17β-Estradiol as a Neuroprotective Agent

The pathophysiology of neurodegeneration in the central nervous system is complex and multifactorial in nature and yet to be fully understood. Broad-spectrum neuroprotective agents with multiple mechanisms of action rather than a single druggable target are, therefore, highly desirable. The main human estrogen, 17β-estradiol, can also be considered a neurosteroid as it forms de novo in the central nervous system, and it possesses beneficial effects against practically all critical contributors to neurodegeneration to collectively thwart both the initiation and the progression of neuronal cell death. This chapter details the main aspects of the hormone’s genomic and non-genomic actions important to protect the highly vulnerably neurons of the central nervous system, as well as translational efforts to successfully realize its powerful neuroprotective potential in clinical setting while ensuring both therapeutic safety and efficacy

The Utility of Oligopeptidase in Brain-Targeting Delivery of an Enkephalin Analogue by Prodrug Design

In a brain-targeting prodrug approach for a metabolically stable enkephalin analogue DADLE, specific enzymes are utilized for in vivo prodrug activation. Prolyl oligopeptidase (POP) may be especially useful in this regard. In vitro metabolic stability of the putative metabolites of prodrugs having various “spacers” has shown that POP provides significantly faster release of DADLE from conjugates having dipeptidyl spacer (specifically Xaa-Pro or Xaa-Ala) than alternative peptidases utilized when single amino acids are used as spacers. In vitro half-lives measured in rat brain homogenate showed excellent correlation with CNS-mediated analgesia using the tail-flick model in rats providing, thus, an in vivo substantiation of the prodrug approach relying on POP as the peptidase to release DADLE

Phenolic Compounds Protect Cultured Hippocampal Neurons against Ethanol-Withdrawal Induced Oxidative Stress

Ethanol withdrawal is linked to elevated oxidative damage to neurons. Here we report our findings on the contribution of phenolic antioxidants (17β-estradiol, p-octyl-phenol and 2,6-di-tert-butyl-4-methylphenol) to counterbalance sudden ethanol withdrawal-initiated oxidative events in hippocampus-derived cultured HT-22 cells. We showed that ethanol withdrawal for 4 h after 24-h ethanol treatment provoked greater levels of oxidative damage than the preceding ethanol exposure. Phenolic antioxidant treatment either during ethanol exposure or ethanol withdrawal only, however, dose-dependently reversed cellular oxidative damage, as demonstrated by the significantly enhanced cell viability, reduced malondialdehyde production and protein carbonylation, compared to untreated cells. Interestingly, the antioxidant treatment schedule had no significant impact on the observed neuroprotection. In addition, the efficacy of the three phenolic compounds was practically equipotent in protecting HT-22 cells in spite of predictions based on an in silico study and a cell free assay of lipid peroxidation. This finding implies that free-radical scavenging may not be the sole factor responsible for the observed neuroprotection and warrants further studies to establish, whether the HT-22 line is indeed a suitable model for in vitro screening of antioxidants against EW-related neuronal damage

Proteomics of synapse

Large-scale phosphoproteome analysis on synaptosome and preparation of post-synaptic density (PSD) were investigated. It was found that protein phosphor is a common event in the synapse, which is consistent with the presence of diverse classes of kinases and phosphatases in the synapse. Synaptic proteomics analysis required the purification of subcellular organelles from the brain regions of interest. Multiple steps of discontinuous density gradient ultra-centrifugation were employed to enrich the distinct organelles. Two-dimensional gel electrophoresis was used to separate and quantify proteins, including post-translational modified forms, from synaptic structures. It was observed that proteomic analysis of the synaptic vesicle identified 36 proteins, including seven integral membrane proteins and vesicle regulatory proteins

Új pathomechanizmusok és kezelési lehetőségek vizsgálata a vese ischémia/reperfúziós károsodásában és krónikus allograft nephropathiában = Investigation of new pathomechanisms and treatment possibilities of renal ischemia/reperfusion injury and chronic allograft nephropathy

Eredményeink az erythropoietin (EPO) védő szerepét igazolták egyoldali vese ischemia/reperfúziós (I/R) károsodásban. Ez a védő szerep elsősorban hímekben igazolható. Hátterében az EPO HSP72-mediálta hatása állhat, amellyel a Na+/K+ ATP-áz funkciójának megtartását segíti elő. Vizsgálataink során az EPO sejt-protektív hatásának hátterében egy új szignál molekulát is sikerült azonosítanunk, a szérum és glükokortikoid aktiválta kináz-1-t (SGK1). Ezek az eredmények az EPO által kifejtett sejtprotekció hátterében álló új pathomechanizmusokat írtak le. Eredményeink alapján az EPO, illetve a leírt útvonalakra ható egyéb szerek további vizsgálata és klinikai hasznosítása jöhet szóba. Másik vizsgálatunk során az I/R-s károsodás kivédésében szerepet játszó mechanizmusok során megfigyelhető nemi különbségeket írtuk le. Igazoltuk, hogy hímekben elsősorban a HIF 1α, míg nőstényekben a HSF útvonal tűnik fontosabbnak. Végül igazoltuk. hogy az SGK1 anti-apoptotikus és sejtvédő funkciójában is nemi különbségek mutathatók ki I/R-t követően. Ezekkel az eredményeinkkel magyarázhatóak az irodalomban korábban leírt és egymásnak ellentmondó közlések, amelyek a tesztoszteron SGK1 reguláló hatását mutatták be. | Our results suggest that EPO protects against severe, unilateral renal I/R injury, especially in male rats. This beneficial effect might be partly the result of EPO’s HSP72-mediated impact on Na+/K+ATPase-α1. Moreover, our data report a new signaling molecule to be involved in EPO cytoprotective actions, since we identified for the first time an important role of SGK1 in the renoprotective effect of EPO. These observations provide insights into a novel signaling mechanism by which EPO partly exerts its potent tissue protective actions. Given our results along with previous reports, the clinical use of EPO possibly leading to reduced cellular damage due to ischemic events should be considered. Our study has revealed a gender-dependent protective mechanism during renal I/R injury. In males mostly the HIF 1α, while in females the HSF is the dominant transcriptional pathway. The EPO treatment results in disappearance of the characteristic signal pathway activation in both genders. The explanation for that could be either a direct negative feedback effect on the transcription factors or an indirect renal protective effect of EPO by which these transcriptional factors do not need to be activated. We could also demonstrate that the anti-apoptotic SGK1 shows a gender-specific expression pattern after renal I/R with higher levels in male rats. These results confirm previous contradictory reports showing that SGK1 might be up-regulated and activated by testosterone

Breakthroughs in Medicinal Chemistry: New targets and mechanisms, new drugs, new hopes

The Editorial Board of the Medicinal Chemistry section of the journal Molecules publishes here its first Editorial, which has been prepared by highlighting, in sub-editorials of about one hundred words, some selected recently published articles that may have a profound impact on drug discovery and therapy. In particular, this editorial highlights new drug targets and mechanisms of action and new classes of drugs, as well as new therapeutic uses for known drugs or the involvement of known biological targets in new diseases. We also discuss some structural biology studies and new computational tools that may pave the way for the rational design or identification of more efficacious and safer drugs. Overall, the findings reported in these highlighted papers raise our hopes for the management of difficult-to-treat diseases that are posing a growing health threat, with new or repurposed drugs that overcome the limitations of currently applied therapies

Unprecedented protection of the retina from glaucoma-induced nerve damage by topical administration of a novel prodrug

Neuroscience - Vision & Functional Brain Imaging Poster SessionThe preclinical development of a prodrug-based site-specific delivery strategy that allows for targeting a potent small-molecule neuroprotectant into the eye, and with preference to the retina, after topical administration as eye drops is being reported. The prodrug has improved physicochemical properties compared to those of the parent compound, which affords enhanced transport into the eye. The initial conversion rate in the retina has been the fastest among all ocular and non-ocular tissues. This observation has indicated that a rapid intraocular bioactivation in the retina results in sequestration and preferential release of the neuroprotective agent in this compartment of the eye. Treatment with the prodrug is not accompanied with toxicity and endocrine side-effects, unlike systemic treatment with the parent compound. In a model for glaucomatous retinopathy, prodrug treatment not only reduced cell death in the retina, but a trend was also observed that its topical application reduced cell death more than treatment with the parent compound and was less variable among sample points. In addition, prodrug treatment significantly preserved visual function and prevented loss of vision, measured as contrast sensitivity at a given spatial frequency. In conclusion, our pharmacological approach has great promise for the development of a novel alternative and complementary approach to glaucoma therapy

Juggling for Effective Learning - Methods to Encourage the Acquisition of New Skills in an Optional Course at Óbuda University

Play and learn, or learn while having fun. Unfortunately, in today's achievement-oriented society, education is all about getting a student to complete a predetermined task on time. This pressure can be very stressful for students, especially if they themselves are perfectionists and want to do their best, and fear failure (repeating a term) and the feeling of underachievement when compared to the abilities of their peers. The "Juggling for Effective Learning" course has already been offered six times to students at Óbuda University. The primary reason for the course was to help students who have a disability, primarily a learning disability (dyslexia or dysgraphia). However, students who are curious about the course are also welcome to attend