Effect of chronic REM sleep deprivation on pituitary, hypothalamus and hippocampus PGE2 and PGD2 biosynthesis in the mouse.

Given the often reported relationships between sleep-wake regulation and the cerebral prostaglandins (PGs), the effect of chronic rapid eye movement (REM) sleep deprivation on brain PGE2 and PGD2 biosynthesis in mouse was evaluated, since they are known to have opposite actions as respectively wake- and sleep-inducing substances. Mice were subjected to 5 and 10 days of REM sleep deprivation by the flower pot technique. After sacrifice, PGE2 and PGD2 were determined in the pituitary, hypothalamus and hippocampus. Except in the pituitary where no changes were shown, the PGE2/PGD2 ratio was significantly enhanced after 5 and 10 days of REM sleep loss, when compared to control. These results showed an alteration of cerebral PGE2 and PGD2 biosynthesis, resulting in a shift from PGD2 toward PGE2. These results were not consistent with a role of PGD2 as a sleep-promoting substance as, if that was the case, it would be increased during the REM sleep deprivation. But they do not rule out its involvement as a facilitating substance.

[Nephrotoxicity of the combination of cyclosporin and aminoglycoside in rats. Comparative study of gentamicin and amikacin]. / Néphrotoxicité de l'association ciclosporine-aminoside chez le rat. Etude comparative de la gentamicine et de l'amikacine.

The renal toxicity of combined administration of cyclosporin and aminoglycosides was evaluated in rats. Increasing doses of amikacin (A) or gentamicin (G) were injected alone or in association with cyclosporin (CS). Creatinine clearance rate, urinary N-acetyl-Beta-D-glucosaminidase (NAG) activity and NAG-B isoenzyme level were determined to evaluate glomerular or tubular dysfunctions. When given alone, high doses of aminoglycosides (100 mg/kg/day of G and 375 mg/kg/day of A) induced transient inhibition of glomerular filtration rate. The concomitant administration of CS caused severe acute renal failures with 50 mg/kg/day of G and only with 375 mg/kg/day of A. With equal doses of G, urinary NAG excretion was seven times higher in association with CS than in monotherapy. In the same conditions, NAG activity was only doubled with A. A specific increased of NAG-B isoenzyme level occurred only during the most nephrotoxic association. This attest of a proximal tubular lesion, preliminary to glomerular dysfunction. The results of this study confirm the potent synergistic nephrotoxicity that CS exerts in combination with aminoglycosides. Nevertheless, the good tolerance of amikacin lead us to reconsider the principle of exclusion of such association in transplant recipients.

[Inhibition of the activity of urinary N-acetyl-beta-D-glucosaminidase (NAG) and its isoenzymes by amikacin]. / Inhibition de l'activité de la N-acétyl-beta-D-glucosaminidase (NAG) urinaire et de ses isoenzymes par l'amikacine.

Our study indicates that amikacin (AK) inhibited urinary N-acetyl-beta-D-glucosaminidase (NAG) activity. In vivo and in vitro experiments showed significant increase of Michaelis constant of urinary NAG, in human and in rat, treated by amikacin. Our data indicate that the inhibition of amikacin on NAG and its isoenzymes was "apparently competitive" rather than competitive as reported by others. In the "apparently competitive" inhibition the amikacin-enzyme binding would be irreversible, including combined action of many hydrogen bonds which could have a strength like covalent bond.

[Influence of aminoglycosides on the activity of urinary N-acetyl-beta-D-glucosaminidase (NAG) and its isoenzymes]. / Influence des aminoglycosides sur l'activité de la N-acétyl-bêta-D-glucosaminidase (NAG) urinaire et de ses isoenzymes.

Lysosomal enzyme activities can be modified by aminoglycosides. In this study, we have investigated the "in vitro" effect of gentamicin (G), tobramycin (T), dibekacin (D), netilmicin (N) and amikacin (AK) on urinary N-acétyl-beta-D-glucosaminidase (NAG) and its isoenzymatic forms. G, D and N are activators of this enzyme, specifically of the B isoenzymatic form, while T inhibits slightly the A, I1 and I2 forms. At usual therapeutical urinary concentration of AK during antibiotherapy, NAG and its isoenzymes are very strongly inhibited (more than 65%). Dixon plot indicates that the nature of inhibition is "competitive apparent", without binding of inhibitor to the active site of the enzyme. This binding of aminoglycosides to NAG as to other lysosomal enzymes may represent one of the accumulation mechanisms of aminoglycosides in tubular cells. It can explain the specific alteration of lysosomes during nephrotoxic antibiotherapy. Consequently, when urinary NAG determination is used as indicator of nephrotoxicity during therapy, the activation or inhibition of the enzyme by aminoglycosides could lead to false assay results.