Effect of treatment with L-deprenyl on age-dependent microanatomical changes in the rat kidney.

The influence of aging and of treatment with L-deprenyl on the structure of the kidney was investigated in 24-month-cld male Sprague Dawley rats by microanatomical techniques associated with image analysis. L-Deprenyl was administrated orally for 5 months at a dose not inhibiting monoamine oxidase (MAO) B activity (1.25/mg/kg/day) and at a dose inhibiting MAO B activity (5 mg/kg/day). In 24 month-old-rats the number and the volume of glomeruli was reduced in comparison with 12-month-old rats used as reference adult animals. Vascular changes characterised by increased thickness of the tunica media, decreased size of arterial lumen and increased wall-to-lumen ratio were also noticeable in 24-month-old rats. Moreover, an increased MAO B reactivity was noticeable within glomerular tufts and renal tubules. Treatment with the low dose of L deprenyl did not cause changes in MAO B reactivity, or in the number of glomeruli, but increased glomerular volume and reduced the wall-to-lumen ratio in medium-sized renal artery branches. The dose of 5 mg/kg/day of L-deprenyl significantly decreased MAO B reactivity within both glomerular tufts and tubules, increased the number and the volume of glomeruli and countered-age-related vascular changes. The above results suggest that treatment with L-deprenyl counters to some extent microanatomical changes occurring in the kidney of aged rats. The observation that the dose of the compound inactive on MAO B activity reduces in part age dependent renal microanatomical changes, indicates that the renal protective effect of L-deprenyl is only in part related to MAO B inhibition.

Effect of long-term treatment with L-deprenyl on the age-dependent microanatomical changes in the rat hippocampus.

Chronic treatment with L-deprenyl increases both mean and maximum life span and improves cognitive functions in the aged rat. The present study was designed to evaluate whether long-term treatment with L-deprenyl at a dosage not inhibiting the monoamine oxidase-B (MAO-B) (1.25 mg/kg/day) or inhibiting the enzyme activity (5 mg/kg/day) had any effect on the age-dependent microanatomical changes in the rat hippocampus. The hippocampus was chosen in view of its key role in learning and memory functions. Treatment with L-deprenyl started at 19 months and lasted until the 24th month of age. Age-matched untreated rats were used as a control, whereas 11-month-old rats were used as an adult reference group. The number of nerve cell and glial fibrillary acidic protein-immunoreactive astrocyte profiles in the CA1 and CA3 fields of the hippocampus and in the dentate gyrus was decreased and increased, respectively in aged compared with adult rats. Treatment with 5 mg/kg/day, but not with 1.25 mg/kg/day L-deprenyl increased the number of neuronal profiles and decreased the number of astrocytes in the hippocampus of aged rats. The density of zinc stores in the associative intrahippocampal pathway of mossy fibres, which was decreased in aged animals, was increased after treatment with the two doses of L-deprenyl. Lipofuscin accumulation within the cytoplasm of pyramidal neurons of the hippocampus was reduced dose dependently by L-deprenyl treatment. These results suggest that long-term treatment with L-deprenyl is able to counter the expression of age-dependent microanatomical changes in the rat hippocampus. These effects seem only partially correlated with the MAO-B inhibitory activity of L-deprenyl.

Influence of treatment with L-deprenyl on the structure of the cerebellar cortex of aged rats.

Treatment with L-deprenyl increases mean and maximum life span in the rat and reverses memory and learning deficits associated with old age. Since only sparse information is available concerning the influence of L-deprenyl administration on the aging brain microanatomy, we have investigated the effect of long-term treatment with L-deprenyl on the structure of the cerebellar cortex in the aged rat. The cerebellar cortex was used since it represents a useful model for assessing age-related changes in nervous system anatomy and function. Male Sprague-Dawley rats were treated from the 19th to the 24th month of age with a daily oral dose of 1.25 mg/kg or 5 mg/kg L-deprenyl. Age-matched rats were left untreated and used as a control group. Eleven-month-old untreated rats were used as an adult reference group. The density of Purkinje and granule neuron profiles as well as the intensity of Nissl's staining within the cytoplasm of Purkinje neurons were reduced in 24-month in comparison with 11-month rats. Moreover, an increased accumulation of lipofuscin was noticeable in the cytoplasm of Purkinje neurons of old rats as well as an increase in MAO-B activity in the molecular layer of the cerebellar cortex. The two doses of L-deprenyl increased the density of both Purkinje and granule neuron profiles and the intensity of Nissl's staining in the cytoplasm of Purkinje neurons and reduced lipofuscin deposition within Purkinje neurons. The lower dose of L-deprenyl caused only a slight decrease in MAO-B activity, whereas the 5-mg/kg/day dose remarkably reduced it. These results suggest that long-term treatment with L-deprenyl counters the expression of some age-related microanatomical changes in the rat cerebellar cortex. The possible independence of the effects of the compound on age-related microanatomical changes of the cerebellar cortex and on MAO-B inhibitory activity is discussed.

Influence of long-term treatment with L-deprenyl on the age-dependent changes in rat brain microanatomy.

The present study was designed to assess whether treatment with the monoamine oxidase-B (MAO-B) inhibitor L-deprenyl, which has been documented to increase both mean and maximum survival in aged rats as well as sexual performance and cognitive function, has any effect on the age-related microanatomical changes occurring in the rat brain. Male Sprague-Dawley rats received a subcutaneous injection of 0.25 mg/kg L-deprenyl every other day from the 19th to the 24th month of age. Age-matched control rats were injected with saline, whereas 11-month-old untreated rats were used as an adult reference group. Both body and brain weight were increased as a function of age, and they were unaffected by treatment with L-deprenyl. The density of nerve cell profiles in the frontal cortex, in the CA-1 and CA-3 subfields of the hippocampus, in the dentate gyrus and in the cerebellar cortex were decreased in aged rats in comparison with adult rats. The density of nerve cell profiles in the above brain areas of L-deprenyl-treated rats was not significantly higher in comparison with age-matched control animals with the exception of Purkinje neuron profiles. The intensity of Nissl's staining, which may be related to the protein synthetic capabilities of nerve cells, is reduced within pyramidal neurons of the hippocampus and Purkinje neurons of the cerebellar cortex of aged rats. The intensity of Nissl's staining in L-deprenyl-treated rats was not different from adult rats. Lipofuscin deposition was significantly increased within the cytoplasm of pyramidal neurons of the frontal cortex, of the CA-3 subfield of the hippocampus and of Purkinje neurons of the cerebellar cortex. L-Deprenyl administration decreased lipofuscin accumulation within the cytoplasm of the above mentioned nerve cell types. The density of sulphide-silver staining in the intrahippocampal pathway of mossy fibres, which participate in the elaboration of passive avoidance responses, is decreased in aged rats. Treatment with L-deprenyl counters this age-related reduction. The above results suggest that long-term treatment with L-deprenyl is able to counter the expression of some microanatomical changes typical of aging brain.

Neuroanatomy of aging brain. Influence of treatment with L-deprenyl.

The present study was designed to assess the influence of long term L-deprenyl treatment on some microanatomical parameters of aging rat frontal cortex and hippocampus. Male Sprague-Dawley rats of 19 months of age were divided into three groups. Rats of the first group received an oral daily dose of 1.25 mg/kg L-deprenyl; animals of the second group were treated with an oral daily dose of 5 mg/kg L-deprenyl, whereas rats of the third group were left untreated and used as control. Treatment lasted for 5 months, and rats were sacrificed at 24 months. At this age they were considered to be old. Another group of 11-month-old rats was used as an adult reference group. The density of nerve cell profiles and of glial fibrillary acidic protein (GFAP) immunoreactive astrocytes was decreased and increased respectively in the frontal cortex and in the different portions of the hippocampus in old in comparison with adult rats. A decrease in the intensity of sulfide silver staining in the mossy fibers of the hippocampus was also observed in old rats. Moreover, a cytoplasmatic accumulation of lipofuscin was noticeable in old rats as well as a significant increase of the monoamine-oxidase (MAO) B reactivity both in the frontal cortex and in the hippocampus. A higher density of nerve cell profiles, of sulfide silver staining, and fewer astrocyte profiles were noticeable in the frontal cortex and in the hippocampus of old rats treated with 5 mg/kg/day of L-deprenyl. This dose of the compound also significantly reduced lipofuscin accumulation and MAO-B reactivity in old rats. However, the lower dose of the compound did not cause any statistically significant effect on the microanatomical parameters investigated with the exception of sulfide silver staining and lipofuscin accumulation, which were increased and decreased respectively after 1.25 mg/kg per day of L-deprenyl. The above results suggest that long-term treatment with L-deprenyl is able to counter some microanatomical changes typical of the aging frontal cortex and hippocampus in the rat. These changes seem to be in part related to the MAO-B inhibitory activity of L-deprenyl.

Repeated administrations of (-)-deprenyl increase [3H]MK801 binding in rat brain and antagonize the impairment of passive avoidance conditioning induced by N-methyl-D-aspartate receptor antagonists.

Repeated but not single administrations of the MAO type B inhibitor (-)-deprenyl (1 mumol/kg s.c. for 21 consecutive days) antagonized the impairment of passive avoidance retention induced by the N-methyl-D-aspartate (NMDA) receptor antagonists 2-amino-5-phosphonovalerate (APV), ketamine and dizocilpine (MK801), in rats. In well-washed membranes prepared from the hippocampi of rats repeatedly treated with (-)-deprenyl, the [3H]MK801 specific binding was increased. In contrast, repeated MAO B-selective doses of pargyline or (+)-amphetamine, as well as single injections with (-)-deprenyl failed to change [3H]MK801 binding. It is suggested that the effects of repeated (-)-deprenyl administrations upon NMDA receptors and upon the impairment of acquisition of a passive avoidance task induced by NMDA antagonists could be independent of MAO inhibition.

Microanatomical changes in the frontal cortex of aged rats: effect of L-deprenyl treatment.

The present study was designed to assess whether treatment with L-deprenyl has any effect on the age-related microanatomical changes in the rat frontal cortex. Male Sprague-Dawley rats of 19 months of age were treated until the 24th month with an oral daily dose of 1.25 mg/kg or of 5 mg/kg of L-deprenyl. Eleven-month-old untreated rats were used as an adult reference group. The density of nerve cell profiles and of glial fibrillary acidic protein-(GFAP) immunoreactive astroglial profiles, lipofuscin accumulation within the cytoplasm of pyramidal neurons, and MAO-B reactivity were assessed. A decreased density of nerve cell profiles and an increased density of astroglial profiles as well as augmented lipofuscin deposition and MAO-B reactivity were observed in the frontal cortex of rats of 24 months in comparison with 12-month-old animals. In the frontal cortex of rats treated with 5 mg/kg/day L-deprenyl, which is a dose inhibiting MAO-B activity, the density of nerve cell and GFAP-immunoreactive astrocyte profiles is increased and decreased respectively in comparison with age-matched untreated subjects. Lipofuscin deposition is reduced. The lower dose of L-deprenyl (1.25 mg/kg/day) which did not affect MAO-B activity, decreased lipofuscin deposition but was without effect on the density of nerve cell or GFAP-immunoreactive astrocyte profiles. The above findings suggest that treatment with L-deprenyl is able to counter some microanatomical changes occurring in the frontal cortex of aged rats. Some of these effects are probably not related to the inhibitory MAO-B activity of the compound.

Improvement of cognitive function by MAO-B inhibitor L-deprenyl in aged rats.

This study evaluated the ability of the selective MAO-B inhibitor, L-deprenyl, to reverse cognitive impairments appearing in aged rats, using the reference memory, Morris Water Maze paradigm. L-Deprenyl significantly improved learning and memory deficits associated with old age in doses of 1.25 and 5 mg/kg PO (escape latency measure) and doses of 1.25, 2.5 and 5 mg/kg PO (path length measure). L-Deprenyl also improved reversal learning impairments in doses of 1.25, 2.5 and 5 mg/kg PO, as expressed by the escape latency measure. The data suggest that L-deprenyl possesses potential cognitive enhancement abilities probably due to an increase in dopaminergic activity.

Effect of ethylcholine mustard aziridinium (AF64A) and of the monoamine oxidase-B-inhibitor L-deprenyl on the morphology of the rat hippocampus.

The effect of intracerebroventricular (ICV) administration of ethylcholine mustard aziridinium (AF64A) and of the monoamine oxidase (MAO)-B inhibitor L-deprenyl on MAO-A and MAO-B activities and on the morphology of the rat neostriatum and hippocampus were studied. The ICV administration of AF64A was without effect on MAO-A and MAO-B in the neostriatum and caused an increase of MAO-B but not of MAO-A in the hippocampus. No changes in neostriatal micro-anatomy were noticeable in AF64A-injected rats, whereas the neurotoxin caused an impairment in hippocampal micro-anatomy consisting in the loss of nerve cells and of silver-gold impregnated fibres in the CA-1--CA-3 fields. The treatment of AF64A-injected animals with doses of L-deprenyl from 11.17 microM/kg/day significantly reduced MAO-B activity in the hippocampus and improved the morphology of the hippocampus formation. L-deprenyl was without effect on MAO-A activity both in the neostriatum and in the hippocampus, as well as on neostriatal MAO-B activity and morphology. The possibility that MAO-B inhibition may represent a principle for the treatment of age-related physiological and pathological changes characterized by increased MAO-B activity is discussed.

A novel class of cholinergic agents structurally related to 2-morpholinol.

A series of esters and ethers of N-alkylmorpholin-2-ols, and their methiodides, which can be considered cyclic analogues of acetylcholine, were synthesized. The amines were obtained by acylation or etherification of morpholinols with the appropriate acyl chlorides and alcohols. All compounds were tested for their ability to interact with the muscarinic receptor M2 (guinea-pig atria) or M3 (rat ileum and urinary bladder) subtype. Some compounds, although endowed with relatively low potency, proved interesting for their organ selectivity. Some considerations on the structure-activity relationship are made and the results obtained with reference agonists and antagonists are also shown.

Mouse gallbladder emptying by egg yolk: a possible new rapid method for antispasmodic activity evaluation in vivo.

Gallbladder emptying was induced in female albino mice by single oral administrations of 30% lyophylized egg yolk suspension. Mice were killed 15 min later, their gallbladders removed and then weighed. Gallbladder emptying was assessed by comparing weights from control and egg yolk administered mice. The ability of the antispasmodic drugs atropine, N-butylscopolamine, papaverine, trimebutine, dicyclomine, and rociverine to delay gallbladder emptying was determined by administering them either intraperitoneally or orally 7.5 or 15 min prior to egg yolk.

[Pharmacologic profile of a new compound with antiinflammatory activity: 2-(4-dimethylvinylphenyl)propionic acid (Gx 258)]. / Profilo farmacologico di un nuovo composto ad attività antiinfiammatoria: l'acido 2-(4-dimetilvinilfenil)propionico (Gx 258).

Gx 258, a new phenylalkanoic acid derivative, was shown in animal tests to possess potent antiinflammatory, analgesic and antipyretic activity. Its antiinflammatory activity was not mediated via the pituitary-adrenal axis, since it was also effective in adrenalectomized rats. Since large doses of Gx 258, 9-83 times greater than those showing antiinflammatory activity, were required to produce gastrointestinal lesions in rats, Gx 258 appears to have a very good therapeutic index. Its therapeutic index as an antiinflammatory and analgesic agent was 2.3-20.5 times greater than that of the parent compound ibuprofen. Gx 258, like ibuprofen, inhibited the biosynthesis of prostaglandins in vitro.