Neuroprotective Activity of a Non-Covalent Imatinib+TP10 Conjugate in HT-22 Neuronal Cells In Vitro.

This study evaluated the probable relevance of a non-covalent conjugate of imatinib with TP10 in the context of a neuroprotective effect in Parkinson's disease. Through the inhibition of c-Abl, which is a non-receptor tyrosine kinase and an indicator of oxidative stress, imatinib has shown promise in preclinical animal models of this disease. The poor distribution of imatinib within the brain tissue triggered experiments in which a conjugate was obtained by mixing the drug with TP10, which is known for exhibiting high translocation activity across the cell membrane. The conjugate was tested on the HT-22 cell line with respect to its impact on MPP+-induced oxidative stress, apoptosis, necrosis, cytotoxicity, and mortality. Additionally, it was checked whether the conjugate activated the ABCB1 protein. The experiments indicated that imatinib+PEG4+TP10 reduced the post-MPP+ oxidative stress, apoptosis, and mortality, and these effects were more prominent than those obtained after the exposition of the HT-22 cells to imatinib alone. Its cytotoxicity was similar to that of imatinib itself. In contrast to imatinib, the conjugate did not activate the ABCB1 protein. These favorable qualities of imatinib+PEG4+TP10 make it a potential candidate for further in vivo research, which would confirm its neuroprotective action in PD-affected brains.

Cell-penetrating peptides improve pharmacokinetics and pharmacodynamics of anticancer drugs.

This review concentrates on the research concerning conjugates of anticancer drugs with versatile cell-penetrating peptides (CPPs). For a better insight into the relationship between the components of the constructs, it starts with the characteristic of the peptides and considers its following aspects: mechanisms of cellular internalization, interaction with cancer-modified membranes, selectivity against tumor tissue. Also, CPPs with anticancer activity have been distinguished and summarized with their mechanisms of action. With respect to the conjugates, the preclinical studies (in vitro, in vivo) indicated that they possess several merits in comparison to the parent drugs. They concerned not only better cellular internalization but also other improvements in pharmacokinetics (e.g. access to the brain tissue) and pharmacodynamics (e.g. overcoming drug resistance). The anticancer activity of the conjugates was usually superior to that of the unconjugated drug. Certain anticancer CPPs and conjugates entered clinical trials.

Publisher Correction: Transportan 10 improves the pharmacokinetics and pharmacodynamics of vancomycin.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Transportan 10 improves the pharmacokinetics and pharmacodynamics of vancomycin.

In the presented study, transportan 10 (TP10), an amphipathic cell penetrating peptide (CPP) with high translocation activity, was conjugated with vancomycin (Van), which is known for poor access to the intracellular bacteria and the brain. The antibacterial activity of the conjugates was tested on selected clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus sp. It turned out that all of them had superior antimicrobial activity in comparison to that of free Van, which became visible particularly against clinical MRSA strains. Furthermore, one of the conjugates was tested against MRSA - infected human cells. With respect to them, this compound showed high bactericidal activity. Next, the same conjugate was screened for its capacity to cross the blood brain barrier (BBB). Therefore, qualitative and quantitative analyses of the conjugate's presence in the mouse brain slices were carried out after its iv administration. They indicated the conjugate's presence in the brain in amount >200 times bigger than that of Van. The conjugates were safe with respect to erythrocyte toxicity (erythrocyte lysis assay). Van in the form of a conjugate with TP10 acquires superior pharmacodynamic and pharmacokinetic.

Drinking "Vodka" or vodka - This is a question.

"Vodka" i.e. 2-methyl-2-butanol (2M2B) is growing in popularity as a substance of abuse, especially among East European youngsters. At present, there is not much data regarding its toxicity both in humans and animals. The direct effect of 2M2B on human tissue was evaluated and compared to that of two other alcohols (ethanol, 3-methyl-1-butanol). The used concentrations corresponded to those obtained from consumers of 2M2B. The experiments were carried out on HEK293 cell line with the use of the following techniques: MTT test, phase contrast and fluorescent microscopy. The MTT test indicated that the toxicity of 2M2B was comparable to that of ethanol, but it was much lower than that observed after 3-methyl-1-butanol (3M1B). The high toxicity of the latter alcohol was confirmed by the microscopy techniques. On the other hand, the toxicity of 2M2B - expressed by the reduction of the number of survived cells - was slightly higher compared to one induced by ethanol. Also, the values of pIC50 for each alcohol reflect its level of toxicity described above. On the basis of the literature data it is possible to argue that the toxicity of the tested alcohols results primarily from membrane damage induced by their solvent properties.

Tyrosine Kinase Inhibitor as a new Therapy for Ischemic Stroke and other Neurologic Diseases: is there any Hope for a Better Outcome?

The relevance of tyrosine kinase inhibitors (TKIs) in the treatment of malignancies has been already defined. Aberrant activation of tyrosine kinase signaling pathways has been causally linked not only to cancers but also to other non-oncological diseases. This review concentrates on the novel plausible usage of this group of drugs in neurological disorders, such as ischemic brain stroke, subarachnoid hemorrhage, Alzheimer's disease, multiple sclerosis. The drugs considered here are representatives of both receptor and non-receptor TKIs. Among them imatinib and masitinib have the broadest spectrum of therapeutic usage. Both drugs are effective in ischemic brain stroke and multiple sclerosis, but only imatinib produces a therapeutic effect in subarachnoid hemorrhage. Masitinib and dasatinib reduce the symptoms of Alzheimer's disease. In the case of multiple sclerosis several TKIs are useful, including apart from imatinib and masitinib, also sunitinib, sorafenib, lestaurtinib. Furthermore, the possible molecular targets for the drugs are described in connection with the underlying pathophysiological mechanisms in the diseases in question. The most frequent target for the TKIs is PDGFR which plays a pivotal role particularly in ischemic brain stroke and subarachnoid hemorrhage. The collected data indicates that TKIs are very promising candidates for new therapeutic interventions in neurological diseases.