Neurobehavioral comorbidities of epilepsy: Role of inflammation

Mazarati, Andréy; Lewis, Megan L.; Pittman, Quentin J.

doi:10.1111/epi.13786

Cited by 81 publications

(63 citation statements)

References 141 publications

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“…Similar findings were reported in animal models of acute symptomatic seizures, febrile and nonfebrile SE, and models of acquired epilepsies, absence epilepsy, and progressive myoclonic epilepsy . Activation of this inflammatory signaling in animals is involved in epileptogenesis and contributes to seizure generation and recurrence, and to neurological comorbidities …”

Section: Anakinrasupporting

confidence: 79%

“…[116][117][118] Activation of this inflammatory signaling in animals is involved in epileptogenesis [119][120][121] and contributes to seizure generation and recurrence, 122 and to neurological comorbidities. 123 Only three studies have addressed the role of anakinra in epileptogenesis. In one, anakinra (100 mg/kg ip, ie, total daily dose = 5 mg/rat, equivalent to human adult dose of 16 mg/kg) 124 was coadministered with an investigational cyclooxygenase-2 (COX-2) antagonist (CAY 10404) 125 at the time of Li + pilocarpine-induced SE in 21-day-old rats, then daily for an additional 10 days.…”

Section: Anakinramentioning

confidence: 99%

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Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

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Section: Anakinrasupporting

confidence: 79%

Section: Anakinramentioning

confidence: 99%

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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“…Furthermore, in LPS‐treated mice, the process leading to the seizure activity appears to require a latent period, with progressive development in both the appearance and the frequency of seizure activity over the 4‐week recording period. Therefore, it appears that the occurrence of an immune challenge during development might initiate pathophysiological alterations that do not manifest until adulthood . We do not know whether the increase in frequency of seizures we see over the 4‐week period is part of this maturation process or indicative of epileptogenesis.…”

Section: Discussionmentioning

confidence: 86%

“…Although there are many limitations to determining the current prevalence of these disorders, particularly in the context of a comorbidity, the high co‐occurrence of ASD and epilepsy suggests that common mechanisms may lead to the copresentation of these clinical conditions. To date, the underlying pathophysiology remains largely unknown; however, both disorders are considered to be multifactorial and involve genetic and environmental contributions …”

Section: Introductionmentioning

confidence: 99%

Comorbid epilepsy in autism spectrum disorder: Implications of postnatal inflammation for brain excitability

et al. 2018

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These findings suggest that an early postnatal immune challenge can increase brain excitability in adult BTBR mice and reveal an underlying epilepsy phenotype. This novel animal model may enable the elucidation of specific molecular alterations that are associated with the concurrent presentation of ASD and epilepsy, which could facilitate the development of targeted therapies for individuals affected by this comorbidity.

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“…It is important to recognize that while a “stressed” microbiome is pro‐epileptic, it does not itself cause epilepsy, although to the best of my knowledge this has never been tested in long‐term stressed animals. However, as the authors suggest, the presence of a dysbiotic microbiome in conditions as varied as autism spectrum disorder and colitis may underlie the increased incidence of co‐morbid epilepsy in these conditions …”

mentioning

confidence: 99%

Stress co‐opts the gut to affect epileptogenesis. Commentary on “Facilitation of kindling epileptogenesis by chronic stress may be mediated by intestinal microbiome”

Neurobehavioral comorbidities of epilepsy: Role of inflammation

Cited by 81 publications

References 141 publications

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Comorbid epilepsy in autism spectrum disorder: Implications of postnatal inflammation for brain excitability

Stress co‐opts the gut to affect epileptogenesis. Commentary on “Facilitation of kindling epileptogenesis by chronic stress may be mediated by intestinal microbiome”

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