Biomedical subjects

M A DeCoster

Publications and source records attributed to M A DeCoster.

24 records · Page 2Linked to original sources

PubMed1994

Neurotoxicity of artemisinin analogs in vitro.

The sesquiterpene endoperoxide antimalarial agents arteether and artemether have been reported to cause neurotoxicity with a discrete distribution in the brain stems of rats and dogs after multiple doses. The nature and distribution of the brain lesions suggest a specific neuronal target, the identity of which is unknown. In order to further investigate artemisinin analog-induced neurotoxicity, we evaluated several in vitro models: fetal rat primary neuronal cultures, fetal rat secondary astrocyte cultures, and transformed neuronal cultures (rat-derived neuroblastoma NG108-15 and mouse-derived neuroblastoma Neuro-2a). Results indicate that toxicity was specific for neuronal cell types but not glial cells. Neurotoxicity, as indexed by liberation of lactate dehydrogenase and/or inhibition of radiolabelled-leucine uptake, was seen in all three neuronal culture types, implicating a common target. In vitro neurotoxicity was dose and time dependent. Acute exposure to drug results in delayed, but not immediate, manifestations of cell toxicity. Structure-activity comparisons indicate that substitutions at positions 9 and 10 and stereoisomerism at position 10 of the artemisinin backbone influence the degree of toxicity. The endoperoxide is necessary but not sufficient for toxicity. Sodium artesunate and dihydroartemisinin, a metabolite common to all artemisinin analogs currently being developed for clinical use, are the most potent of all analogs tested. These results are consistent with a specific neuronal target, but the identity of the target(s) remains unknown.

Animals↗

PubMed1994

Kappa opioids: therapeutic considerations in epilepsy and CNS injury.

Epilepsy and CNS injury identify a heterogenous group of diseases, many of which exhibit refractoriness (e.g., the partial epilepsies) to established drug therapy or, as in the case of brain and spinal cord injuries of variable etiologies, remain a formidable target for successful drug development. As such, the search for safe, effective antiepileptic and neuroprotective drugs continues. Although several CNS targets have been identified for drug development, especially the excitatory amino acid receptors, free-radical systems, gangliosides, and nitric oxide, etc., the opioid system and its diversity of receptors have, until recently, received little attention. This review attempts to focus on one opioid system, namely the kappa receptor class of opioid ligands, specifically addressing the potential anticonvulsant and neuroprotective properties of the arylacetamide series of kappa opioid analgesics as novel pharmacotherapeutic approaches to the treatment of epilepsy, stroke, or trauma related brain or spinal cord injury.

Analgesics, Opioid↗

PubMed1992

Calcium dynamics in neurons treated with toxic and non-toxic concentrations of glutamate.

Intracellular calcium concentration ([Ca2+]i) dynamics were simultaneously monitored in multiple cultured rat neurons loaded with Fluo-3 and continuously stimulated with glutamate (GLU). Three response types were observed: 10 microM GLU caused an initial transient increase in [Ca2+]i; 20 microM a biphasic response characterized by a 150-350 s 'calcium trough' between peaks; and 40 microM an initial sustained increase in [Ca2+]i. Neurons in calcium-free medium treated with 40 microM GLU showed only an initial transient increase in [Ca2+]i, demonstrating the dependence of sustained secondary increases in [Ca2+]i on extracellular calcium sources. We observed synchronized responses of multiple neurons within a given culture well, after GLU treatment, supporting the hypothesis that sustained influx of extracellular calcium may be stimulated by depletion of intracellular calcium and/or the release of endogenous excitatory amino acids.

Aniline Compounds↗

PubMed1989

Evidence that the axolemmal mitogen for cultured Schwann cells is a positively charged, heparan sulfate proteoglycan-bound, heparin-displaceable molecule.

Treatment of axolemma with pH 9 buffer results in a pellet enriched two-fold in the mitogen for cultured Schwann cells. Heparitinase treatment releases 8% of the mitogen into solution, while heparin selectively solubilizes the mitogen, resulting in an extract which has a specific mitogenic activity approximately 2.5 times greater than the mitogenicity of the starting axolemma membrane. These data support a model in which the axolemmal mitogen is a positively charged molecule associated with negatively charged sulfated proteoglycans.

Animals↗

PubMedDate not supplied

Micropatterning of nanoengineered surfaces to study neuronal cell attachment in vitro.

Methods for producing protein patterns with defined spatial arrangement and micro- and nanoscale features are important for studying cellular-level interactions, including basic cell-cell communications, cell signaling, and mechanisms of drug action. Toward this end, a straightforward, versatile procedure for fabricating micropatterns of bioactive nanofilm coatings as multifunctional biological testbeds is demonstrated. The method, based on a combination of photolithography and layer-by-layer self-assembly (LbL), allows for precise construction of nanocomposite films of potentially complex architecture, and patterning of these films on substrates using a modified lift-off (LO) procedure. As a first step in evaluating nanostructures made with this process, "comparison chips," comprising two coexisting regions of square patterns with relevant proteins/polypeptides on a single substrate, were fabricated with poly(diallyldimethylammonium chloride) (PDDA) as a cell-repellent background. Using neuronal cells as a model biological system, comparison chips were produced with secreted phospholipase A2 (sPLA2), a known membrane-active enzyme for neurons, for direct comparison with gelatin, poly-l-lysine (PLL), or bovine serum albumin (BSA). Fluorescence microscopy, surface profilometry, and atomic force microscopy techniques were used to evaluate the structural properties of the patterns on these chips and show that the patterning technique was successful. Preliminary cell culture studies show that neurons respond and bind specifically to the sPLA2 enzyme embedded in the polyelectrolyte thin films and present as the outermost layer. These findings point to the potential for this method to be applied in developing test substrates for a broad array of studies aimed at identifying important biological structure-function relationships.

Animals↗

PubMedDate not supplied

Experimental models and their use in studies of diabetic retinal microangiopathy.

Diabetes produces dramatic changes in retinal microvasculature, triggering endothelial cell proliferation and microaneurysms. Capillaries become weakened, releasing blood into vitreal and retinal spaces. Photoreceptors become occluded and separated from the choriocapillaris, resulting in visual acuity decline, detachment and cell death. Several models have been developed that have proved useful for the study of this disease, resulting in a better understanding of the processes involved. Streptozotocin treatment affects the pancreatic beta cells, rapidly reducing them until insulin is no longer synthesized in sufficient amounts. The galactosemic model shifts metabolism away from glucose, increasing aldose reductase and retinal polyol metabolism. Finally, two weeks of cycled oxygen from high to low tension every 24 hours, followed by return to room air, triggers microangiogenesis in developing retinas. Use of these models, separately or in combination, as well as electroretinographic analysis, has begun to reveal the events taking place as diabetic retinopathy progresses. Endothelial cells become separated from pericytes as basement membranes thicken, and vascular endothelial growth factor increases, triggering their proliferation. Finally, early changes occurring within photoreceptors can now be studied.

Animals↗