Microbial transformation of hydroxy metabolites of 1-oxohexyl derivatives of theobromine by Cunninghamella echinulata NRRL 1384

Aim:  The biotransformation of pentoxifylline (PTX), propentofylline (PPT) and their racemic hydroxy metabolites ((±)-OHPTX and (±)-OHPPT) by using the fungus Cunninghamella echinulata NRRL 1384.
Methods and Results:  A fungus Cunninghamella echinulata NRRL 1384 was used to catalyse the ( S )-selective oxidation of the racemic hydroxy metabolites: (±)-OHPTX and (±)-OHPPT and for reduction of PTX and PPT. The first oxidation step appears to be selective and relatively fast while the second reduction step is slower and more selective with PTX. Modifications involving supplementing the bioconversion with glucose give yields and enantiomeric excess (ee) values similar to those obtained without glucose.
Conclusions:  The bioconversion of (±)-OHPTX gave an ( R )-enantiomer (LSF-lisofylline) with a higher enantiopurity (maximum approximately 93% ee) compared to the bioconversion of (±)-OHPPT, when the maximum ee value for ( R )-OHPPT was recorded at 83%.
Significance and Impact of the Study:  The conversion of (±)-OHPTX and (±)-OHPPT using Cunninghamella echinulata can be recognized as a process, which may be recommended as an alternative to the methods used to obtain ( R )-OHPTX and ( R )-OHPPT.     

Effects of an inhibitor of adenosine deaminase,deoxycoformycin, and of nucleoside transport,propentofylline, on post-ischemic recovery of adenine nucleotides in rat brain

The effects of an adenosine deaminase inhibitor (deoxycoformycin, 500 μg/kg) and of an inhibitor of nucleoside transport (propentofylline, 10 mg/kg) on adenosine and adenine nucleotide levels in the ischemic rat brain were investigated. The brains of the rats were microwaved before, at the end of a 20 min period of cerebral ischemia (4 vessel occlusion+hypotension), or after 5, 10, 45, and 90 min of reperfusion. Deoxycoformycin increased brain adenosine levels during both ischemia and the initial phases of reperfusion. AMP levels were elevated during ischemia and after 5 min of reperfusion. ATP levels were elevated above those in the non-treated animals after 10 and 45 min of reperfusion. ADP levels were elevated above the non-drug controls at 90 min. These increases in ATP, ADP and AMP resulted in significant increases in total adenylates during ischemia, and after 10 min and 90 min of reperfusion. Propentofylline administration resulted in enhanced AMP levels during ischemia but did not alter adenosine or adenine nucleotide levels during reperfusion in comparison with non-treated controls.     

Transient adenosine efflux in the rat caudate-putamen

Adenosine is an endogenous byproduct of metabolism that regulates cerebral blood flow and modulates neurotransmission. Four receptors, with affinities ranging from nanomolar to micromolar, mediate the effects of adenosine. Real-time measurements are needed to understand the extracellular adenosine concentrations available to activate these receptors. In this study, we measured the subsecond time course of adenosine efflux in the caudate–putamen of anesthetized rats after a 1 s, high-frequency stimulation of dopamine neurons in the substantia nigra. Fast-scan cyclic voltammetry at carbon-fiber microelectrodes was used for simultaneous detection of adenosine and dopamine, which have different oxidation potentials. While dopamine was immediately released after electrical stimulation, adenosine accumulation was slightly delayed and cleared in about 15 seconds. The concentration of adenosine measured after electrical stimulation was 0.94 ± 0.09 μM. An adenosine kinase inhibitor, adenosine transport inhibitor, and a histamine synthetic precursor were used to pharmacologically confirm the identity of the measured substance as adenosine. Adenosine efflux was also correlated with increases in oxygen, which occur because of changes in cerebral blood flow. This study shows that extracellular adenosine transiently increases after short bursts of neuronal activity in concentrations that can activate receptors.