Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunction

Lenz, Quéli Fernandes; Arroyo, Daniela S.; Temp, Fernanda R.; Poersch, A.B.; Masson, C; Jesse, Ana Cláudia; Marafiga, Joseane Righes; Reschke, Cristina R.; Iribarren, Pablo; Mello, Carlos Fernando

doi:10.1016/j.neuroscience.2014.07.058

Cited by 50 publications

(46 citation statements)

References 51 publications

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“…The early findings by Palmer and colleagues (1981) that LTD 4 increases neuronal firing rate together with the demonstration that montelukast and a putative synthetic LTD 4 pathway inhibitor dose-dependently suppress the development of kindled seizures, as well as pilocarpine-induced spontaneous recurrent seizures, support this view [16]. Moreover, Lenz and colleagues (2014) have shown that montelukast not only has anticonvulsant effect but also protects against BBB disruption and leukocyte infiltration in a cannula-lesioned cortical area, suggesting that montelukast also decreases neuroinflammation and/or exposure to blood-borne elements [15]. It is well known that areas of focal hyperexcitability can develop in the brain after trauma, infection, ischemia, and excitotoxicity, probably due to neuroinflammation and/or exposure to blood-borne elements [43][44][45][46][47][48][49].…”

Section: Discussionmentioning

confidence: 98%

“…wakefulness) from basal and after treatment periods were identified in EEG recording and divided in 15 s segments and a 4 s epoch from each segment (without artifacts) was used to carry out the power analysis by the conversion into frequency domain by fast Fourier transformation (FFT) method. The resultant power values displayed for each frequency were grouped into 5 bands represented by delta (0.1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and gamma . For power analysis of decomposed waves, the power sum from all frequencies (0.1-80 Hz) was considered as 100%.…”

Section: Electrocorticographic Recording Analysis and Seizure Evaluamentioning

confidence: 99%

“…Similarly, Liu and colleagues (2014) have shown that zileuton, a 5-LOX inhibitor, decreases spike-wave discharges in pilocarpine epileptic rats [14]. Interestingly, it has been recently shown that while LTD 4 facilitates and montelukast, pranlukast (a CysLT 1 antagonist) and Bay-u9773 (a dual CysLT 1 /CysLT 2 antagonist) decrease PTZ-induced seizures and BBB permeability disruption [15]. Notwithstanding, low doses of LTD 4 (0.2 and 2 pmol, i.c.v.)…”

Section: Introductionmentioning

confidence: 99%

“…prevent the anticonvulsant, but not the protective effect of MTK on BBB. The dissociation of these effects suggests that BBB maintenance does not determine the anticonvulsant effect of montelukast [15], and that an alternative mechanism to decrease excitability shall exist. In fact, it has been long known that LTD 4 increases the firing rate of Purkinje cells in vivo [16], suggesting an excitatory role for this lipid mediator.…”

Section: Introductionmentioning

confidence: 99%

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Montelukast potentiates the anticonvulsant effect of phenobarbital in mice: An isobolographic analysis

Fleck

Marafiga

Jesse

et al. 2015

Pharmacological Research

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Section: Discussionmentioning

confidence: 98%

Section: Electrocorticographic Recording Analysis and Seizure Evaluamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Montelukast potentiates the anticonvulsant effect of phenobarbital in mice: An isobolographic analysis

Fleck

Marafiga

Jesse

et al. 2015

Pharmacological Research

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“…This unstable epoxide can be further hydrolyzed to LtB4 [34] . Alternatively, LtA4 may be converted to LtC4 which get transformed by gamma glutamyl transpeptidase to LtD4 and LtE4 [35] .…”

Section: Zaki Y ; Et Al…… -596-discussionmentioning

confidence: 99%

Protective Effect of Montelukast Against Pentylenetetrazole-Induced Acute Seizures and Kindling in Mice

Abdel-Kader

Khorshid

Motteleb

et al. 2017

Zagazig University Medical Journal

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Background: Montelukast, a selective reversible cysteinyl leukotriene1 (CysLT1) receptor antagonist, is used in treatment of asthma, exercise induced-bronchospasm, allergic rhinitis and urticaria. It was shown to protect against cerebral ischemia/reperfusion injury. Objectives: To examine the possible anticonvulsant effect of montelukast, either alone or in combination with a known antiepileptic drug "valproate" against pentylenetetrazole (PTZ)-induced seizures. Methods: 112 adult male Swiss albino mice were used in the study and divided into two main groups, each containing 5 subgroups (Gp). The first main group "acute PTZ model (PTZ-a)" contains: Gp1 "vehicle-treated group" was injected with saline (10 ml/kg, intraperitoneally "i.p." in a single dose ), Gp2 "acute PTZ-control" injected with a single dose of PTZ (60 mg/kg, i.p.), Gp3 injected with valproate (50 mg/kg, i.p.) 30 minutes before PTZ, Gp4 injected with a single dose of montelukast (10 mg/kg, i.p.) 30 minutes before PTZ and Gp5 injected with both montelukast and valproate 30 minutes before PTZ administration. The second main group "kindling model (PTZ-k)" contains: Gp1 was injected with saline (i.p.) every other day for 17 days, Gp2 "PTZ-kindled control" received 9 PTZ injections in a dose of (40 mg/kg, i.p.) on alternate days for 17 days, Gp3 injected with valproate (50 mg/kg, i.p.) for 17 days, 30 minutes before PTZ, Gp4 daily injected with montelukast (10 mg/kg, i.p.) for 17 days 30 minutes before PTZ and Gp5 received both montelukast (10 mg/kg, i.p.) and valproate (50 mg/kg, i.p.) daily for 17 days, 30 minutes before administration of PTZ. Results: Single and repeated PTZ administration produced stage 4 seizures associated with a significant reduction in the brain level of reduced glutathione (GSH), concomittent with significant elevation in the brain levels of malondialdehyde (MDA), inteleukin1β (IL1β), tumor necrosis factor α (TNFα) and leukotriene D4 (LtD4). The use of valproate alone and its combination with montelukast suppressed the incidence of stage 4 seizures in acute PTZ induced convulsion while montelukast, valproate and their combination decreased the percentage of animals reaching stage 4 seizures in kindled mice. In both PTZ acute and kindled models, montelukast, valproate and their combined administration significantly elevated brain level of GSH and significantly decreased brain levels of MDA, IL1β, TNFα and LtD4 as compared to PTZ control groups. Interestingly, co-administration of valproate and montelukast resulted in a significant elevation in the brain level of GSH concomitant with a significant reduction in the brain levels of MDA, IL1β, TNFα and LtD4 as compared to each of the valproate and the montelukast groups in both models. Conclusion: Montelukast, either alone or in combination with valproate protects against PTZ induced seizures via blockade of leukotreine receptors & amelioration of oxidative stress and inflammatory cascades.

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Angiotensin Receptor Blockers for Hypertension and Risk of Epilepsy

Wen,

Otoo,

Tang

et al. 2024

JAMA Neurol

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ImportanceAnimal and human studies have suggested that the use of angiotensin receptor blockers (ARBs) may be associated with a lower risk of incident epilepsy compared with other antihypertensive medications. However, observational data from the US are lacking.ObjectiveTo evaluate the association between ARB use and epilepsy incidence in subgroups of US patients with hypertension.Design, Setting, and ParticipantsThis retrospective cohort study used data from a national health administrative database from January 2010 to December 2017 with propensity score (PS) matching. The eligible cohort included privately insured individuals aged 18 years or older with diagnosis of primary hypertension and dispensed at least 1 ARB, angiotensin-converting enzyme inhibitor (ACEI), β-blocker, or calcium channel blocker (CCB) from 2010 to 2017. Patients with a diagnosis of epilepsy at or before the index date or dispensed an antiseizure medication 12 months before or 90 days after initiating the study medications were excluded. The data analysis for this project was conducted from April 2022 to April 2024.ExposuresPropensity scores were generated based on baseline covariates and used to match patients who received ARBs with those who received either ACEIs, β-blockers, CCBs, or a combination of these antihypertensive medications.Main Outcomes and MeasuresCox regression analyses were used to evaluate epilepsy incidence during follow-up comparing the ARB cohort with other antihypertensive classes. Subgroup and sensitivity analyses were conducted to examine the association between ARB use and epilepsy incidence in various subgroups.ResultsOf 2 261 964 patients (mean [SD] age, 61.7 [13.9] years; 1 120 630 [49.5%] female) included, 309 978 received ARBs, 807 510 received ACEIs, 695 887 received β-blockers, and 448 589 received CCBs. Demographic and clinical characteristics differed across the 4 comparison groups prior to PS matching. Compared with ARB users, patients receiving ACEIs were predominantly male and had diabetes, CCB users were generally older (eg, &gt;65 years), and β-blocker users had more comorbidities and concurrent medications. The 1:1 PS-matched subgroups included 619 858 patients for ARB vs ACEI, 619 828 patients for ARB vs β-blocker, and 601 002 patients for ARB vs CCB. Baseline characteristics were equally distributed between comparison groups after matching with propensity scores. Use of ARBs was associated with a decreased incidence of epilepsy compared with ACEIs (adjusted hazard ratio [aHR], 0.75; 95% CI, 0.58-0.96), β-blockers (aHR, 0.70; 95% CI, 0.54-0.90), and a combination of other antihypertensive classes (aHR, 0.72; 95% CI, 0.56-0.95). Subgroup analyses revealed a significant association between ARB use (primarily losartan) and epilepsy incidence in patients with no preexisting history of stroke or cardiovascular disease.Conclusions and RelevanceThis cohort study found that ARBs, mainly losartan, were associated with a lower incidence of epilepsy compared with other antihypertensive agents in hypertensive patients with no preexisting stroke or cardiovascular disease. Further studies, such as randomized clinical trials, are warranted to confirm the comparative antiepileptogenic properties of antihypertensive medications.

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Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunction

Cited by 50 publications

References 51 publications

Montelukast potentiates the anticonvulsant effect of phenobarbital in mice: An isobolographic analysis

Montelukast potentiates the anticonvulsant effect of phenobarbital in mice: An isobolographic analysis

Protective Effect of Montelukast Against Pentylenetetrazole-Induced Acute Seizures and Kindling in Mice

Angiotensin Receptor Blockers for Hypertension and Risk of Epilepsy

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