Cannabinoids: a new hope for drug resistance epilepsy (review)

Background:Treatment-resistant epilepsy (TRE) affects 30% of epilepsy patients and is associated with severe morbidity and increased mortality. Unfortunately, available anti-epileptic drugs (AEDs) provide only limited success in controlling seizures in TREs and there are limits to their safety and efficacy especially when used in multidrug regimens and at high doses. As a result, the need for different other therapeutic options to manage epilepsy is still a current issue and There has been an enormous interest in developing antiepileptic drugs with novel mechanisms of action. Here we tried to gather recent clinical and pre-clinical studies around antiepileptic effect of cannabinoids and critically reviewed their findings to survey its potential use for treatment of TREs. Methods:We searched for relevant studies across a broad range of online databases platforms including Google Scholar, ScienceDirect, PubMed, and Scopus, which allowed the identification of both peer reviewed and grey literature. Epilepsy resistance, convulsion, cannabinoids were used as keywords. The present review is to provide an up-to-date information of the advantages and disadvantages of cannabinoids in the use for TREs. Results:Table 1. shows outcomes achieved on the basis of notable pre-clinical studies regarding to anticonvulsant activity of cannabinoids and their novel mechanism of action. Table 2. shows outcomes achieved on the basis of notable clinical studies regarding to anticonvulsant activity of cannabinoids and their effect on TREs. Discussion:Evidence obtained from multiple studies shows that phytocannabinoids have consistently beneficial therapeutic effects in many various preclinical models of seizures, epilepsy, epileptogenesis, and neuroprotection which determines their potential efficacy in favor of a remedy for numerous kind of epileptic syndromes notably drug resistant lennox gastaut syndrome (LGS) and dravet syndrome(DS). Several mechanisms have been reported for anticonvulsant activity of cannabinoids, among which their actions can be appeared through cannabinoid receptor-mediated pathways (mainly CB1R) that can be detected in Δ9-tetrahydrocannabinol and WIN, or non receptor-mediated pathways of a similar kind as cannabidiol (CBD(.even though we know that between the two cannabinoid receptors, CB1R is the one which has been proved to be responsible for anticonvulsant effect and CB2R principally participate in neuronal excitation, nevertheless, Since Interactions between the brain regions involved in a given disease model and the relative contributions made by endocannabinoid signaling in these regions appear to influence outcome, a complexity most often illustrated by species-specific differences in response. It should also be mentioned that A functional interaction exists between cannabinoids and PPAR receptors in the modulation of seizure susceptibility. Furthermore, cannabinoids demonstrate neuroprotection by interacting with transient receptor potential vanilloid 1 (TRPV1) and regulate the function of σ1R (opiate receptor) as a σ1R antagonist to reduce NMDAR activity. On the other hand, similar results are obtained from human studies. In particular, anecdotal reports describe dramatic improvements in patients with drug-resistant epilepsies next to a more tolerable profile of adverse effect. Findings collected from several Open-label experiences and high-quality randomized controlled trials using cannabinoids, support efficacy in a broader range of TREs, including those associated with TSC, FIRES, focal epilepsy, and other syndromes. Although More research is needed to assess the long term safety and efficacy of this product, particularly in the developing brain. Subsequently, On June26, 2018, CBD was approved by the US Food and Drug Administration for the treatment of patients with DS and LGS. Eventually, due to the several mechanisms in which cannabinoids contribute in, many novel targets revealed to be advantageous in drug resistant epilepsy and hopefully lead us to a promising approach for a future pharmacological strategy to challenge drug resistant epilepsy.

Keywords:

Epilepsy resistance , convulsion , cannabinoids