TRPV1 channel in the pathophysiology of epilepsy and its potential as a molecular target for the development of new antiseizure drug candidates.

Identification of transient receptor potential cation channel, subfamily V member 1 (TRPV1), also known as capsaicin receptor, in 1997 was a milestone achievement in the research on temperature sensation and pain signalling. Very soon after it become evident that TRPV1 is implicated in a wide array of physiological processes in different peripheral tissues, as well as in the central nervous system, and thereby could be involved in the pathophysiology of numerous diseases. Increasing evidence suggests that modulation of TRPV1 may also affect seizure susceptibility and epilepsy. This channel is localized in brain regions associated with seizures and epilepsy, and its overexpression was found both in animal models of seizures and in brain samples from epileptic patients. Moreover, modulation of TRPV1 on non-neuronal cells (microglia, astrocytes, and/or peripheral immune cells) may have an impact on the neuroinflammatory processes that play a role in epilepsy and epileptogenesis. In this paper, we provide a comprehensive and critical overview of currently available data on TRPV1 as a possible molecular target for epilepsy management, trying to identify research gaps and future directions. Overall, several converging lines of evidence implicate TRPV1 channel as a potentially attractive target in epilepsy research but more studies are needed to exploit the possible role of TRPV1 in seizures/epilepsy and to evaluate the value of TRPV1 ligands as candidates for new antiseizure drugs.

In Vivo and In Vitro Characterization of Close Analogs of Compound KA-11, a New Antiseizure Drug Candidate.

Epilepsy is a neurological disorder involving a number of disease syndromes with a complex etiology. A properly matched antiseizure drug (ASD) gives remission in up to 70% of patients. Nevertheless, there is still a group of about 30% of patients suffering from drug-resistant epilepsy. Consequently, the development of new more effective and/or safer ASDs is still an unmet clinical need. Thus, our current studies were focused on the structural optimization/modifications of one of the leading compounds, KA-11, aiming at the improvement of its antiseizure activity. As a result, we designed and synthesized two close analogs with highly pronounced drug-like physicochemical properties according to in silico predictions, namely KA-228 and KA-232, which were subsequently tested in a panel of animal seizure models, i.e., MES, 6 Hz (32 mA), scPTZ and ivPTZ. Among these compounds, KA-232, which was designed as a water-soluble salt, was distinctly more effective than KA-228 and assured similar antiseizure protection as its chemical prototype KA-11. With the aim of a more detailed characterization of both new molecules, in vitro binding tests were performed to evaluate the potential mechanisms of action. Furthermore, KA-232 was also evaluated in several ADME-Tox studies, and the results obtained strongly supported its drug-like potential. The proposed chemical modification of KA-11 enabled the identification of new pharmacologically active chemotypes, particularly water-soluble KA-232, which, despite the lack of better efficacy than the leading compound, may be used as a chemical prototype for the development of new ASDs, as well as substances potentially active in other neurological or neurodegenerative conditions.

[Epidemiology and etiology of posterior fossa tumors with particular emphasis on astrocytomas from the Malopolska and Podkarpacki regions]. / Epidemiologia i etiologia guzów tylnej jamy czaszki ze szczególnym uwzglednieniem gwiazdziaków z terenu województw malopolskiego i podkarpackiego.

Brain tumors in children are rare compared with other diseases childhood. Virtually every pediatrician working at the local hospital has been in contact or brain tumor diagnosis was that more half of them recognized the posterior fossa tumor. Analysis of surveys showed difficulties in the interpretation of basic neurological symptoms. Lessons learned from these studies point to the fact that the success of the surgery affects mainly the histological type of tumor and its location. It is extremely important to analyze complaints and symptoms young patients, we should listen to the parents of children with, because usually just parents are the first to notice that their offspring something was wrong.

Overexpression of 5-lipoxygenase in sporadic colonic adenomas and a possible new aspect of colon carcinogenesis.

PURPOSE: We aimed to study the intracellular expression of 5-lipoxygenase (5-LOX), the primary competitor with cyclooxygenase-2 in arachidonic acid metabolism, as inflammatory enzymes may be involved in blocking apoptosis and promoting cancer growth by changing arachidonic acid metabolism within cells. Our purpose was to investigate the possible connection between 5-LOX expression and colon carcinogenesis by characterizing 5-LOX expression in histologically different colonic adenomas, determining the relationship between high expression of 5-LOX and various conventional clinicopathological features of adenomas, and finally characterizing the histological localization of cells with 5-LOX overexpression. METHODS: A total of 111 patients were examined and 120 histologically different colonic adenomas analyzed (including four cases of intramucosal adenocarcinoma in a polyp). Immunohistochemical staining with polyclonal anti-5-LOX antibodies was performed. RESULTS: There was a significant correlation between high 5-LOX expression and patient age, increased polyp size, high grade of intraepithelial neoplasia, villous and tubulovillous adenoma, and histological epithelial localization. CONCLUSIONS: We observed a strong positive correlation between 5-LOX overexpression and the appearance of typical high-risk factors for malignant transformation in adenomatous polyps. The results support the role of 5-LOX in early stages of colon carcinogenesis.