درمان طولانی مدت موش نر F344 با دپرنیل: ارزیابی اثرات بر طول عمر، رفتار و عملکرد مغز

Abstract L-Deprenyl (selegiline) was chronically administered to male Fischer 344 rats via their drinking water beginning at 54 weeks of age (estimated daily dose: 0.5 mg/kg/day). Beginning at 84 weeks of age, the rats were behaviorally evaluated using a sensorimotor battery, a motor-learning task, and the Morris water maze. At 118 weeks of age, cerebellar noradrenergic function was evaluated in the surviving rats using in vivo electrochemistry. The rats were then sacrificed to measure brain monoamine oxidase activity and perform quantitative autoradiography to evaluate the effect of chronic deprenyl treatment on β-adrenergic receptors in the cerebellum, α2-adrenergic receptors several brain regions, and D1 and D2 dopamine receptors in the striatum. Deprenyl treatment reduced brain monoamine oxidase B activity by 85%, but had no effect on brain monoamine oxidase A. A clear effect of chronic deprenyl treatment upon longevity was not observed. Several measures of CNS function were altered in the deprenyl-treated animals: 1) spatial learning in the Morris water maze was improved; 2) electrochemical signals recorded following local application of NE were reduced, and the responsiveness to the reuptake blocker nomifensine was enhanced, in the cerebellum; 3) β-adrenergic receptor binding affinity was increased in the cerebellum; 4) α2-adrenergic receptor density was increased in the inferior colliculus; and 5) striatal D1 dopamine receptor density was reduced but binding affinity was enhanced. In contrast, chronic deprenyl treatment did not cause changes in: 1) sensorimotor function, as evaluated by balance beam, inclined screen, or wire hang tasks; 2) motor learning; 3) α2-adrenergic receptor density in any region examined except for the inferior colliculus, or binding affinity in any region examined; or 4) striatal D2 dopamine receptor number or affinity. Thus, long-term oral administration of deprenyl extended the functional life span of rats with respect to cognitive, but not motor, performance.

Results 4.1. Effect of Deprenyl on Longevity and MAO Activity Treatment of the rats with deprenyl (approximately 0.5 mg/kg/day, PO) began when the animals were 54 weeks of age. From this time point, the weights of the animals were regularly recorded during the remainder of the study. While food intake was not monitored, at no time was a significant difference in body weight between the deprenyl-treated and control rats observed. The survival curves for the two groups are shown in the upper portion of Fig. 1. A calculation based upon the longevity of the 16 control and 14 deprenyl-treated animals that died of natural causes prior to 118 weeks of age indicated that mean life span was significantly longer for the deprenyl-treated rats than for the controls (control: 103.5 ± 3.1 weeks; deprenyl: 111.0 ± 1.5 weeks; p < 0.05, two-tailed Student’s t-test). However, an analysis that also considered the rats that were still living [48] indicated that there was no significant difference in longevity between the groups (p = 0.21). Closer examination of the survival data ( Fig. 1, bottom) showed that deprenyl-treated rats exhibited higher survival rates at all time points after 62 weeks of age. The difference between the control and deprenyl-treated rats was maximum during the interval between approximately 100 and 108 weeks of age. Thereafter, the survival advantage of the deprenyl-treated rats rapidly declined, approaching no difference by 118 weeks of age. Top: survival curves for male F344 rats that were either untreated or given ... Fig. 1. Top: survival curves for male F344 rats that were either untreated or given deprenyl in the drinking water beginning at 54 weeks of age. Bottom: difference in percent survival between the populations of deprenyl-treated and control rats. The deprenyl-treated group had greater survival at all time points after 62 weeks of age. However, the difference between groups was maximal during the period between 100–108 weeks of age. Accelerated mortality in the deprenyl group resulted in a marked reduction in the group difference after 110 weeks of age. Figure options The effect of deprenyl treatment upon the activities of monoamine oxidase (MAO) A and B was determined in samples taken from the striatum, hippocampus, and cerebellum of the four control and six experimental rats that survived to the age of 118 weeks (Fig. 2). There was no significant effect of deprenyl treatment on the activity of MAO-A in any brain region examined. In contrast, 85 to 88% inhibition of MAO-B activity was observed, depending upon the brain region sampled. Thus, administration of deprenyl via the drinking water was an effective method of drug delivery, and, at the dose employed, caused a selective inhibition of MAO-B activity. Effect of chronic deprenyl on brain monoamine oxidase (MAO) activity. MAO-A ... Fig. 2. Effect of chronic deprenyl on brain monoamine oxidase (MAO) activity. MAO-A (top) and MAO-B (bottom) were assayed in three brain regions after 64 weeks of deprenyl treatment. MAO-A activity was not affected; in contrast, MAO-B activity was significantly reduced. ∗∗p < 0.01.