phenobarbital-sodium and Brain-Ischemia

In the present study Renyi entropy and L-Z complexity were used to characterize heart rate variability (HRV) of rats that were suffered from brain asphyxia and ischemia. Two groups of rats were studied: (a) rats (n=5) injected with NAALADase inhibitor, 2-PMPA, which has been proven neuroprotective in asphyxia injury and (b) control subjects (n=5) without medication. Renyi entropy and L-Z complexity of the R-R intervals (RRI) at different experiment stages were investigated in the two groups. The results show that both measures indicate less injury and better recovery in the drug injection group. The dynamic change of 90 min RRI signal after the asphyxia was investigated. The sudden reduction of the two parameters shows their sensitivity to the asphyxia insult.

Topics: Animals; Arrhythmias, Cardiac; Asphyxia; Brain; Brain Ischemia; Diagnosis, Computer-Assisted; Electrocardiography; Heart Rate; Male; Neuroprotective Agents; Organophosphorus Compounds; Rats; Rats, Wistar; Treatment Outcome

Two representative glutamate carboxypeptidase II (GCP II) inhibitors, 2-(hydroxypentafluorophenylmethyl-phosphinoylmethyl)pentanedioic acid 2 and 2-(3-mercaptopropyl)pentanedioic acid 3, were synthesized in high optical purities (>97%ee). The two enantiomers of 2 were prepared from previously reported chiral intermediates, (R)- and (S)-2-(hydroxyphosphinoylmethyl)pentanedioic acid benzyl esters 8. The synthesis of (R)- and (S)-3 involves the hydrolysis of (R)- and (S)-3-(2-oxo-tetrahydro-thiopyran-3-yl)propionic acids, (R)- and (S)-11, the corresponding optically pure thiolactones delivered by chiral chromatographic separation of the racemic 11. GCP II inhibitory assay revealed that (S)-2 is 40-fold more potent than (R)-2. In contrast, both enantiomers of 3 inhibited GCP II with nearly equal potency. The efficacy observed in subsequent animal studies with these enantiomers correlated well with the inhibitory potency in a GCP II assay.

Topics: Analgesics; Animals; Brain Ischemia; Cerebral Cortex; Constriction, Pathologic; Crystallography, X-Ray; Glutamate Carboxypeptidase II; Glutarates; Infarction, Middle Cerebral Artery; L-Lactate Dehydrogenase; Molecular Structure; Neuroprotective Agents; Pain; Peripheral Nervous System Diseases; Phosphinic Acids; Rats; Stereoisomerism; Structure-Activity Relationship; Sulfhydryl Compounds; Tissue Culture Techniques

A series of hydroxamic acids has been prepared as potential inhibitors of glutamate carboxypeptidase II (GCP II). Compounds based on a P1' residue (primed-side inhibitors) were more potent than those based on a P1 group (unprimed-side inhibitors). Inhibitory potency of the primed-side GCP II inhibitors was found to be dependent on the number of methylene units between the hydroxamate group and pentanedioic acid. Succinyl hydroxamic acid derivative, 2-(hydroxycarbamoylmethyl)pentanedioic acid, is the most potent GCP II inhibitor with an IC(50) value of 220nM. The comparison of the results to those of other classes of GCP II inhibitors as well as hydroxamate-based MMP inhibitors provides further insight into the structure-activity relationships of GCP II inhibition.

Topics: Aeromonas; Brain Ischemia; Crystallography, X-Ray; Dose-Response Relationship, Drug; Glutamate Carboxypeptidase II; Hydroxamic Acids; Indicators and Reagents; Protease Inhibitors; Stereoisomerism; Structure-Activity Relationship

We describe here a new strategy for the treatment of stroke, through the inhibition of NAALADase (N-acetylated-alpha-linked-acidic dipeptidase), an enzyme responsible for the hydrolysis of the neuropeptide NAAG (N-acetyl-aspartyl-glutamate) to N-acetyl-aspartate and glutamate. We demonstrate that the newly described NAALADase inhibitor 2-PMPA (2-(phosphonomethyl)pentanedioic acid) robustly protects against ischemic injury in a neuronal culture model of stroke and in rats after transient middle cerebral artery occlusion. Consistent with inhibition of NAALADase, we show that 2-PMPA increases NAAG and attenuates the ischemia-induced rise in glutamate. Both effects could contribute to neuroprotection. These data indicate that NAALADase inhibition may have use in neurological disorders in which excessive excitatory amino acid transmission is pathogenic.

Topics: Animals; Brain Ischemia; Carboxypeptidases; Culture Techniques; Dipeptides; Disease Models, Animal; Drug Tolerance; Enzyme Inhibitors; Glutamate Carboxypeptidase II; Glutamic Acid; Ischemic Attack, Transient; Mice; Mice, Inbred ICR; Neuroprotective Agents; Organophosphorus Compounds; Rats; Rats, Sprague-Dawley; Stroke