were performed in CD1 mice, in which we firstly evaluated the HFD effects on some metabolic and behavioral parameters in order to have a baseline reference for kindling experiments assessed in the second section of our protocol. We detected that HFD predisposes towards seizure development in the PTZ-kindling model and this was linked to a reduction in glucose transporter-1 (GLUT-1) expression as observed in GLUT-1 deficiency syndrome in humans but accompanied by a compensatory increase in expression of GLUT-3. While we confirmed that HFD induced neuropsychiatric alterations in the treated mice, it did not change the development of kindling comorbidities. Furthermore, we propose that the beneficial effects of metformin we observed towards seizure development, are related to a normalization of both GLUT-1 and GLUT-3 expression levels. Overall, our results support the hypothesis that an altered glycometabolic profile could play a pro-epileptic role in human patients. We therefore recommend that MetS or T2DM should be constantly monitored and possibly avoided in patients with epilepsy, since they could further aggravate this latter condition.

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Modeling poststroke epilepsy and preclinical development of drugs for poststroke epilepsy

Cited by 8 publications

References 116 publications

Preclinical examination of early‐onset thalamic‐cortical seizures after hemispheric stroke

Preclinical examination of early‐onset thalamic‐cortical seizures after hemispheric stroke

Past, present and future of zebrafish in epilepsy research

Metabolic Alterations Predispose to Seizure Development in High-Fat Diet-Treated Mice: the Role of Metformin

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