Increased susceptibility to pentylenetetrazol following survival of cerebral malaria in mice

Grauncke, Ana Claudia Beck; Souza, Thaíze Lopes de; Ribeiro, Leandro Rodrigo; Brant, Fátima; Machado, Fabiana S.; Oliveira, Mauro Schneider

doi:10.1111/epi.13425

Cited by 7 publications

(7 citation statements)

References 17 publications

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“…Moreover, decreases in seizure threshold of postpilocarpine SE rats, as measured by PTZ infusion, correlated directly with onset of SRS weeks after SE, further supporting the potential that seizure threshold is an etiologically relevant biomarker of SRS. Furthermore, cerebral malaria in C57Bl6 mice promotes increased susceptibility to myoclonic and tonic–clonic seizures induced by low‐dose PTZ up to 45 days after infection . Indeed, TMEV‐infected mice develop SRS and reductions in seizure threshold weeks after infection .…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, cerebral malaria in C57Bl6 mice promotes increased susceptibility to myoclonic and tonic-clonic seizures induced by low-dose PTZ up to 45 days after infection. 40 Indeed, TMEV-infected mice develop SRS and reductions in seizure threshold weeks after infection. 12,13 That MIN treatment during the acute seizure phase can mitigate chronic proconvulsant effects associated with infection suggests that seizure threshold is a useful biomarker of TMEV-induced disease progression.…”

Section: Discussionmentioning

confidence: 99%

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Acute treatment with minocycline, but not valproic acid, improves long‐term behavioral outcomes in the Theiler's virus model of temporal lobe epilepsy

et al. 2016

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Summary Objective Infection with Theiler’s murine encephalomyelitis virus (TMEV) in C57Bl/6J mice induces acute seizures and development of spontaneous recurrent seizures and behavioral comorbidities weeks later. The present studies sought to determine whether acute therapeutic intervention with an anti-inflammatory–based approach could prevent or modify development of TMEV-induced long-term behavioral comorbidities. Valproic acid (VPA), in addition to its prototypical anticonvulsant properties, inhibits histone deacetylase (HDAC) activity, which may alter expression of the inflammasome. Minocycline (MIN) has previously demonstrated an antiseizure effect in the TMEV model via direct anti-inflammatory mechanisms, but the long-term effect of MIN treatment on the development of chronic behavioral comorbidities is unknown. Methods Mice infected with TMEV were acutely administered MIN (50 mg/kg, b.i.d. and q.d.) or VPA (100 mg/kg, q.d.) during the 7-day viral infection period. Animals were evaluated for acute seizure severity and subsequent development of chronic behavioral comorbidities and seizure threshold. Results Administration of VPA reduced the proportion of mice with seizures, delayed onset of symptomatic seizures, and reduced seizure burden during the acute infection. This was in contrast to the effects of administration of once-daily MIN, which did not affect the proportion of mice with seizures nor delay onset of acute symptomatic seizures. However, VPA-treated mice were no different from VEH-treated mice in long-term behavioral outcomes, including open field activity and seizure threshold. Once-daily MIN treatment, despite no effect on the maximum observed Racine stage seizure severity, was associated with improved long-term behavioral outcomes and normalized seizure threshold. Significance Acute seizure control alone is insufficient to modify chronic disease comorbidities in the TMEV model. This work further supports the role of an inflammatory response in the development of chronic behavioral comorbidities and further highlights the utility of this platform for the development of mechanistically-novel pharmacotherapies for epilepsy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Acute treatment with minocycline, but not valproic acid, improves long‐term behavioral outcomes in the Theiler's virus model of temporal lobe epilepsy

et al. 2016

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“…By using the chronic changes in seizure threshold and behavioral outcomes, we have been able to demonstrate long‐term disease modification with acutely administered agents. Indeed, a reduction in the threshold to pentylenetetrazol‐induced tonic–clonic seizures is also observed following rescue from cerebral malaria, suggesting that seizure threshold is a useful biomarker of the disease process. W. Löscher's group utilizes the intravenous pentylenetetrazol assay as a biomarker of spontaneous recurrent seizures following status epilepticus, thereby further supporting this assay as an appropriate means to clearly demonstrate disease modifying and/or antiepileptogenic outcomes following TMEV infection.…”

Section: Epileptogenesis In a Murine Model Of Viral Encephalitismentioning

confidence: 99%

Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy

et al. 2017

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Animal models have provided a wealth of information on mechanisms of epileptogenesis and comorbidogenesis and have significantly advanced our ability to investigate the potential of new therapies. Processes implicating brain inflammation have been increasingly observed in epilepsy research. Here, we discuss the progress on animal models of epilepsies and comorbidities that inform us on the potential role of inflammation in epileptogenesis and comorbidity pathogenesis in rodent models of West syndrome and the Theiler’s murine encephalomyelitis virus (TMEV) mouse model of viral encephalitis-induced epilepsy. Rat models of infantile spasms were generated in rat pups after right intracerebral injections of pro-inflammatory compounds (lipopolysaccharides with or without doxorubicin, or cytokines) and were longitudinally monitored for epileptic spasms and neurodevelopmental and cognitive deficits. Anti-inflammatory treatments were tested after the onset of spasms. The TMEV mouse model was induced with intracerebral administration of TMEV and prospective monitoring for handling-induced seizures or seizure susceptibility, as well as long-term evaluations of behavioral comorbidities of epilepsy. Inflammatory processes are evident in both models and are implicated in the pathogenesis of the observed seizures and comorbidities. A common feature of these models, based on the data so far available, is their pharmacoresistant profile. The presented data support the role of inflammatory pathways in epileptogenesis and comorbidities in two distinct epilepsy models. Pharmacoresistance is a common feature of both of these inflammation-based models. Utilization of these models may facilitate the identification of age-specific, syndrome- or etiology- specific therapies for the epilepsies and attendant comorbidities, including the drug resistant forms.

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“…In previous work, seizures have been observed during the acute infectious stage of CM202122, but spontaneous recurrent seizures following infection have not been observed22. We observed epilepsy as a sequela of CM across genetic background of host and parasite combinations for both outbred stock (SW) and inbred animal strains (CBA and C57BL/6).…”

Section: Discussionmentioning

confidence: 54%

A Murine Model to Study Epilepsy and SUDEP Induced by Malaria Infection

Ssentongo

Robuccio

Thuku

et al. 2017

Sci Rep

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One of the largest single sources of epilepsy in the world is produced as a neurological sequela in survivors of cerebral malaria. Nevertheless, the pathophysiological mechanisms of such epileptogenesis remain unknown and no adjunctive therapy during cerebral malaria has been shown to reduce the rate of subsequent epilepsy. There is no existing animal model of postmalarial epilepsy. In this technical report we demonstrate the first such animal models. These models were created from multiple mouse and parasite strain combinations, so that the epilepsy observed retained universality with respect to genetic background. We also discovered spontaneous sudden unexpected death in epilepsy (SUDEP) in two of our strain combinations. These models offer a platform to enable new preclinical research into mechanisms and prevention of epilepsy and SUDEP.

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Increased susceptibility to pentylenetetrazol following survival of cerebral malaria in mice

Cited by 7 publications

References 17 publications

Acute treatment with minocycline, but not valproic acid, improves long‐term behavioral outcomes in the Theiler's virus model of temporal lobe epilepsy

Acute treatment with minocycline, but not valproic acid, improves long‐term behavioral outcomes in the Theiler's virus model of temporal lobe epilepsy

Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy

A Murine Model to Study Epilepsy and SUDEP Induced by Malaria Infection

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