Early Gabapentin Treatment during the Latency Period Increases Convulsive Threshold, Reduces Microglial Activation and Macrophage Infiltration in the Lithium-Pilocarpine Model of Epilepsy

Rossi, Alicia Raquel; Murta, Verónica; Auzmendi, Jerónimo; Ramos, Alberto Javier

doi:10.3390/ph10040093

Cited by 12 publications

(19 citation statements)

References 88 publications

(135 reference statements)

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“…Similar protective effects and increased latency to seizures resulted from prolonged PGB treatment in the pilo‐SE model . Brief (4‐8 days) GBP treatment (400 mg/kg/d) beginning 1 day after SE reduced gliosis, inflammation, and hippocampal neuronal loss, increased seizure threshold, and reduced evoked seizure severity . GBP also has similar protective effects in brain ischemic injury, following direct cortical trauma, and with cortical freeze lesions .…”

Section: Gabapentinoids As Repurposed Antiepileptogenic Drugsmentioning

confidence: 73%

“…205 Brief (4-8 days) GBP treatment (400 mg/ kg/d) beginning 1 day after SE reduced gliosis, inflammation, and hippocampal neuronal loss, 206 increased seizure threshold, and reduced evoked seizure severity. 207 GBP also has similar protective effects in brain ischemic injury, 208 following direct cortical trauma, 199,209 and with cortical freeze lesions. 201,202,210 Progressive increases in excitatory connectivity and epileptogenesis, shown using laser scanning photostimulation of caged glutamate 2 weeks following neocortical trauma in the "undercut" model, are markedly reduced by even a brief 3-day GBP treatment after injury (100 mg/kg ip 3×/d).…”

Section: As Repurposed Antiepileptogenic Drugsmentioning

confidence: 83%

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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: Gabapentinoids As Repurposed Antiepileptogenic Drugsmentioning

confidence: 73%

Section: As Repurposed Antiepileptogenic Drugsmentioning

confidence: 83%

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

et al. 2020

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“…The lithium-pilocarpine model of TLE is a well-established epilepsy paradigm that reproduces most of the features of human TLE, by inducing a precipitating event (SE) followed by a silent epileptogenic period, and subsequently developing spontaneous epileptic seizures (reviewed in Curia et al, 2008). SE induced by lithium-pilocarpine treatment produces sustained reactive gliosis and neurodegeneration in piriform cortex and hippocampus, which are hypothesized to be essential for epileptogenesis (Rossi et al, 2013, 2017). Here, animals received the HMGB-1 blocking drug glycyrrhizin twice a day for 4 days, after developing SE (4DPSE) by lithium-pilocarpine administration and were analyzed after 15 days (15DPSE) (Figure 6).…”

Section: Resultsmentioning

confidence: 99%

“…The pilocarpine experimental model of TLE reproduces in rodents most features of human TLE, including the IPE induced by acute SE and a latency period before the onset of spontaneous seizures (reviewed in Curia et al, 2008). Previous studies performed in our laboratory, during the latency period that follows pilocarpine-induced seizures, have shown early neuroinflammation, macrophage infiltration and exacerbated neuronal plasticity, which seem to have a main role in the epileptogenesis (Rossi et al, 2013, 2017).…”

Section: Introductionmentioning

confidence: 86%

Detrimental Effects of HMGB-1 Require Microglial-Astroglial Interaction: Implications for the Status Epilepticus -Induced Neuroinflammation

Rosciszewski

Cadena

Auzmendi

et al. 2019

Front. Cell. Neurosci.

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Temporal Lobe Epilepsy (TLE) is the most common form of human epilepsy and available treatments with antiepileptic drugs are not disease-modifying therapies. The neuroinflammation, neuronal death and exacerbated plasticity that occur during the silent period, following the initial precipitating event (IPE), seem to be crucial for epileptogenesis. Damage Associated Molecular Patterns (DAMP) such as HMGB-1, are released early during this period concomitantly with a phenomenon of reactive gliosis and neurodegeneration. Here, using a combination of primary neuronal and glial cell cultures, we show that exposure to HMGB-1 induces dendrite loss and neurodegeneration in a glial-dependent manner. In glial cells, loss of function studies showed that HMGB-1 exposure induces NF-κB activation by engaging a signaling pathway that involves TLR2, TLR4, and RAGE. In the absence of glial cells, HMGB-1 failed to induce neurodegeneration of primary cultured cortical neurons. Moreover, purified astrocytes were unable to fully respond to HMGB-1 with NF-κB activation and required microglial cooperation. In agreement, in vivo HMGB-1 blockage with glycyrrhizin, immediately after pilocarpine-induced status epilepticus (SE), reduced neuronal degeneration, reactive astrogliosis and microgliosis in the long term. We conclude that microglial-astroglial cooperation is required for astrocytes to respond to HMGB-1 and to induce neurodegeneration. Disruption of this HMGB-1 mediated signaling pathway shows beneficial effects by reducing neuroinflammation and neurodegeneration after SE. Thus, early treatment strategies during the latency period aimed at blocking downstream signaling pathways activated by HMGB-1 are likely to have a significant effect in the neuroinflammation and neurodegeneration that are proposed as key factors in epileptogenesis.

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“…Status epilepticus was induced in 230–250 g Wistar male rats using the lithium -pilocarpine paradigm as previously described (Rossi et al, 2013, 2017). Briefly, sodium lithium chloride was injected (127 mg/kg- i.p), and 20 h later pilocarpine (30 mg/kg, i.p.…”

Section: Methodsmentioning

confidence: 99%

Convulsive Stress Mimics Brain Hypoxia and Promotes the P-Glycoprotein (P-gp) and Erythropoietin Receptor Overexpression. Recombinant Human Erythropoietin Effect on P-gp Activity

et al. 2019

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Erythropoietin (EPO) is not only a hormone that promotes erythropoiesis but also has a neuroprotective effect on neurons attributed to its known anti-apoptotic action. Previously, our group has demonstrated that recombinant-human EPO (rHu-EPO) can protect neurons and recovery motor activity in a chemical focal brain hypoxia model ( Merelli et al., 2011 ). We and others also have reported that repetitive seizures can mimic a hypoxic- like condition by HIF-1α nuclear translocation and high neuronal expression P-gp. Here, we report that a single 20-min status epilepticus (SE) induces P-gp and EPO-R expression in cortical pyramidal neurons and only P-gp expression in astrocytes. In vitro , excitotoxic stress (300 μM glutamate, 5 min), can also induce the expression of EPO-R and P-gp simultaneously with both HIF-1α and NFkB nuclear translocation in primary cortical neurons. Primary astrocytes exposed to chemical hypoxia with CoCl 2 (0.3 mM, 6 h) increased P-gp expression as well as an increased efflux of Rhodamine 123 (Rho123) that is a P-gp substrate. Tariquidar, a specific 3 er generation P-gp-blocker was used as an efflux inhibitor control. Astrocytes treated with rHu-EPO showed a significant recovery of the Rho123 retention in a similar way as seen by Tariquidar, demonstrating for first time that rHu-EPO can inhibit the P-gp-dependent efflux activity. Taking together, these data suggest that stimulation of EPO depending signaling system could not only play a central role in brain cell protection, but this system could be a new tool for reverse the pharmacoresistant phenotype in refractory epilepsy as well as in other pharmacoresistant hypoxic brain diseases expressing P-gp.

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Early Gabapentin Treatment during the Latency Period Increases Convulsive Threshold, Reduces Microglial Activation and Macrophage Infiltration in the Lithium-Pilocarpine Model of Epilepsy

Cited by 12 publications

References 88 publications

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

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

Detrimental Effects of HMGB-1 Require Microglial-Astroglial Interaction: Implications for the Status Epilepticus -Induced Neuroinflammation

Convulsive Stress Mimics Brain Hypoxia and Promotes the P-Glycoprotein (P-gp) and Erythropoietin Receptor Overexpression. Recombinant Human Erythropoietin Effect on P-gp Activity

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