Joseph Deutsch
Hebrew University of Jerusalem
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Neurochemical Research | 1997
Joseph Deutsch; Stanley I. Rapoport; A. D. Purdon
To ascertain effects of total ischemia on brain phospholipid metabolism, anesthetized rats were decapitated and unesterified fatty acids and long chain acyl-CoA concentrations were analyzed in brain after 3 or 15 min. Control brain was taken from rats that were microwaved. Fatty acids were quantitated by extraction, thin layer chromatography and gas chromatography. Long-chain acyl-CoAs were quantitated by solubilization, solid phase extraction with an oligonucleotide purification cartridge and HPLC. Unesterified fatty acid concentrations increased significantly after decapitation, most dramatically for arachidonic acid (76 fold at 15 min) followed by docosahexaenoic acid. Of the acyl-CoA molecular species only the concentration of arachidonoyl-CoA was increased at 3 min and 15 min after decapitation, by 3–4 fold compared with microwaved brain. The concentration of docosahexaenoyl-CoA fell whereas concentrations of the other acyl-CoAs were unchanged. The increase in arachidonoyl-CoA after decapitation indicates that reincorporation of arachidonic acid into membrane phospholipids is possible during ischemia, likely at the expense of docosahexaenoic acid.
Life Sciences | 1998
David Lichtstein; Michael Steinitz; Irith Gati; Sarah Samuelov; Joseph Deutsch; Joseph Orly
The biosynthesis of digitalis-like compounds (DLC) was determined in bovine and rat adrenal homogenates, as well as in primary rat adrenal cells, by following changes in the concentration of DLC using three independent sensitive bioassays: inhibition of [3H]-ouabain binding to red blood cells and competitive ouabain and bufalin ELISA. The amounts of DLC in bovine and rat adrenal homogenates, as measured by the two first bioassays, increased with time when the mixtures were incubated under tissue culture conditions. Rat primary adrenal cells were incubated in the presence of [1,2-(3)H]-25-hydroxycholesterol, [26,27-(3)H]-25-hydroxycholesterol or [7-(3)H]-pregnenolone. The radioactive products, as well as the digitalis-like activity, were fractionated by three sequential chromatography systems. When [1,2-(3)H]-25-hydroxycholesterol or [7-(3)H]-pregnenolone was added to the culture medium, the radioactivity was co-eluted with digitalis-like activity, suggesting that at least one of the DLC might originate in hydroxycholesterol. In contrast, when the culture medium was supplemented with [26,27-(3)H]-25-hydroxycholesterol, the radioactivity was not co-eluted with the digitalis-like activity, indicating that side chain cleavage is the first step in the synthesis of digitalis-like compounds by rat adrenal.
Journal of Neurochemistry | 2002
Eric Grange; Joseph Deutsch; Quentin R. Smith; Michael Chang; Stanley I. Rapoport; A. David Purdon
Abstract: In vivo rates of palmitate incorporation into brain phospholipids were measured in awake rats following programmed intravenous infusion of unesterified [9,10‐3H]palmitate to maintain constant plasma specific activity. Animals were killed after 2–10 min of infusion by microwave irradiation and analyzed for tracer distribution in brain phospholipid and phospholipid precursor, i.e., brain unesterified palmitate and palmitoyl‐CoA, pools. [9,10‐3H]Palmitate incorporation into brain phospholipids was linear with time and rapid, with >50% of brain tracer in choline‐containing glycerophospholipids at 2 min of infusion. However, tracer specific activity in brain phospholipid precursor pools was low and averaged only 1.6–1.8% of plasma unesterified palmitate specific activity. Correction for brain palmitoyl‐CoA specific activity increased the calculated rate of palmitate incorporation into brain phospholipids (0.52 nmol/s/g) by ∼60‐fold. The results suggest that palmitate incorporation and turnover in brain phospholipids are far more rapid than generally assumed and that this rapid turnover dilutes tracer specific activity in brain palmitoyl‐CoA pool owing to release and recycling of unlabeled fatty acid from phospholipid breakdown.
Acta Neurologica Scandinavica | 2000
N. H. Greig; E. De Micheli; H. W. Holloway; Q.‐S. Yu; T. Utsuki; T. A. Perry; D. K. Ingram; Joseph Deutsch; D. Lahiri; T. T. Soncrant
Phenserine, a phenylcarbamate of physostigmine, is a new potent and highly selective acetylcholinesterase (AChE) inhibitor, with a >50‐fold activity versus butyrylcholinesterase (BChE), in clinical trials for the treatment of Alzheimers disease (AD). Compared to physostigmine and tacrine, it is less toxic and robustly enhances cognition in animal models. To determine the time‐dependent effects of phenserine on cholinergic function, AChE activity, brain and plasma drug levels and brain extracellular acetylcholine (ACh) concentrations were measured in rats before and after phenserine administration. Additionally, its maximum tolerated dose, compared to physostigmine and tacrine, was determined. Following i.v. dosing, brain drug levels were 10‐fold higher than those achieved in plasma, peaked within 5 min and rapidly declined with half‐lives of 8.5 and 12.6 min, respectively. In contrast, a high (>70%) and long‐lasting inhibition of AChE was achieved (half‐life >8.25 h). A comparison between the time‐dependent plasma AChE inhibition achieved after similar oral and i.v. doses provided an estimate of oral bioavailability of 100%. Striatal, in vivo microdialysis in conscious, freely‐moving phenserine‐treated rats demonstrated >3‐fold rise in brain ACh levels. Phenserine thus is rapidly absorbed and cleared from the body, but produces a long‐lasting stimulation of brain cholinergic function at well tolerated doses and hence has superior properties as a drug candidate for AD. It selectively inhibits AChE, minimizing potential BChE side effects. Its long duration of action, coupled with its short pharmacokinetic half‐life, reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly.
Cancer Chemotherapy and Pharmacology | 1990
Shigeru Genka; Joseph Deutsch; Paul L. Stahle; Umesha Shetty; Varghese John; Cynthia Robinson; S. Rapoport
SummaryBy a sensitive and quantitative fluorometric assay, brain and plasma time-dependent concentration profiles were generated for phosphoramide mustard (PM) and active alkylating metabolites derived from cyclophosphamide (CPA) administration to rats. Whereas PM rapidly disappeared from plasma, with a monophasic half-life of 15.1 min, equimolar administration of CPA generated active metabolites in plasma that disappeared monoexponentially, with a composite half-life of 63 min. As a consequence, the time-dependent concentration integral of active alkylating metabolites derived from CPA administration, calculated between 5 min and infinity, was 3-fold that of PM. Pharmacokinetic parameters were calculated for each compound. The brain/plasma concentration-integral ratios of PM and active alkylating metabolites derived from CPA were 0.18 and 0.20, respectively. The cerebrovascular permeability-surface area product of PM was 7.5×10−5s−1, which is similar to that of other watersoluble anticancer agents that are restricted from entering the brain. The activities of a range of daily doses of PM and CPA were assessed against subcutaneous and intracerebral implants of Walker 256 carcinosarcoma tumor in rats. Inhibition of subcutaneous tumor growth by 50% was caused by CPA and PM doses of 6.6 and 12.0 mg/kg (daily for 5 consecutive days, starting 36 h after tumor implantation), respectively. However, administration of daily doses of up to 40 mg/kg did not significantly increase the survival of animals with intracerebral tumor implants. These studies indicate that active metabolites of CPA are restricted from entering the brain and that only subtherapeutic concentrations are achieved in brain tissue after systemic administration of CPA or PM.
Life Sciences | 1986
David Lichtstein; Sylvia Kachalsky; Joseph Deutsch
An ouabain-like compound (OLC) was purified from toad skin. The purification procedure consisted of three sequential separations on HPLC using amino and reverse phase chromatography. Using UV, NMR and Mass spectroscopy the structure of the purified material is suggested to be mono-hydroxy-14,15-epoxy-20,22-dienolide glycoside (resibufogenin). Evidence is presented that this compound is also present in the toad plasma. It is suggested that the endogenous bufodienolide derivative participates in the physiological regulation of the Na+,K+-ATPase activity.
Journal of Neurochemistry | 2002
Olivier Rabin; Joseph Deutsch; Eric Grange; Karen D. Pettigrew; Michael C. J. Chang; Stanley I. Rapoport; A. David Purdon
Abstract: Transient global cerebral ischemia affects phospholipid metabolism and features a considerable increase in unesterified fatty acids. Reincorporation of free fatty acids into membrane phospholipids during reperfusion following transient ischemia depends on conversion of fatty acids to acyl‐CoAs via acyl‐CoA synthetases and incorporation of the acyl group into lysophospholipids. To study the effect of ischemia‐reperfusion on brain fatty acid and acyl‐CoA pools, the common carotid arteries were tied for 5 min in awake gerbils, after which the ligatures were released for 5 min and the animals were killed by microwave irradiation. Twenty percent of these animals (two of 10) were excluded from the ischemia‐reperfusion group when it was demonstrated statistically that brain unesterified arachidonic acid concentration was not elevated beyond the range of the control group. Brain unesterified fatty acid concentration was increased 4.4‐fold in the ischemic‐reperfused animals, with stearic acid and arachidonic acid increasing the most among the saturated and polyunsaturated fatty acids, respectively. The total acyl‐CoA concentration remained unaffected, indicating that reacylation of membrane lysophospholipids is maintained during recovery. However, there was a substantial increase in the stearoyl‐ and arachidonoyl‐CoA and a marked decrease in palmitoyl‐ and docosahexaenoyl‐CoA. These results suggest that unesterified fatty acid reacylation into phospholipids is reprioritized according to the redistribution in concentration of acyl‐CoA molecular species, with incorporation of stearic acid and especially arachidonic acid being favored.
Analytical Biochemistry | 1976
Joseph Deutsch; Aharon Razin; John Sedat
Abstract A method is described for the unambiguous rapid identification and quantitation of the minor base, 5-methylcytosine, in DNA using high resolution mass spectrometry. This method can detect one 5-methylcytosine residue per 5500 nucleotides in φχ 174 DNA, in a sample of less than 10 μg and requires less than 1 μg of calf thymus DNA in which the molar ratio of 5-methylcytosine/cytosine is about 0.05.
Journal of Neurochemistry | 2002
Olivier Rabin; Michael C. J. Chang; Eric Grange; Jane M. Bell; Stanley I. Rapoport; Joseph Deutsch; A. David Purdon
Abstract: Awake gerbils were subjected to 5 min of forebrain ischemia by clamping the carotid arteries for 5 min and then allowing recirculation. Radiolabeled arachidonic or palmitic acid was infused intravenously for 5 min at the start of recirculation, after which the brains were prepared for quantitative autoradiography or chemical analysis. Dilution of specific activity of the acyl‐CoA pool was independently determined for these fatty acids in control gerbils and following 5 min of ischemia and 5 min of reperfusion. Using a quantitative method for measuring regional in vivo fatty acid incorporation into and turnover within brain phospholipids and determining unlabeled concentrations of acyl‐CoAs following recirculation, it was shown that reperfusion after 5 min of ischemia was accompanied by a threefold increase compared with the control in the rate of reincorporation of unlabeled arachidonate that had been released during ischemia, whereas reincorporation of released palmitate was not different from the control. Selective and accelerated reincorporation of arachidonate into brain phospholipids shortly after ischemia may ameliorate specific deleterious effects of arachidonate and its metabolites on brain membranes.
Neurochemical Research | 2002
Joseph Deutsch; Stanley I. Rapoport; Thad A. Rosenberger
A rapid and reliable method was developed to quantify brain concentrations of coenzyme A (CoA) and short-chain acyl-CoAs having chain length ≤ 4 carbon atoms. The method employs tissue extraction and isolation using an oligonucleotide purification cartridge and quantifies concentrations by peak area analysis following high-performance liquid chromatography (HPLC). In adult anesthetized rats subjected to 4-s high-energy microwave irradiation to stop brain metabolism, the brain concentrations of CoA, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), acetyl-CoA, and butyryl-CoA equaled 68.7 ± 18.5, 2.7 ± 1.5, 7.6 ± 2.3, and 30.6 ± 15.9 nmol·g−1, respectively. After 5 min of complete ischemia, the brain concentrations of CoA and HMG-CoA increased 2- and 12-fold compared to controls, whereas acetyl-CoA and butyryl-CoA concentrations did not change. Markedly elevated levels of CoA and HMG-CoA following cerebral ischemia may reflect disturbed energy metabolism and altered formation of cholesterol and isoprenoids.