Synthesis and evaluation of polymyxins bearing reductively labile disulfide-linked lipids

Microbial Biotechnolog

Synthesis and Evaluation of Polymyxins Bearing Reductively Labile Disulfide-Linked Lipids

Polymyxins are a class of lipopeptide anti-infective agents with potent and specific activity against Gram-negative bacteria. While toxicity concerns associated with polymyxin B and E (colistin) have historically limited their clinical application, today they are increasingly used as last-resort antibiotics given the rise of multidrug-resistant Gram-negative pathogens. The adverse side effects of polymyxins are well known, particularly as related to their nephrotoxicity. Here, we describe the synthesis and evaluation of a novel series of polymyxin analogues, aimed at reducing their nephrotoxic effects. Using a semisynthetic approach, we explored modifications of the exocyclic part of the polymyxin scaffold, namely, the terminal amino acid and lipophilic tail. By incorporating a reductively labile disulfide linkage in the lipid tail, we obtained novel polymyxins that exhibit potent antibacterial activity on par with polymyxin B but with reduced toxicity toward human renal proximal tubular epithelial cells

Medial amygdala lesions differentially influence stress responsivity and sensorimotor gating in rats.

Contains fulltext : 87611.pdf (publisher's version ) (Closed access)BACKGROUND: The amygdala is involved in the coordination of stress but is also an important gatekeeper involved in the regulation of vigilance. The amygdala is structurally complex, consisting of several nuclei with specific functions in the affective response to environmental stimuli. There are indications that the medial amygdaloid nucleus may be a pivotal player in acute responses to emotional environmental stimuli. METHODS: The present study therefore aimed to study the effects of bilateral electrolytic lesions of the medial amygdala on unconditioned anxiety-related behavior as well as a sensorimotor gating parameter (prepulse inhibition, PPI) in rats. Anxiety-related behavior was assessed with the use of stress-induced hyperthermia (SIH), light-enhanced startle (LES) and open field behavior. RESULTS: Bilateral electrolytic lesions of the medial amygdala decreased the SIH response and anxiety-related open field behavior. In contrast, lesioned animals displayed augmented LES and disrupted PPI. No changes in basal locomotor activity, body temperature and acoustic startle were found between lesioned and sham animals. CONCLUSIONS: The present study suggests that the medial amygdala is an important player in response to acute environmental stimuli. Decreased unconditioned psychological stress responses were found, whereas LES was enhanced and sensorimotor processing was disrupted. However, considering the existing data on basolateral amygdala involvement in PPI and bed nucleus of the stria terminalis involvement in LES, local infusion studies into the MeA should be performed to further substantiate these findings

Environmental enrichment has antidepressant-like action without improving learning and memory deficits in olfactory bulbectomized rats

Item does not contain fulltextDepression, especially in the elderly, is associated with poor cognitive functioning. Exercise has received much attention in the treatment for depression and also dementia. Here we studied the effect of an enriched environment combined with voluntary exercise (EE/VE) on the olfactory bulbectomized (OBX) rat. The OBX rat is hyperactive in an open field, which is normalized by chronic antidepressant treatment, and suffers from learning and memory impairments. Neurotrophic factors are thought to be involved in the antidepressant action of EE/VE. Hyperactivity and cognitive functioning (both hippocampal dependent and independent tasks) were investigated before and after EE/VE. We quantified hippocampal mRNA levels of the neurotrophic factors BDNF, VGF and VEGF. VEGF receptor (FLK-1) inhibition was achieved by i.c.v administration of the antagonist SU5416 during the period of EE/VE. OBX almost completely blocked fear memory acquired either 48 h or 28 days before surgery. EE/EV normalized OBX-induced hyperactivity in open field, while having no effect on the decrease in hippocampal dependent learning and memory. VEGF mRNA levels in hippocampus were significantly increased both in OBX and control rats following EE/VE. OBX reduced BDNF mRNA levels, but EE did not reverse this. Inhibition of the FLK-1 receptor did not suppress EE/VE induced normalization of the hyperactivity of the OBX rat. The lack of effect of EE/VE on cognitive parameters, while normalizing hyperactivity, suggests different neuronal mechanisms underlying OBX-induced behavioral changes. Since EE/VE still normalizes the OBX-induced hyperactivity while the FLK-1 receptor was blocked, we assume that VEGF is not obligatory for the antidepressant effect of EE/VE. This article is part of a Special Issue entitled 'Anxiety and Depression'

Reversal of startle gating deficits in transgenic mice overexpressing corticotropin-releasing factor by antipsychotic drugs.

Item does not contain fulltextChronically elevated levels of corticotropin-releasing factor (CRF) in transgenic mice overexpressing CRF in the brain (CRF-OE) appear to be associated with alterations commonly associated with major depressive disorder, as well as with sensorimotor gating deficits commonly associated with schizophrenia. In the present study, we tested the hypothesis that antipsychotics may be effective in normalizing prepulse inhibition (PPI) of acoustic startle in CRF-OE mice, which display impaired sensorimotor gating compared to wild-type (WT) mice. The typical antipsychotic haloperidol and atypical antipsychotic risperidone improved PPI in the CRF-OE mice, but were ineffective in WT mice. The atypical antipsychotic clozapine did not influence PPI in CRF-OE mice, but reduced gating in WT mice. This effect of clozapine in the CRF-OE mice may thus be regarded as a relative improvement, consistent with the observed effect of haloperidol and risperidone. As expected, the anxiolytic, nonantipsychotic chlordiazepoxide was devoid of any effect. All four compounds dose-dependently reduced the acoustic startle response irrespective of genotype. These results indicate that antipsychotic drugs are effective in improving startle gating deficits in the CRF-OE mice. Hence, the CRF-OE mouse model may represent an animal model for certain aspects of psychotic depression, and could be a valuable tool for research addressing the impact of chronically elevated levels of CRF on information processing

Recellularized Native Kidney Scaffolds as a Novel Tool in Nephrotoxicity Screening

Contains fulltext : 195621.pdf (publisher's version ) (Closed access