Jonathan E Friedman

Malaria (Plasmodium spp) and human African trypanosomiasis (Trypanosoma brucei spp) are vector borne, deadly parasitic diseases. While chemotherapeutic agents for both diseases are available, difficulty in their eradication and development of drug resistance requires that new therapies targeting unexplored pathways or exploiting novel modes of acti...

Zinc plays a key pathophysiological role in major neurological disorders as well as diabetes, while being essential for the activity of numerous zinc binding proteins. A major challenge in chelation based therapy must take into consideration these apparently conflicting effects of zinc. One approach is to limit the activity of the chelator to regio...

One of the hypotheses for the development of familial amyotrophic lateral sclerosis (ALS) is that mutations in the superoxide dismutase 1 enzyme lead to aberrant properties of the copper within the active site of the enzyme which then causes increased oxidative damage. The lipophilic metal chelators DP-109 and DP-460 which chelate calcium, copper,...

DP-155 is a lipid prodrug of indomethacin that comprises the latter conjugated to lecithin at position sn-2 via a 5-carbon length linker. It is cleaved by phospholipase A2 (PLA)(2) to a greater extent than similar compounds with linkers of 2, 3, and 4 carbons. Indomethacin is the principal metabolite of DP-155 in rat serum and, after DP-155 oral ad...

Indomethacin has been suggested for the treatment of Alzheimer's disease (AD), but its use is limited by gastrointestinal and renal toxicity. To overcome this limitation, D-Pharm Ltd. (Rehovot, Israel) developed DP-155 (mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido] hexanoyl}-Sn-glycero-3-phos...

DP-109, a lipophilic bivalent metal ion modulator currently under preclinical development for neurodegenerative disorders, was designed to have membrane-associated activity, thereby restricting its action to the vicinity of cell membranes. We describe the application of a colorimetric phospholipid/polydiacetylene (PDA) biomimetic membrane assay in...

Metals such as zinc, copper and iron contribute to aggregation of amyloid-beta (Abeta) protein and deposition of amyloid plaques in Alzheimer's disease (AD). We examined whether the lipophilic metal chelator DP-109 inhibited these events in aged female hAbetaPP-transgenic Tg2576 mice. Daily gavage administration of DP-109 for 3 months markedly redu...

Neurotrophins support neuronal survival and differentiation via Trk receptors, yet can also induce cell death via the p75 receptor. In these studies, we investigated signaling mechanisms governing p75-mediated death of hippocampal neurons, specifically the role of caspases. Although p75 is structurally a member of the Fas/TNFR1 receptor family, cas...

Disturbance in metallochemical reactions and metal-protein association are associated with chronic neurodegenerative conditions, such as Alzheimer's and Parkinson's disease, as well as with neurodegeneration triggered by acute cerebral ischaemia. Many neurological diseases have been linked directly or indirectly to perturbed homeostasis of Ca, Fe,...

Cultured neocortical neurons respond rapidly to oxygen deprivation. Within minutes they demonstrate an increase in intracellular calcium and pronounced changes in their morphology. These changes include swelling, bleb formations, process retraction and a change in shape of the soma from pyramidal or ellipsoidal to round. Since the cytoskeleton is r...

An important cause of anoxia-induced nerve injury involves the disruption of the ionic balance that exists across the neuronal membrane. This loss of ionic homeostasis results in an increase in intracellular calcium, sodium, and hydrogen and is correlated with cell injury and death. Using time-lapse confocal microscopy, we have previously reported...

Although it is well documented that glutamate receptor subtypes are differentially expressed during central nervous system development postnatally, how glutamate affects neurons during postnatal development is unclear. We therefore examined the development of the intrinsic neuronal response to glutamate receptor activation by studying single, hippo...

We have investigated the role of 9-O-acetylated gangliosides identified by the Jones monoclonal antibody (Jones mAb) in the elongation of neurites extended by neurons of embryonic rat dorsal root ganglia (DRG) explants grown on laminin substratum. The behavior of individual growth cones was recorded using a time-lapse video-enhanced imaging system...

Following our previous observations that anoxia induces a drop in extracellular Na+ in the brain slice and that removal of extracellular Na+ prevents the anoxia-induced morphological changes in dissociated hippocampal neurons, we hypothesized that intracellular Na+ increases during anoxia in isolated neurons. Using the fluorophore Sodium Green in f...

Anoxia is believed to cause nerve injury and death in part, by inducing sustained, elevated levels of intracellular Ca2+. The increased concentration of intracellular Ca2+ is capable, by itself, of inducing nerve injury and death, even without the added stress of anoxia. However, we have recently shown that an increased level of intracellular Ca2+...

Although we and others have previously shown that newborn central mammalian neurons are more tolerant to anoxia than their adult counterparts, we do not know whether neonatal nerve cells accumulate free cytosolic calcium (Ca2+i) less than adults in response to O2 deprivation. In order to determine whether anoxia increases Ca2+i in adult and neonata...

In the search for a functional role of cytoskeletal proteins in the mechanism(s) of stimulus-secretion coupling, we have previously demonstrated that the actomyosin system might be involved in the transport of cations across the plasma membrane of bovine adrenal chromaffin cells [(1986) J. Biol. Chem. 261, 5745-5750]. To establish whether actin and...

We have incorporated the myosin fragment heavy meromyosin (HMM), which is known to interact mechanochemically and enzymatically with actin filaments, into intact chromaffin cells of the bovine adrenal medulla, in order to study the possible involvement of actin and myosin in stimulus-secretion coupling. HMM was found to stimulate secretion of catec...

The intrinsic fluorescence of catecholamines can be exploited for a simple and speedy fluorescence assay of secretion from bovine adrenal chromaffin cells. Catecholamines are separated from concomitantly secreted proteins by centrifugation in 0.4 M perchloric acid, and their fluorescence is measured directly in a conventional spectrofluorometer wit...

Changes in plasma membrane potential of isolated bovine adrenal chromaffin cells were measured independently by two chemical probe methods and related to corresponding effects on catecholamine secretion. The lipophilic cation tetraphenylphosphonium (TPP+) and the carbocyanine dye 3,3'-dipropylthiadicarbocyanine [DiS-C3-(5)] were used. The necessity...

Small unilamellar liposomes with an average external diameter of approximately 550 A were prepared by high pressure extrusion in a French press. Liposomes, composed of phosphatidylcholine, phosphatidylserine, and cholesterol at a molar ratio of 7:1:2, were incubated with suspensions of bovine adrenal chromaffin cells. The cell-liposome interactions...

Plasma membranes of chromaffin cells are isolated from the bovine adrenal medulla. Treatment of the membranes in the French press gives vesicles of uniform size, ~85% of which are closed. These are oriented right-side-out to ~95%, as indicated by α-Bungarotoxin-binding, enzymatic activities, aggregation by lectins and presence of membrane-associate...

Chromaffin cells of the bovine adrenal medulla were fused with liposomes containing DNAaseI. Resting membrane potential measurements, obtained by the use of the cyanine dye diS-C3 (5), showed that DNAaseI incorporation causes depolarization from −56 to −31 mV, which is similar to that induced by ouabain. The level of basal secretion which occurs af...