Lovastatin decreases the synthesis of inflammatory mediators during epileptogenesis in the hippocampus of rats submitted to pilocarpine-induced epilepsy

Gouveia, Telma Luciana Furtado; Scorza, Fúlvio A.; Iha, Higor A.; Frangiotti, Maria Isabel Berzaghi; Perosa, Sandra Regina; Cavalheiro, Ésper A.; Silva, J.A.; Feliciano, Regiane dos Santos; Almeida, Antonio Carlos de; Naffah-Mazzacoratti, Maria da Graça

doi:10.1016/j.yebeh.2014.04.009

Cited by 34 publications

(21 citation statements)

References 42 publications

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“…For example, IL-1β and TNFα levels are rapidly augmented in the cortex and hippocampus of rats following exposure to sarin (Chapman et al, 2006). However, unlike IL-1β and TNFα, the mRNA expression of IL-10 remains relatively unchanged following pilocarpine induced status epilepticus (Gouveia et al, 2014). ELISA was performed to measure the level of IL-1β, TNFα and IL-10 in protein homogenates prepared from the forebrains of rats administered DFP and euthanized at various time points after the onset of status epilepticus.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus

et al. 2015

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Exposure to high levels of organophosphorus compounds (OP) can induce status epilepticus (SE) in humans and rodents via acute cholinergic toxicity, leading to neurodegeneration and brain inflammation. Currently there is no treatment to combat the neuropathologies associated with OP exposure. We recently demonstrated that inhibition of the EP2 receptor for PGE2 reduces neuronal injury in mice following pilocarpine-induced SE. Here, we investigated the therapeutic effects of an EP2 inhibitor (TG6-10-1) in a rat model of SE using diisopropyl fluorophosphate (DFP). We tested the hypothesis that EP2 receptor inhibition initiated well after the onset of DFP-induced SE reduces the associated neuropathologies. Adult male Sprague-Dawley rats were injected with pyridostigmine bromide (0.1 mg/kg, sc) and atropine methylbromide (20 mg/kg, sc) followed by DFP (9.5 mg/kg, ip) to induce SE. DFP administration resulted in prolonged upregulation of COX-2. The rats were administered TG6-10-1 or vehicle (ip) at various time points relative to DFP exposure. Treatment with TG6-10-1 or vehicle did not alter the observed behavioral seizures, however six doses of TG6-10-1 starting 80-150 min after the onset of DFP-induced SE significantly reduced neurodegeneration in the hippocampus, blunted the inflammatory cytokine burst, reduced microglial activation and decreased weight loss in the days after status epilepticus. By contrast, astrogliosis was unaffected by EP2 inhibition 4 d after DFP. Transient treatments with the EP2 antagonist 1 h before DFP, or beginning 4 h after DFP, were ineffective. Delayed mortality, which was low (10%) after DFP, was unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor within a time window that coincides with the induction of cyclooxygenase-2 by DFP is neuroprotective and accelerates functional recovery of rats.

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Section: Resultsmentioning

confidence: 99%

Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus

et al. 2015

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“…This was associated with reduced lesion‐induced expression of IL‐1β and TNF at 3 days after kainate lesion, suppression of kainate‐induced reactive astrocytosis 4‐6 months after kainate lesion, and attenuation of loss of CA3 pyramidal neurons and dentate hilar interneurons, and reduced mossy fiber sprouting at 4‐6 months . Finally, lovastatin 20‐mg/kg/d treatment for 15 days starting 2 hours after pilo‐induced SE onset decreased the levels of increased IL‐1β, TNF, and IL‐6 during the latent phase and of IL‐1β and TNF during the chronic phase, and increased expression of the anti‐inflammatory cytokine IL‐10 …”

Section: Atorvastatin and Other Statinsmentioning

confidence: 92%

“…154 Finally, lovastatin 20-mg/kg/d treatment for 15 days starting 2 hours after pilo-induced SE onset decreased the levels of increased IL-1β, TNF, and IL-6 during the latent phase and of IL-1β and TNF during the chronic phase, and increased expression of the anti-inflammatory cytokine IL-10. 155 No antiepileptogenic animal studies of statins done to date have shown disease prevention, only disease modification. There are no preclinical studies of antiepileptogenic effects of statins when administered at clinically relevant latency after injury, nor any studies after TBI or stroke.…”

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confidence: 99%

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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“…Epileptogenesis is a process in which a healthy brain becomes predisposed to epileptic seizures. Excitotoxicity with proinflammatory cytokines, such as interleukin-1B (IL-1B), IL-6 and tumour necrosis factor (TNF), is highly linked to epileptogenesis, forming a vicious circle of epileptogenesis and seizures [23]. Kuzawi nska et al [24] reported considerably higher expression for IL-1B, IL-6 and TNF in the trigeminal ganglion neurons of male mice than in those of female mice.…”

Section: Discussionmentioning

confidence: 99%

Male, old age and low income to predispose epilepsy in migraineurs

Harnod

Wang

Tseng

2016

Eur J Clin Investigation

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Lovastatin decreases the synthesis of inflammatory mediators during epileptogenesis in the hippocampus of rats submitted to pilocarpine-induced epilepsy

Cited by 34 publications

References 42 publications

Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus

Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus

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

Male, old age and low income to predispose epilepsy in migraineurs

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