Drug-resistant epilepsy: Drug target hypothesis and beyond the receptors.

Epilepsy is a chronic neurological disorder that affects more than 50 million people worldwide. Despite a recent introduction of antiseizure drugs for the treatment of epileptic seizures, one-third of these patients suffer from drug-resistant epilepsy (DRE). The therapeutic target hypothesis is a cited theory to explain DRE. According to the target hypothesis, the failure to achieve seizure freedom leads to alteration of the structure and/or function of the antiseizure medication (ASM) target. However, this hypothesis fails to explain why patients with DRE do not respond to antiseizure medications of different targets. This review presents different conditions, such as epigenetic mechanisms and protein-protein interactions that may result in alterations of diverse drug targets using different mechanisms. These novel conditions represent new targets to control DRE.

Cannabidiol modifies the seizure expression and effects of antiseizure drugs in a rat model of recurrent severe seizures.

PURPOSE: To evaluate the effects of cannabidiol alone or in combination with antiseizure drugs in the expression of recurrent generalized seizures in a rat model. METHODS: Group A: Male Wistar rats received 3-mercaptopropionic acid (MP) every 12 h for 5 days to induce recurrent generalized seizures. Thereafter, the animals were submitted to a crossover protocol to receive different treatments with cannabidiol, phenytoin and phenobarbital, alone and in combination. Group B: Rats were manipulated as group A, but they received cannabidiol during the induction of recurrent seizures. RESULTS: Minor and major seizures were induced after each MP administration. Status epilepticus (SE) detected during the last MP administrations was considered a sign of high seizure severity. Cannabidiol did not modify the expression of the MP induced seizures but reduced the prevalence of SE in both experimental groups. Phenytoin decreased the expression of major seizures but did not modify the prevalence of SE (groups A and B). Cannabidiol combined with phenytoin did not modify these effects. Phenobarbital diminished the expression of major seizures, an effect more evident when combined with cannabidiol (groups A and B). The combination of phenobarbital and cannabidiol reduced the expression of SE of group B. The mortality rate of groups A and B at the end of the crossover protocol was 30% and 9%, respectively (p=0.2). CONCLUSION: CBD associated with appropriate antiseizure drugs reduces the severity and prevalence of generalized seizures. In contrast, CBD alone reduces the seizure severity, but does not avoid the expression of generalized seizures.

Is cannabidiol a drug acting on unconventional targets to control drug-resistant epilepsy?

Cannabis has been considered as a therapeutic strategy to control intractable epilepsy. Several cannabis components, especially cannabidiol (CBD), induce antiseizure effects. However, additional information is necessary to identify the types of epilepsies that can be controlled by these components and the mechanisms involved in these effects. This review presents a summary of the discussion carried out during the 2nd Latin American Workshop on Neurobiology of Epilepsy entitled "Cannabinoid and epilepsy: myths and realities." This event was carried out during the 10th Latin American Epilepsy Congress in San José de Costa Rica (September 28, 2018). The review focuses to discuss the use of CBD as a new therapeutic strategy to control drug-resistant epilepsy. It also indicates the necessity to consider the evaluation of unconventional targets such as P-glycoprotein, to explain the effects of CBD in drug-resistant epilepsy.

Castleman disease. Histopathological and immunohistochemical analysis of 39 cases. / Enfermedad de Castleman. Análisis histopatológico e inmunohistoquímico de treinta y nueve casos.

Introduction: Castleman disease (CD) is a rare lymphoproliferative that comprises two distinct clinical subtypes (unicentric and multicentric) and has two basic histopathology patterns that are hyaline-vascular (HV) and plasma-cell (PC) type. Some cases of multicentric PC disease are associated with HHV-8 infection. Objective: To present the histopathologic and immunohistochemical characteristics of 39 cases of CD. Methods: A review of cases with the diagnosis CD from the files of the Department of Pathology of the ABC Medical Centre in Mexico City was performed. Thirty-nine cases of CD were identified, and a detailed paraffin immunophenotypic study of 9 of them was completed using desmin, cytokeratin OSCAR (CO) and Epidermal growth factor receptor (EGFR), to evaluate the dendritic cell population. Results and Conclusions: Of the 39 cases of CD, 24 were HV and 15 CP. All HV cases were unicentric and only one case of CP was multicentric. The most frequent localization in both subtypes was in lymph nodes; 21/24 cases in HV and 15 cases of CP. All cases were immunostained with CD20 that was expressed in the germinal centers (CGs), CD3 in the paracortical zone, and CD21 in follicular dendritic cells (CDF) within CGs, with expansion towards the area of the hyperplastic mantle zone (only in the HV variant). One case of CD CP was positive for HHV-8. Of the nine cases (6 HV and 3 PC cases) that were detailed with IHC, we found EGFR expression in FDC in all but one of the 9 cases studied and desmin was positive in fibroblastic reticulum cells (FRC) in all, but one of the cases of CD. CO was positive FRC in 3 of 6 cases of HV type and all (3) of the PC type. Clinical, histopathological and HIV and HHV-8 status markers, allow for the classification of CD into groups with markedly different outcomes and disease associations.

Dopamine abnormalities in the neocortex of patients with temporal lobe epilepsy.

Experiments were designed to evaluate different variables of the dopaminergic system in the temporal cortex of surgically treated patients with temporal lobe epilepsy (TLE) associated with mesial sclerosis (MTLE, n=12) or with cerebral tumor or lesion (n=8). In addition, we sought to identify dopaminergic abnormalities in those patients with epilepsy that had comorbid anxiety and depression. Specifically, we investigated changes in dopamine and its metabolites, D1 and D2 receptors, tyrosine hydroxylase (TH) and dopamine transporter. Results obtained from patients with epilepsy were compared with those found in experiments using autopsy material. The neocortex of patients with MTLE demonstrated high D1 expression (1680%, p<0.05) and binding (layers I-II, 31%, p<0.05; layers V-VI, 28%, p<0.05), and decreased D2 expression (77%, p<0.05). The neocortex of patients with TLE secondary to cerebral tumor or lesion showed high expression of D1 receptors (1100%, p<0.05), and D2-like induced activation of G proteins (layers I-II, 503%; layers III-IV, 557%; layers V-VI, 964%, p<0.05). Both epileptic groups presented elevated binding to the dopamine transporter and low tissue content of dopamine and its metabolites. Analysis revealed the following correlations: a) D1 receptor binding correlated negatively with seizure onset age and seizure frequency, and positively with duration of epilepsy; b) D2 receptor binding correlated positively with age of seizure onset and negatively with duration of epilepsy; c) dopamine transporter binding correlated positively with duration of epilepsy and frequency of seizures; d) D2-like induced activation of G proteins correlated positively with the age of patients. When compared with autopsies and patients with anxiety and depression, patients without neuropsychiatric disorders showed high D2-like induced activation of G proteins, an effect that correlated positively with age of patient and seizure onset age, and negatively with duration of epilepsy. The present study suggests that alterations of the dopaminergic system result from epileptic activity and could be involved in the physiopathology of TLE and the comorbid anxiety and depression.