Depletion of GDNF from primary afferents in adult rat dorsal horn following peripheral axotomy.

Glial cell line-derived neurotrophic factor (GDNF) is produced in a subset of adult rat spinal ganglion neurons and anterogradely transported to the superficial dorsal horn. In this study the effect of sciatic nerve axotomy on the expression of GDNF protein in the dorsal horn was investigated, using immunocytochemistry. Image analysis showed a 44% decrease relative to the non-transected side after 5 days survival, progressing to more than 80% decrease after 10 days and remaining so for at least 100 days. This rapid and strong decrease suggests active down-regulation of GDNF protein after peripheral axotomy. The observed down-regulation of GDNF is compared with changes observed for other substances in primary afferents after peripheral axotomy and is discussed in light of its presumed trophic or transmitter role in nociception.

Extracellular brain glutamate during acute liver failure and during acute hyperammonemia simulating acute liver failure: an experimental study based on in vivo brain dialysis.

Hyperammonemia is thought to be important in the pathogenesis of hepatic encephalopathy. However, the mechanism leading to ammonia toxicity is still not known. Since the metabolism of the most important excitatory neurotransmitter, glutamate, is closely linked to that of ammonia, it has been postulated that hyperammonemia lowers the availability of the neurotransmitter glutamate. To study this hypothesis, we used brain dialysis to measure glutamate levels in extracellular cerebral fluid from rabbits with acute ischemic liver failure or acute hyperammonemia. The basal glutamate concentration was found to be increased during both acute liver failure (start of experiments 4.9 +/- 1.7 mumol/l; end of experiments 9.5 +/- 2.1 mumol/l, n = 6, difference p < 0.05) and acute hyperammonemia (start of experiments 4.4 +/- 1.2 mumol/l; end of experiments 7.3 +/- 1.8 mumol/l, n = 7, difference p > 0.05) (mean +/- SEM). Both the veratridine- and the potassium-evoked glutamate release were increased during acute liver failure but appeared normal during hyperammonemia. We conclude that during acute liver failure and acute hyperammonemia in the rabbit there is no decreased glutamate availability in the extracellular space of the cortical brain; on the contrary, we found evidence for increased extracellular glutamate concentrations in the cortical brain, which were more pronounced in acute liver failure. Experimental hepatic encephalopathy is thus not due to cerebral glutamate deficiency.

Pharmacokinetics and systemic bioavailability of menogaril, an anthracycline antitumor agent, in the mouse, dog, and monkey.

Menogaril is an antitumor agent of the anthracycline type which is less cardiotoxic than doxorubicin in a chronic rabbit model and is active in experimental tumor systems when given by p.o. or parenteral routes. It is currently undergoing i.v. and p.o. Phase II clinical evaluation. We report here the results of pharmacokinetic and systemic bioavailability studies of menogaril in three species (mouse, dog, and monkey). Upon i.v. administration, menogaril plasma concentration-time curves declined in a biexponential (dog) or triexponential (mouse and monkey) manner, with the terminal disposition half-life (t1/2) being considerably shorter in the dog (2.86 +/- 0.47 h) than in the mouse and monkey (21.6 and 19.0 +/- 3.7 h, respectively). The systemic clearance (CL, in liters/h/kg) was highest in mouse (6.2), followed by dog (2.9) and then monkey (1.4). The drug was extensively distributed in all three species, with steady state volumes of distribution being 88.5, 9.8, and 27.9 liters/kg in the mouse, dog, and monkey, respectively. One, two, and three metabolites were detected in the plasma of mice, monkeys, and dogs, respectively, using reverse phase high performance liquid chromatography. The major fluorescent metabolite in all species coeluted with authentic N-demethyl-menogaril; the other two metabolites were present at low concentrations relative to unchanged menogaril and its putative N-demethylated metabolite. One of these metabolites, which was found in both the dog and monkey, eluted with authentic (7R)-nogarol. Mean maximum plasma concentrations of the putative N-demethylmenogaril metabolite were approximately one-tenth those of menogaril in all three species following i.v. drug administration. Upon p.o. treatment, first-pass metabolism or incomplete absorption reduced the systemic bioavailability to 12% in the dog and 33% in the mouse and monkey. N-Demethylmenogaril was the major fluorescent metabolite observed in the plasma of p.o. treated animals. Interspecies comparison of menogaril pharmacokinetic parameters in mice, dogs, monkeys, and humans using allometric techniques indicated that the parameters for mice, monkeys, and humans were highly correlated; in each of these species presystemic metabolism of p.o. administered menogaril reduced its systemic bioavailability to an equivalent extent (30-35%). To determine if metabolically formed N-demethylmenogaril might contribute to the overall antitumor activity of menogaril, we determined the effect of synthetic N-demethylmenogaril on the life span of mice bearing P388 leukemia. Results indicated that the metabolite is marginally active compared to menogaril itself.

The primary vestibulocerebellar projection in the rabbit: absence of primary afferents in the flocculus.

The central projection of vestibular nerve fibers was investigated with anterograde axonal transport of wheatgerm agglutinin-horseradish peroxidase (WGA-HRP) and tritiated leucine following injection in the vestibular ganglion. Labeled fibers and terminal ramifications were observed throughout the vestibular complex, but absent from the lateral vestibular nucleus. Termination in the cortex was restricted to the vermis. Small numbers of mossy fiber terminals were present bilaterally, close to the midline in lobules I and II, and in the depth of the main fissures separating lobules II-VI. In the posterior vermis labeled mossy fiber terminals were found in lobule X and the ventral aspect of lobule IXd. Here, the entire ipsilateral hemivermis contained a large number of terminals, while contralaterally the medial one-third hemivermis contained fewer terminals. Labeled mossy fibers and terminals were absent in the flocculus and adjacent ventral paraflocculus.

Anatomical and physiological observations on supraspinal control of bladder and urethral sphincter muscles in the cat.

In 15 cats injections of 3H-leucine were made in the pontine tegmentum. Injections in the medial part of the dorsolateral pontine tegmentum (M-region) resulted in specific projections to the sacral intermediomedial and intermediolateral cell groups. The intermediolateral cell group contains preganglionic parasympathetic neurons that form the motor supply of the detrusor muscle of the bladder. Injections in the lateral part of the pontine tegmental field (L-region) produced labeled fibers in the nucleus of Onuf, which contains motoneurons innervating the pelvic floor including the anal and urethral sphincters. L-region projections to the sacral preganglionic parasympathetic neurons and M-region projections to the nucleus of Onuf were very limited or absent. In 12 cats physiological experiments were performed. Electrical stimulation in the L-region elicited a prompt increase in the pelvic floor EMG and urethral pressure but had little influence on the intravesical pressure. Stimulation in the M-region elicited a prompt decrease in the pelvic floor EMG and urethral pressure followed, after a delay of 2 seconds, by an increase in the intravesical pressure, so simulating normal micturition.