Montelukast: The New Therapeutic Option for the Treatment of Epilepsy

Figures & data

Figure 1 Biosynthesis pathway of the Cys-LT and their receptors. Biosynthesis of CysLTs starts with the release of arachidonic acid from plasma membrane by the action of phospholipase. Arachidonic acid is metabolized to leukotriene A₄ that in turn is metabolized to both non-cysteine leukotriene, LTB4, and cysteine leukotrienes. The CysLTs act on the receptors, CysLT1R and CysLT2R. Montelukast competitively block the effects of CysLTs on these receptors. The red color of the arrows show the site where montelukast acts.

Abbreviations: 5-Lox, 5-lipoxygenase; FLAP, 5-lipoxygenase activating protein; 5HPETE, 5-hydroperoxyeicosatetraenoic acid; LTB4, leukotriene B4; CysLTs, cysteinyl leukotrienes; CysLT1Rs, cysteinyl leukotrienes 1 receptor; CysLT2Rs, cysteinyl leukotrienes 1 receptor; TNF-α, tumour necrosis factor alpha; IL-6, interleukin-6; IL-1β, interleukin 1 beta; MMP, matrix metallopeptidases.

Table 1 Preclinical Studies Done on the Antiepileptic Effect of Montelukast

Experimental Approaches	Study Subjects	Interventions	Major Outcome(s)	References
PTZ-induced seizures	Male Swiss mice weighed between 25–28 g and aged 42 days	Three groups of PTZ kindled mice: phenobarbital treated group, montelukast treated group, and normal saline treated group	Both montelukast and phenobarbital improved the latency period to generalized seizures.	[^Citation12]
Montelukast against PTZ induced acute seizure	112 adult Swiss albino male mice weighing 15–35g and aged 8 weeks were used	Two animal study models were used. The first was an acute PTZ model where mice were divided into five groups and treated with single IP dose; saline, PTZ, valproate, montelukast, and both montelukast and valproate. The second was a kindling model where mice were divided into five groups and treated daily for 17 days IP with; saline, PTZ, valproate, montelukast, both montelukast, and valproate.	Montelukast, alone or in combination with valproate blocked CysLTRs and protected the mice’s brain against PTZ induced seizures. Montelukast, alone or in combination with valproate also reduced oxidative stress and inflammatory cascades. The authors reported a significantly increased level of GSH and significantly reduced levels of MDA, IL1β, TNFα, and LTD4 as compared to PTZ treated control groups.	[^Citation69]
PTZ-induced seizure: electroencephalography (EEG), Racine’s Convulsion Scale (RCS), onset times of first myoclonic jerk (FMJ), Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were determined	48 male Sprague-Dawley rats were used (weighed between 200–250 g)	Rats were grouped into two as group “A” to study EEG and “B” for behavioral studies. Group “A” were further divided into A1, A2, A3, and A4 and treated with IP; normal saline and 25, 50, and 100 mg/kg of montelukast. Animals in Group “B” were similarly divided as B1 B2, B3, and B4 and treated with IP normal saline and 25, 50, and 100 mg/kg of montelukast.	Montelukast showed significant anticonvulsant and anti-oxidant action. Rats administered with 50 or 100 mg/kg of montelukast significantly lowered RCS and significantly elevated FMJ onset time compared to the controls. A significantly lower MDA and higher SOD levels were also found in the animals treated with 25, 50, or 100 mg/kg (p<0.001) of montelukast as compared to the saline treated group.	[^Citation13]
Isobolographic analysis of the synergistic activity of montelukast and phenobarbital on PTZ induced seizures	A total of 134 adult female Swiss mice (25 ± 3 g) were used:	Five different groups of animals were treated with montelukast, phenobarbital, montelukast plus phenobarbital, montelukast plus LTD4, and vehicle respectively.	The combination of montelukast and phenobarbital was found to have a synergistic effect. The group of animals treated with the combination showed an increased latency period to PTZ-induced tonic–colonic seizures. The ED50 of phenobarbital for anti-seizure activity was also significantly lowered by montelukast.	[^Citation70]
Effect of CYSLT receptor antagonists on PTZ induced seizure and BBB integrity	Male albino Swiss mice weighing 25±3.5gm were used	Mice were divided into five groups and treated with the antagonists (montelukast, pranlukast, Bay u-9773), agonist (LTD4), and a solvent respectively. This was followed by an injection with PTZ after 30 minutes.	All three antagonists prolonged the latency period to generalized seizures. They also decreased mean EEG amplitudes during seizure episodes. Montelukast also stopped PTZ induced BBB leakages.	[^Citation34]
Effect of montelukast and 1,2,3,4, tetrahydroisoquinoline on PTZ induced seizures and pilocarpine induced status epilepticus	Male albino mice weighed 25±2g were used	Animals categorized into 8 groups as Group I - Group VIII were treated with vehicle only, PTZ only, low dose montelukast plus PTZ, medium dose montelukast plus PTZ, high dose montelukast plus PTZ, low dose 1,2,3,4 tetrahydroisoquinoline plus PTZ, medium dose 1,2,3,4 tetrahydroisoquinoline plus PTZ, and high dose 1,2,3,4 tetrahydroisoquinoline plus PTZ respectively.	Both montelukast and 1,2,3,4, tetrahydroisoquinoline halted the development of PTZ kindled seizure and pilocarpine-induced status epilepticus significantly and in a dose-dependent manner.	[^Citation21]

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