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Biomedical subjects

J Knoll

Publications and source records attributed to J Knoll.

At least 37 records · Page 2Linked to original sources
PubMed1995

cDNA sequence, genomic organization, and evolutionary conservation of a novel gene from the WAGR region.

A new gene (239FB) with predominant and differential expression in fetal brain has recently been isolated from a chromosome 11p13-p14 boundary area near FSHB. The corresponding mRNA has an open reading frame of 294 amino acids, a 3' untranslated region of 1247 nucleotides, and a highly GC-rich 5' untranslated region. The coding and 3' UT sequence is specified by 6 exons within nearly 87 kb of isolated genomic locus. The 5' end region of the transcript maps adjacent to the only genomically defined CpG island in a chromosomal subregion that may be associated with part of the mental retardation of some WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome patients. In addition to nucleotide and amino acid similarity to an EST from a normalized infant brain cDNA library, the predicted protein has extensive similarity to two Caenorhabditis elegans polypeptides of, as yet, unknown function. The 239FB locus is, therefore, likely part of a family of genes with two members expressed in human brain. The extensive conservation of the predicted protein suggests a fundamental function of the gene product and will enable evaluation of the role of the 239FB gene in neurogenesis in model organisms.

Amino Acid Sequence↗
PubMed1995

Enhanced catecholaminergic and serotoninergic activity in rat brain from weaning to sexual maturity: rationale for prophylactic (-)deprenyl (selegiline) medication.

Food deprived rats in the late developmental phase of life (2 months of age) are significantly more active than those in the early postdevelopmental phase (4 months of age), pointing to enhanced catecholaminergic activity during the developmental phase. We therefore measured the resting release of dopamine from the striatum, substantia nigra and tuberculum olfactorium, and of noradrenaline from the locus coeruleus, as an indicator of the basic activity of catecholaminergic neurons in the brain, in 2,4,8,16 and 32 weeks old male and female rats. We also measured the release of serotonin from the raphe. Both in male and female rats, the resting release of transmitters from brain catecholaminergic and serotoninergic neurons between weaning and the end of the 2nd month of age, i.e. during the crucial developmental phase of their life, was significantly higher than either before or after that period, signalling a transition from a developmental to a postdevelopmental (aging) phase of life and indicating that safe and effective measures are needed to maintain the catecholaminergic system at a higher activity level during the postdevelopmental phase. Daily administration of low doses (0.01-0.25 mg/kg) of (-)deprenyl for 21 days significantly enhances the resting release of catecholamines and diminishes that of serotonin, providing a rationale for prophylactic medication with this drug during the postdevelopmental lifespan. We also show that (-)methamphetamine, the parent compound of (-)deprenyl and (-)1-phenyl-2-propylaminopentane (PPAP), a deprenyl analogue free of MAO-B inhibitory potency but otherwise possessing the same pharmacological profile as (-)deprenyl, act similarly, furnishing direct evidence that enhancement of catecholaminergic activity in the brain by multiple, small dose administration of (-)deprenyl is unrelated to MAO-B inhibition.

Age Factors↗
PubMed1995

Responses of forebrain neurons to the MAO-B blocker L-deprenyl.

Despite the large amount of neuropharmacological data concerning catecholamine (CA) mechanisms of the mammalian brain, little is known yet about the effects of MAO-inhibitors on single neurons. The present series of experiments aim to elucidate these specific neurochemical attributes of forebrain cells. Single neuron activity was recorded by means of multi-barreled microelectrodes in the caudate nucleus, globus pallidus, and amygdala of both anesthetized rats and anesthetized or alert monkeys during microelectrophoretic application of the MAO-B blocker L-deprenyl (DEPR). CAs (dopamine and noradrenaline), glutamate, GABA, and acetylcholine were also applied. Nearly the half (46%) of all forebrain neurons tested responded, exclusively with inhibition, to DEPR, and the CA-sensitive cells were especially responsive to the MAO-B inhibitor. The time course of DEPR-induced neuronal suppression was short. In some cases, amphetamine (AMPH) and clorgyline (CLOR) were also applied microelectrophoretically. AMPH elicited similar activity changes to those seen after DEPR administrations, whereas CLOR applications were less effective. Our results provide evidence that DEPR can effectively modulate the activity of CA-sensitive neurons in the three different forebrain regions of two different species. On the basis of this data, the possible neurochemical mechanisms of DEPR action are discussed.

Acetylcholine↗
PubMed1995

Rationale for (-)deprenyl (selegiline) medication in Parkinson's disease and in prevention of age-related nigral changes.

(-)Deprenyl (selegiline, jumex, eldepryl, movergan), a close structural relative to phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. It is a highly potent and selective, irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain. The activity of this enzyme significantly increases with age. (-)deprenyl, the first selective inhibitor of MAO-B described in literature, has become the universally used research tool for selectively blocking B-type MAO. It is the only selective MAO-B inhibitor in clinical use. (-)Deprenyl interferes with the uptake of catecholamines and indirectly acting sympathomimetics because it is handled by the catecholaminergic neuron in a way similar to the physiological substances transported through the axonal end organ and vesicular membrane. The unique behavior of (-)deprenyl is that, in striking contrast to PEA and its relatives it does not displace the transmitter from storage, ie it is not a releaser. The net result is that (-)deprenyl inhibits the releasing effect of tyramine, and at present, is the only safe MAO inhibitor that can be administered without dietary precautions. Maintenance on (-)deprenyl selectively enhances superoxide dismutase (SOD) and catalase activity in the striatum. This effect is unrelated to its effect on MAO-B and the inhibitory effects of the drug on neurotransmitter uptake. Maintenance on (-)deprenyl facilitates the activity of the catecholaminergic system in the brain, and this effect, too, is unrelated to either its effects on MAO or on neurotransmitter uptake. (-)Deprenyl protects the nigrostriatal dopaminergic neurons against selective neurotoxins (6-hydroxydopamine, MPTP, DSP-4).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Sexually low performing male rats die earlier than their high performing peers and (-)deprenyl treatment eliminates this difference.

Out of 1600 sexually inexperienced 28-week old Wistar-Logan male rats 94 sexually inactive ('low performing', LP) and 99 highly active ('high performing', HP) rats were selected. The rats were treated from the 8th month of their life three times a week, subcutaneously, with either 0.9% NaCl or 0.25 mg/kg (-)deprenyl until they died. Their copulatory activity was tested once a week and their learning performance was measured in the shuttle box once in three months. The salt treated LP rats (n = 44) never displayed ejaculation during their life time, they were extremely dull in the shuttle box and lived 134.58 +/- 2.29 weeks. Their (-)deprenyl-treated peers (n = 48) became sexually active, their mating performance was substantially increased and lived 152.54 +/- 1.36 weeks, significantly longer than their salt-treated peers and as long as the salt-treated HP rats. The salt treated HP rats (n = 49) displayed 14.04 +/- 0.56 ejaculations during the first 36-week testing period and due to aging they produced 2.47 +/- 0.23 ejaculations between the 73-108th week of testing. Their learning performance was high. They displayed 78.45 +/- 3.01 conditioned avoidance responses (CAR) during the first 36-week testing period and this dropped to 50.67 +/- 2.99 (p < 0.01) during the 73-108th week of testing. They lived 151.24 +/- 1.36 weeks, significantly (p < 0.001) longer than their LP peers. The (-)depre-nyl-treated HP rats (n = 50) were sexually much more active than their salt-treated peers. They displayed 30.04 +/- 0.85 ejaculations during the first 36-week testing period and 7.40 +/- 0.32 ejaculations between the 73-108th week of testing. Also their learning performance was substantially increased. They produced 113.98 +/- 3.23 CARs during the first 36-week-testing period and 81.68 +/- 2.14 CARs during the 73-108th week of testing. They lived 185.30 +/- 1.96 weeks, significantly more than their salt-treated peers and out of the 50 rats 17 lived longer than the estimated technical life span (TLS).

Animals↗
PubMed1993

Further proof that (-)deprenyl fails to facilitate mesolimbic dopaminergic activity.

The selective monaminooxidase (MAO)-B inhibitor (-)deprenyl facilitates the nigrostriatal dopamine (DA)-ergic system by a complex mechanism that includes inhibition of DA reuptake and increase of DA turnover. In this study, DA reuptake and DA turnover were measured in the olfactory tubercle of rats treated with 0.25 mg/kg (-)deprenyl for 28 days. There was no difference between these rats and the saline-treated group. In another series of experiments, we analysed how (-)deprenyl influences the action of some indirectly acting DA agonists, such as amphetamine (AM) and phenylethylamine (PEA). The effect on different behavioural patterns related either to the nigrostriatal (stereotyped behaviour) or the mesolimbic (rearing, locomotion) DAergic system was investigated. As expected, the PEA-induced stereotyped behaviour was tremendously potentiated by (-)deprenyl and the AM-induced stereotypy was reduced. At the same time there was no change in locomotion and rearing. The results give further biochemical and behavioural proof that (-)deprenyl enhances the function of the nigrostriatal DAergic system and leaves the mesolimbic DAergic neurons unaffected.

Amphetamine↗
PubMed1993

The pharmacological basis of the beneficial effects of (-)deprenyl (selegiline) in Parkinson's and Alzheimer's diseases.

(-)Deprenyl (Selegiline, Jumex, Eldepryl, Movergan), structurally closely related to phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. It is a highly potent and selective irreversible inhibitor of B-type monoamine oxidase (MAO) and interferes with the uptake of catecholamines and indirectly acting symphathomimetics. In striking contrast to PEA and its relatives, which displace the transmitter from the storage places, (-)deprenyl inhibits the releasing effect of tyramine and is up to the present the only safe MAO inhibitor which can be administered without dietary restrictions. Maintenance on (-)deprenyl enhances selectively superoxide dismutase (SOD) and catalase activities in the striatum. This effect is unrelated to the MAO and uptake inhibitory effects of the drug. Maintenance on (-)deprenyl facilitates the activity of the nigrostriatal dopaminergic neurons with remarkable selectivity and this effect too, is unrelated to either the MAO or the uptake inhibitory effects of the drug. Maintenance on (-)deprenyl prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substantia nigra. As a consequence of its complex spectrum of activity male rats maintained on (-)deprenyl live longer, lose their capacity to ejaculate later, show improved performance in learning tests and maintain this activity for a longer period than their untreated peers. Patients with Parkinson's disease maintained on levodopa plus (-)deprenyl (10 mg daily) live significantly longer than those on levodopa alone. Freshly diagnosed patients treated with (-)deprenyl need levodopa later than their placebo-treated peers. Continuous administration of (-)deprenyl improves the performance of patients with Alzheimer's disease.

Aging↗
PubMed1992

Pharmacological basis of the therapeutic effect of (-)deprenyl in age-related neurological diseases.

(-)Deprenyl (Selegiline, Jumex, Eldepryl, Movergan), a close structural relative to phenylethylamine (PEA), is a drug of a unique pharmacological spectrum. (a) It is highly potent and selective irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain, the activity of which significantly increases with age. (-)Deprenyl was the first selective inhibitor of MAO-B described in literature, became the worldwide research tool used for blocking selectively B-type MAO, and is still the only MAO-B inhibitor in clinical use. (b) (-)Deprenyl interferes with the uptake of catecholamines and indirectly acting sympathomimetics because it is handled by the catecholaminergic neuron similarly to the physiological substances transported through the axonal end-organ and vesicular membrane. The unique behavior of (-)deprenyl is that, in striking contrast to PEA and its relatives, it does not push the transmitter from the storage places, i.e., it is not a releaser. The net result is that (-)deprenyl inhibits the releasing effect of tyramine and is presently the only safe MAO inhibitor which can be administered without dietary restrictions. (c) Maintenance on (-)deprenyl enhances selectively superoxide dismutase (SOD) and catalase activity in the striatum. This effect is unrelated to the MAO and uptake inhibitory effects of the drug. (d) Maintenance on (-)deprenyl facilitates the activity of the nigrostriatal dopaminergic neurons with remarkable selectivity. This effect is also unrelated to either the MAO or the uptake inhibitory effects of the drug. All in all, (-)deprenyl maintains the activity of the nigrostriatal dopaminergic machinery on a higher activity level and slows down its age-related decline. Male rats maintained on (-)deprenyl lost their capacity to ejaculate later, retained their learning ability longer, and lived longer than their saline-treated peers. Parkinsonians on levodopa plus (-)deprenyl (10 mg daily) lived significantly longer than those on levodopa alone. (-)Deprenyl is the first drug which retards the progress of Parkinson's disease. Freshly diagnosed parkinsonians maintained on (-)deprenyl did not require levodopa until significantly later than their placebo-treated peers. Maintenance on (-)deprenyl significantly improved the performance of patients with Alzheimer's disease. It is concluded that in Parkinson's disease and Alzheimer's disease patients need to be treated daily with 10 mg (-)deprenyl from diagnosis until death, irrespective of other medication.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1992

(-)deprenyl and (-)parafluorodeprenyl-treatment prevents age-related pigment changes in the substantia nigra. A TV-image analysis of neuromelanin.

With the aid of TV-image analysis the number, the area and the density features of melanin granules in neurocytes of the substantia nigra in a group of 3-month-old naive male rats and in a 21-month-old group of male rats treated for 18 months with saline, (-)deprenyl and (-)parafluorodeprenyl, respectively, were determined. According to the Kolmogorov 2-sample test the two drug-treated groups do not differ significantly from each other in the number, total area and area of one pigment granule. In the aged saline-treated group the number of melanin granules decreased significantly and the area of the melanin granules increased in comparison to young controls as well as to the drug-treated groups.

Aging↗
PubMed1992

A procedure for measuring neuromelanin in neurocytes by a TV-image analyser.

With the aid of a Robotron A6471 type TV-image analyser the number, total area, area of one granule and density features (sum, average of gray values and average gray value of one pigment granule) of melanin granules in neurocytes of the substantia nigra in 3-month-old and 3-year-old male rats were determined. The number of cells in sections of identical areas was similar in the young and old rats. A statistically non-significant difference between the two age cohorts in the proportion of neurocytes with and without melanin was found; 773 (48.1%) and 853 (51.8%), in the young rats and 1219 (65.1%) and 652 (34.8%) in the old ones. Within the melanin containing neurocytes, however, statistically conspicuous, age-related differences in the number, area and density features of melanin granules were discovered. The majority of the neurocytes in young rats contained numerous, small sized neuromelanin granules, whereas in the majority of the neurocytes of old rats smaller numbers of large sized, neuromelanin granules were detected.

Aging↗
PubMed1992

(-)Deprenyl-medication: a strategy to modulate the age-related decline of the striatal dopaminergic system.

(-)Deprenyl (Selegiline, Jumex, Eldepryl, Movergan), a close structural relative to phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. (1) It is a highly potent and selective, irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain. The activity of this enzyme significantly increases with age. (-)Deprenyl, the first selective inhibitor of MAO-B described in literature, has become the universally used research tool for selectively blocking B-type MAO. It is the only MAO-B inhibitor in clinical use. (2) (-)Deprenyl interferes with the uptake of catecholamines and indirectly acting sympathomimetics because it is handled by the catecholaminergic neuron in a way similar to the physiological substances transported through the axonal end organ and vesicular membrane. The unique behavior of (-)deprenyl is that, in striking contrast to PEA and its relatives, it does not displace the transmitter from storage, ie, it is not a releaser. The net result is that (-)deprenyl inhibits the releasing effect of tyramine, and, at present, is the only safe MAO inhibitor that can be administered without dietary precautions. (3) Maintenance on (-)deprenyl selectively enhances superoxide dismutase (SOD) and catalase activity in the striatum. This effect is unrelated to its effect on MAO-B and the inhibitory effects of the drug on neurotransmitter uptake. (4) Maintenance on (-)deprenyl facilitates the activity of the nigrostriatal dopaminergic neurons with remarkable selectivity, and this effect, too, is unrelated to either its effects on MAO or on neurotransmitter uptake. (5) Maintenance on (-)deprenyl prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substantia nigra. All in all, (-)deprenyl increases the activity of the nigrostriatal dopaminergic system and slows its age-related decline. Maintenance of male rats on (-)deprenyl delays the loss of the capacity to ejaculate, slows the decline of learning and memory, and significantly lengthens the life-span as compared with saline-treated rats. Parkinson's disease patients on levodopa plus (-)deprenyl (10 mg daily) live significantly longer than those on levodopa alone. (-)Deprenyl is the first drug that retards the progress of Parkinson's disease. Newly diagnosed Parkinson's disease patients maintained on (-)deprenyl need levodopa significantly later than their placebo-treated peers. Maintenance on (-)deprenyl improves significantly the performance of patients with Alzheimer's disease. It is concluded that Parkinson's disease and Alzheimer's disease patients need to be treated daily with 10 mg (-)deprenyl from diagnosis until death, irrespective of other medication.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1992

The pharmacological profile of (-)deprenyl (selegiline) and its relevance for humans: a personal view.

(-)Deprenyl (selegiline, jumex, eldepryl, movergan) which is closely related to phenylethylamine (PEA) is a drug with a unique pharmacological spectrum. Single dose effects: (a) It is a highly potent and selective inhibitor of B-type monoamine oxidase (MAO). (b) In contrast to other MAO inhibitors it inhibits the noradrenaline releasing effect of tyramine, is therefore free of the 'cheese effect'. Multiple dose effects unrelated to MAO inhibition: (a) It enhances superoxide dismutase and catalase activity in the striatum. (b) It facilitates the activity of the nigrostriatal dopaminergic neurones. (c) It prevents age-related morphological changes in the neurocytes of the substantia nigra. Consequences of multiple dose effects: Compared to salt solution-treated rats, male rats maintained on (-)deprenyl loose their capacity to ejaculate later on; retain for longer their learning ability; and live longer. Freshly diagnosed Parkinson's patients maintained on (-)deprenyl, required levodopa later than their placebo-treated peers. Patients treated with levodopa plus (-)deprenyl live longer than those on levodopa alone. Chronic treatment with (-)deprenyl improves the performance of patients with Alzheimer's disease.

Alzheimer Disease↗
PubMed1992

Extension of lifespan in mice treated with Dinh lang (Policias fruticosum L.) and (-)deprenyl.

The effect of Dinh lang root extract (DLRE) and (-)deprenyl on memory function and lifespan was examined in OFA-1 male mice. Treatments of either DLRE, (-)deprenyl or their combination were carried out 3 times a week starting at 12 months of age and following to the end of life. DLRE and (-)deprenyl significantly increased the memory function as well as surviving time of aged mice. The drug-treated animals showed a lower rate of loss of body weight than saline treated ones. It suggested that DLRE and (-)deprenyl did not prolong lifespan of mice by suppressing food intake. The combined treatment of DLRE and (-)deprenyl proved to be the most effective.

Animals↗
PubMed1992

Effect of (-)-para-fluoro-deprenyl on survival and copulation in male rats.

Six-month old male rats were treated with 0.25 mg/kg, s.c., (-)p-fluoro-deprenyl (n = 40) or salt solution (n = 20) three times a week for 25 months. Three of the 20 saline-treated and 15 of the 40 drug-treated males survived (p = 0.05). Sexual activity of the survivors was tested at the end of the experiment. Three of the (-)p-fluoro-deprenyl-treated 31-month-old males proved to be sexually fully active, though, Wistar rats lose their ability to ejaculate by completing their second year of life. Non-copulator, 13 month old male rats were treated instead of the usually used 0.25 mg/kg dose with 0.01 mg/kg, s.c., (-)deprenyl (n = 9), (-)p-fluoro-deprenyl (n = 9) and salt solution (n = 9), three times a week, for 82 weeks and mating activity was tested weekly. The lifespan of the non-copulators was very short: 102 weeks for saline (n = 9), 106 weeks for (-)deprenyl (n = 8) and 104 weeks for (-)p-fluoro-deprenyl (n = 7). Survival was lightly changed by this very small dose treatment, one (-)deprenyl-treated male and two (-)p-fluoro-deprenyl-treated rats remained alive. The copulatory activity, however, was substantially improved.

Animals↗
PubMed1992

(-)Deprenyl (selegiline) is devoid of amphetamine-like behavioural effects in rats.

Central effects of high dose (-)deprenyl (50-100 mg/kg sc) was compared to that of (+)deprenyl and (+/-)amphetamine (AM). (+)Deprenyl and AM induced stereotyped behaviour, increased spontaneous motility in smaller and decreased it in higher doses, inhibited escape behaviour and shuttle-box avoidance. (-)Deprenyl failed to possess any of these effects, providing further evidence that AM-type metabolites have no share in the action of (-)deprenyl.

Amphetamine↗
PubMed1992

Being a family. The experience of raising a child with a disability or chronic illness.

This chapter examined the experiences of families of children with a variety of specialized needs, families who, as pioneers in family-centered, community-based care, are defining the future of services. It also looked at the services that are supposed to support the families in their efforts. On one hand, we have exposed the reader to the tension between traditional approaches to services for children with special needs and the expressed needs of families for coherence and empowerment. On the other hand, the data testify to the development of a new definition of the parent-professional relationship as individual professionals and select service systems around the country strive to work out what it means to support families. When the testimony of these families is carefully read, we are left with an impression of a schizophrenic system of public and private supports for home care for children with severe disabilities and specialized health care needs. The official rhetoric affirms the primacy of the family, and yet the experience of these families is otherwise. Again and again, the families told of benefits managers, case managers, discharge planners, social workers, program administrators, special educators, and the like who implied that parents were out to "milk the system." This attitude was conveyed even in dealing with entitlements and plans to which the parents had long contributed. Families were treated as beneficiaries of benevolent charity for which they should be grateful. Families, already struggling to come to terms with their child's impairment and the care demands associated with it, find themselves stigmatized, impoverished, and degraded. In a society of rugged individualists they are forced to ask for help. That in itself is more than some of the parents can deal with. It should be clear that these parents are not asking for charity. No one here is out to "milk the system." They are simply seeking support to meet some of the extraordinary demands associated with raising their children. As parents, they are not looking for the state to assume their responsibilities. Rather, they seek supports that will enable them to devote their energies to being parents. Their testimony suggests the need for states to recognize support for the family as an entitlement that affirms that the family. They base this call on the fact that support for families is the most cost effective service the state can provide.(ABSTRACT TRUNCATED AT 400 WORDS)

Child↗