Structural features of PGBX (a prostaglandin polymer) deduced by analogies with dimers derived from 15-keto-prostaglandin B.

The polymeric prostaglandin, PGBX, has a beneficial effect on oxidative phosphorylation of damaged mitochondria in vitro and has manifested interesting effects in vivo. Its chemical structure has been partially elucidated by comparison of its 13C-NMR (nuclear magnetic resonance) spectrum with the spectra of prostaglandin monomers. Reported here is subsequent comparison of PGBX with two prostaglandin dimers derived from 15-keto-PGB1, which provide more complete structural information. The two prostaglandin dimers were synthesized and analyzed by 13C-MNR and by other techniques, with particular attention to positions of linkages between the two monomeric prostaglandin subunits of the dimers. Based on these data, some proposals are presented regarding probable locations of linkages between prostaglandin monomeric subunits in the polymeric PGBX.

Facilitation of recovery from ischemic brain damage in rabbits by polymeric prostaglandin PGBx, a mitochondrial protective agent.

Administration of polymeric prostaglandin PGBx to rabbits after a 20-minute period of almost total obstruction of blood flow to the brain resulted in marked improvement of recovery from brain damage as measured by recovery of brain function. This beneficial effect of PGBx on recovery from acute ischemic tissue damage, analogous to that observed in cardiac tissue of monkeys, may be due to the positive effect of PGBx on phosphorylation in damaged mitochondria as observed previously in vitro. A convenient surgical technique for producing reversible cerebral ischemia in rabbits was developed for and used in this pharmacological study.

Recovery of monkeys after myocardial infarction with ventricular fibrillation. Effects of PGB.

PGBx, a polymeric, stable, free radical derivative of 15-keto-prostaglandin B1, that conserves oxidative phosphorylation in mitochondria under degenerative conditions in vitro, affected survival of male Rhesus monkeys (5-9 kg) anesthetized with pentobarbital and subjected to coronary ligation and induced ventricular fibrillation (VF). In tests performed in sequence with intervening periods for recover, intracardiac injections of norepinephrine (NE), cardiac massage (CM), and electrical defibrillation (EDF) were used to restore cardiac function both in controls and experimental animals, but the latter were injected also with 1 mg/kg PGBx. Recovery was established by maintenance of effective blood pressure without exogenous support. In the control group the cumulative survival for fibrillation episodes of 4, 6, 8, and 12 min was 60, 40, 31, and 25% respectively. In the PGBx-treated group survival for equivalent periods was 100, 93, 93, and 88% respectively. In separate studies, African Green monkeys were subjected to single episodes of VF of either 8 or 12 min. Combined survival was 36% for the controls, 93% for the PGBx-treated animals. Clearly PGBx radically improved cardiac recovery after circulatory arrest due to VF in the presence of acute myocardial infarction. The results also suggest a synergistic action between norepinephrine and PGBx in achieving such recovery.

Protection and reactivation of oxidative phosphorylation in mitochondria by a stable free-radical prostaglandin polymer (PGBx).

A stable free-radical polymeric derivative of prostaglandin B1 (PGBx) has been synthesized that exhibits regenerative effects on oxidative phosphorylation in aged mitochondria. The molecular weights of the most active preparations fall between 2000 and 2600. PGBx is characterized by a single-line electron spin resonance spectrum that is stable at room temperature. PGBx restores phosphorylating ability and net ATP synthesis in isolated mitochondria aged for 4 days at 0 degrees C and protects against further degradation of phosphorylating activity when such aged mitochondria are preincubated at 28 degrees C in the absence of adenine nucleotide phosphate acceptors. This compound has been reported to exert beneficial effects in vivo in experimental pathological conditions, such as regional ischemia, in which the mitochondria of the ischemic region may have been damaged.

Studies on PGBx, a polymeric derivative of prostaglandin B1: I. Synthesis and purification of PGBx.

PGBx, a new polymeric derivative of PGB1, previously was shown to (a) restore oxidative phosphorylation to degraded isolated rat liver mitochondria in vitro and (b) to reverse the effects of cardiogenic ischemia in monkeys and cerebral ischemia in rabbits. This report describes in detail the synthesis and purification of PGBx via PGB1, starting with azelaic acid. Details of the in vitro mitochondrial assay are also reported. Purified PGBx exhibiting maximal reactivation of mitochondrial phosphorylation has a mean molecular weight of 2350. Yield of PGBx based on azelaic acid is 4% and based on PGB1 is 25%.

Dose dependence of PGBX, a polymeric derivative of prostaglandin B1, for normalization of hereditary diabetes of the mouse.

A polymeric derivative of prostaglandin B1, PGBX, which reactivates phosphorylation in damaged mitochondria, is shown to normalize the high blood glucose, obesity, and excessive appetite of the hereditary diabetic mouse. The degree of normalization is shown to vary with dosage.

Some in vitro and in vivo effects of a new prostaglandin derivative.

PIP: In vitro experiments were carried out under the premise that fatigue/stress could be defined bodily in terms of energy demand under conditions of limited supply. The experiments demonstrated some new biochemical correlates of stress and some of their hormonal control factors. It was seen that both physical and psychological stress--e.g., sleep deprivation, combat flying--caused an elevation of phospholipid G (phosphatidyl glycerol). This reaction was consistent, despite the type of stress. Other phospholipids varied with the stress conditions. The triggering factor for this raised phospholipid level may be explained by the fact that injection of various PGs (prostaglandins) causes major elevation in G and lesser changes in other phospholipids. The different types of PGs cause varying reactions in the different phospholipids. The work with PGs indicates a means of channelling biological energy in ways that will enhance bodily tolerance to stress.^ieng

Stable free-radical forms of plasma proteins or simpler related structures which induce brain excitatory effects.

Stable free radicals have been prepared from purified plasma proteins, pituitary peptides, and simpler related structures like 5-OH tryptophan and melatonin by oxidation with the free-radical nitrosyl disulfonate in alkaline solution under controlled conditions. The presence of tyrosine or trytophan amino acid residues in the protein was found essential for free-radical formation. These red-colored, stable free radicals showed electron spin resonance spectra in aqueous solutions at room temperature and maintained this characteristic for weeks when stored at 5 degrees C. Illumination, by visible light, of the free-radical proteins and peptides separated from excess nitrosyl disulfonate by salt fractionation or chromatography enhanced the free-radical concentration in the light. The increased signal decayed in the dark. Intravenous administration of the free-radical proteins or peptides into rabbits equipped with chronic cranial electrodes and sedated with a small dose of pentobarbital caused a sudden EEG arousal accompanied by behavioral changes indicative of brain excitation. Illumination of the free-radical compounds prior to administration enhanced the effects. Untreated control proteins or peptides had no effects. The observations are interpreted to suggest the involvement of free-radical structures in the transfer of energy in nervous tissue.