Abstract
Several studies have addressed the antiepileptic mechanisms of levetiracetam (LEV); however, its effect on catecholamines and the inflammatory mediators that play a role in epilepsy remain elusive. In the current work, lithium (Li) pretreated animals were administered LEV (500 mg/kg i.p) 30 min before the induction of convulsions by pilocarpine (PIL). Li-PIL-induced seizures were accompanied by increased levels of hippocampal prostaglandin (PG) E2, myeloperoxidase (MPO), tumor necrosis factor-α, and interleukin-10. Moreover, it markedly elevated hippocampal lipid peroxides and nitric oxide levels, while it inhibited the glutathione content. Li-PIL also reduced hippocampal noradrenaline, as well as dopamine contents. Pretreatment with LEV protected against Li-PIL-induced seizures, where it suppressed the severity and delayed the onset of seizures in Li-PIL treated rats. Moreover, LEV reduced PGE2 and MPO, yet it did not affect the level of both cytokines in the hippocampus. LEV also normalized hippocampal noradrenaline, dopamine, glutathione, lipid peroxides, and nitric oxide contents. In conclusion, alongside its antioxidant property, LEV anticonvulsive effect involves catecholamines restoration, as well as inhibition of PGE2, MPO, and nitric oxide.
Highlights
Levetiracetam (LEV) is a unique broad-spectrum secondgeneration antiepileptic drug (AED), which is used clinically as monotherapy or an add-on drug [1,2]
Regarding the effect on catecholamines, Li-PIL decreased both noradrenaline and dopamine in the hippocampus by about 60% (Figure 1A and 1B), as compared to the control animals, effects that were opposed by LEV pretreatment
LEV Antiepileptic Efficacy Is Documented in Clinical as Well as in Experimental Settings Including Li-PIL status epilepticus (SE) Seizure Model [1,2,4,5,6]
Summary
Levetiracetam (LEV) is a unique broad-spectrum secondgeneration antiepileptic drug (AED), which is used clinically as monotherapy or an add-on drug [1,2]. LEV indirectly impedes neuronal release of glutamate [10], halting excitotoxicity and cellular injury [11] Such effects are achieved by reducing high-voltageactivated Ca2+ current by blocking N- and P/Q-type Ca2+ channels [10,12] and suppressing rectifier potassium current [13] resulting in neuronal hyperpolarization. In kindled animals, LEV downregulates the overexpressed brain-derived neurotrophic factor and neuropeptide Y and increases neuropeptide Y1- and 5-like receptors [5], preventing central modulation of seizure activity. To date, the mechanistic pathways of LEV to prevent early seizure onset of SE has not been fully delineated, the present study aimed to investigate the potential role of some inflammatory mediators, free radical-induced injury, as well as catecholamines on the LEV anticonvulsant effect using the lithium (Li)-PIL-induced seizure model in rats
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