Effective treatments of prolonged status epilepticus in developing rats

Hasson, Henry; Kim, Mimi; Moshé, Solomon L.

doi:10.1016/j.yebeh.2008.02.008

Cited by 24 publications

(17 citation statements)

References 37 publications

(37 reference statements)

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“…Age (Dube et al, 2001; Priel et al, 1996; Sankar et al, 1997), strain (Xu et al, 2004), pilocarpine dose (Cavalheiro et al, 1987; Priel et al, 1996), presence of lithium (Clifford et al, 1987), electrode implantation techniques (Boast et al, 1976; Loscher et al, 1995), attenuation of SE with benzodiazepine (Hasson et al, 2008) or paraldehyde (Kubova et al, 2005), as well as both timing and type of injury assessment have all been postulated to affect the degree of detectable neuronal loss. Table 2 summarizes some of the parameters used previously to assess for neuronal damage outside the hippocampus in immature animals after LiPC induced SE (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat

2013

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Although hippocampal sclerosis is frequently identified as a possible epileptic focus in patients with temporal lobe epilepsy, neuronal loss has also been observed in additional structures, including areas outside the temporal lobe. The claim from several researchers using animal models of acquired epilepsy that the immature brain can develop epilepsy without evidence of hippocampal neuronal death raises the possibility that neuronal death in some of these other regions may also be important for epileptogenesis. The present study used the lithium pilocarpine model of acquired epilepsy in immature animals to assess which structures outside the hippocampus are injured acutely after status epilepticus. Sprague Dawley rat pups were implanted with surface EEG electrodes, and status epilepticus was induced at 20 days of age with lithium pilocarpine. After 72 h, brain tissue from 12 animals was examined with Fluoro-Jade B, a histochemical marker for degenerating neurons. All animals that had confirmed status epilepticus demonstrated Fluoro-Jade B staining in areas outside the hippocampus. The most prominent staining was seen in thalamus (mediodorsal, paratenial, reuniens, and ventral lateral geniculate nuclei), amygdala (ventral lateral, posteromedial, and basomedial nuclei), ventral premammillary nuclei of hypothalamus, and paralimbic cortices (perirhinal, entorhinal, and piriform) as well as parasubiculum and dorsal endopiriform nuclei. These results demonstrate that lithium pilocarpine-induced status epilepticus in the immature rat brain consistently results in neuronal injury in several distinct areas outside of the hippocampus. Many of these regions are similar to areas damaged in patients with temporal lobe epilepsy, thus suggesting a possible role in epileptogenesis.

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Section: Discussionmentioning

confidence: 99%

Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat

2013

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“…Hasson et al. () have also shown that the ability to control prolonged kainate‐ or pilocarpine‐induced SE is age dependent, with total failure of the tested drugs in postnatal (P) day 9 rats, whereas the same treatments were effective in P15 and P21 animals. These models represent a viable screen for the acute effects of putative ASDs as a function of age.…”

Section: Animal Models Of Drug‐resistant Pediatric Epilepsymentioning

confidence: 99%

Issues related to development of new antiseizure treatments

et al. 2013

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Summary This report represents a summary of the discussions led by the anti-seizure treatment working group of the ILAE/AES Working Groups joint meeting in London (London Meeting). We review here what is currently known about the pharmacological characteristics of current models of refractory seizures, both for adult and pediatric epilepsy. In addition, we address how the NINDS-funded Anticonvulsant Screening Program (ASP) is evolving to incorporate appropriate animal models in the search for molecules that might be sufficiently novel to warrant further pharmacological development. We also briefly address what we believe is necessary, going forward, to achieve the goal of stopping seizures in all patients, with a call to arms for funding agencies, the pharmaceutical industry, and basic researchers.

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“…In such cases, antiseizure effect could be secondary to “insult modification,” and comparisons of its efficacy with other drugs that do not share this mechanism will be difficult without dose–response experiments or testing in models with distinct mechanisms. In addition, the efficacy of a drug may change depending on when it is administered (prior to a seizure, immediately after a brief seizure, or after established status epilepticus),34, 35, 36 and can be altered by multiple factors including vehicle, species, age and sex factors, brain permeability, and pharmacokinetics. Drug effects in disease‐naive conditions may be very different from those during an established disease process, due to changes in the expression or function of key drug targets during the course of a disease 37, 38, 39, 40, 41, 42, 43.…”

Section: Interpreting Preclinical Therapy Trialsmentioning

confidence: 99%

Not all that glitters is gold: A guide to critical appraisal of animal drug trials in epilepsy

Galanopoulou

Mowrey

2016

Epilepsia Open

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SummaryPreclinical studies have produced numerous drugs with antiseizure properties that currently are the standard of care. One third of the human population with epilepsy still continues to have seizures despite the ongoing discoveries. The recognized clinical gaps of care that need to be addressed are the identification of antiepileptogenic and disease‐modifying treatments, and treatments for refractory seizures or for seizures and epilepsies with limited or unsatisfactory treatments, such as early life epileptic encephalopathies. In this invited review, we provide a historical summary of the international efforts to reevaluate the strategies adopted in preclinical epilepsy therapy discovery studies. We discuss issues that may affect the quality, interpretation, and validation of preclinical studies and their translation to successful therapies for humans affected with epilepsy. These include the selection of animal models and the study design; research practices that affect rigor (such as appropriate use of statistics and reporting of study methods and results, their validation across models, labs, and preclinical‐clinical studies); the need to harmonize research methods and outcome assessment; and the importance of improving translation to clinically appropriate situations. The epilepsy research community is incrementally adopting collaborative research, including consortia or multicenter studies to meet these needs. Improving the infrastructure that can support these efforts will be instrumental in future success.

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Effective treatments of prolonged status epilepticus in developing rats

Cited by 24 publications

References 37 publications

Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat

Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat

Issues related to development of new antiseizure treatments

Not all that glitters is gold: A guide to critical appraisal of animal drug trials in epilepsy

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