Role of inflammation in epilepsy and neurobehavioral comorbidities: Implication for therapy

Paudel, Yam Nath; Shaikh, Mohd Farooq; Shah, Sadia; Kumari, Yatinesh; Othman, Iekhsan

doi:10.1016/j.ejphar.2018.08.020

Cited by 103 publications

(62 citation statements)

References 116 publications

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“…IL‐1β drives the pathologic role of brain inflammation in epilepsy . Studies on surgically resected epileptogenic foci from drug‐resistant forms of epilepsy with structural or infectious etiologies showed that the IL‐1α–IL‐1R1 axis is activated in neurons, glia, and endothelial cells of the BBB .…”

Section: Anakinramentioning

confidence: 99%

“…IL-1β drives the pathologic role of brain inflammation in epilepsy. [104][105][106][107][108][109][110][111][112] Studies on surgically resected epileptogenic foci from drug-resistant forms of epilepsy with structural or infectious etiologies showed that the IL-1α-IL-1R1 axis is activated in neurons, glia, and endothelial cells of the BBB. 104,107,[113][114][115] Similar findings were reported in animal models of acute symptomatic seizures, febrile and nonfebrile SE, and models of acquired epilepsies, 107,114 absence epilepsy, and progressive myoclonic epilepsy.…”

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: Anakinramentioning

confidence: 99%

Section: Anakinramentioning

confidence: 99%

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

et al. 2020

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“…On a pressing note, future investigations should focus to establish HMGB1 as a target for epilepsy and related comorbid conditions that share a bidirectional relationship with it; namely cognitive decline, depression, anxiety, autism, and schizophrenia (Paudel et al 2018b). Among this array of comorbid conditions, cognitive dysfunction stands out as being highly associated with persons with epilepsy (PWE).…”

Section: Future Perspective Of Hmgb1mentioning

confidence: 99%

“…neurobehavioral and neuropsychiatric disorders, with significant consequences for patients, their families, and society (Yang et al 2017). But much remains to be elucidated about the precise mechanisms of epileptogenesishowever, a plethora of findings over the past decade have highlighted the crucial pathophysiological role of brain inflammation in epilepsy Webster et al 2017;Paudel et al 2018b).…”

mentioning

confidence: 99%

High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

Paudel

Semple

Jones

et al. 2019

Journal of Neurochemistry

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Epilepsy is a serious neurological condition exhibiting complex pathology and deserving of more serious attention. More than 30% of people with epilepsy are not responsive to more than 20 anti‐epileptic drugs currently available, reflecting an unmet clinical need for novel therapeutic strategies. Not much is known about the pathogenesis of epilepsy, but evidence indicates that neuroinflammation might contribute to the onset and progression of epilepsy following acquired brain insults. However, the molecular mechanisms underlying these pathophysiological processes are yet to be fully understood. The emerging research suggests that high‐mobility group box protein 1 (HMGB1), a DNA‐binding protein that is both actively secreted by inflammatory cells and released by necrotic cells, might contribute to the pathogenesis of epilepsy. HMGB1 as an initiator and amplifier of neuroinflammation, and its activation is implicated in the propagation of seizures in animal models. The current review will highlight the potential role of HMGB1 in the pathogenesis of epilepsy, and implications of HMGB1‐targeted therapies against epilepsy. HMGB1 in this context is an emerging concept deserving further exploration. Increased understanding of HMGB1 in seizures and epilepsy will pave the way in designing novel and innovative therapeutic strategies that could modify the disease course or prevent its development.

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“…Anti-inflammatory drugs, such as acetaminophen, celecoxib or aspirin, along with other anti-inflammatory agents such as anti-MGB1 antibodies and COX-2 inhibitors have been shown to possess anti-convulsant properties [73]. Therefore, we suggest incorporating anti-inflammatory drugs into anti-epileptic treatments or therapy could be beneficial in the management of epilepsy and ameliorating comorbidities and side effects that could be exacerbated by neuroinflammation.…”

Section: Resultsmentioning

confidence: 99%

Inflammation: Cause or Consequence of Epilepsy?

Lee¹,

Shaikh²

2019

Epilepsy - Advances in Diagnosis and Therapy

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Epilepsy is the third most common neurological disorder, affecting about 70 million people worldwide. It is defined as a central nervous system disorder which affects the neuronal activity in the brain, causing unprovoked seizures and other behavioral changes. Unfortunately, one-third of epilepsy patients are unresponsive to available therapies and patients who respond to antiepileptic drugs often complain of debilitating side effects. In the effort of devising a suitable therapy for epilepsy treatment, researchers delved into the origin of seizures and the epileptogenic process and found an association between epilepsy and inflammation. Here, we discuss the involvement of inflammatory mediators in the development and progression of seizures and epileptogenesis, supported by clinical shreds of evidence. Subsequently, we discuss the role of inflammation in the generation of seizures, as it is debatable whether inflammation is the cause or consequence of epilepsy, along with experimental models in inflammation and epilepsy research.

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Role of inflammation in epilepsy and neurobehavioral comorbidities: Implication for therapy

Cited by 103 publications

References 116 publications

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

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

High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

Inflammation: Cause or Consequence of Epilepsy?

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