Anti-idiotypic antibodies as probes of prolactin receptor.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
M B Youdim
Publications and source records attributed to M B Youdim.
Brain monoamine oxidase (MAO) B: a unique neurotoxin and neurotransmitter producing enzyme.
The notion that monoamine oxidase (MAO) functions solely to inactivate neurotransmitter and other biogenic amines needs to be re-evaluated. It is now apparent that MAO-B is capable of oxidizing inert non-polar amines such as MPTP (N-methyl-4-phenyl-1,2,3,6, tetrahydropyridine) and milacemide (2-n-pentylaminoacetamide) into neuroactive substances giving rise to Parkinson inducing dopaminergic neurotoxin, MPP+ and inhibitory amino acid neurotransmitter, glycine respectively. These findings accord new prospectives for neuropsychotherapy with selective MAO-B inhibitors and substrates.
Animals↗
Putative biological mechanisms of the effect of iron deficiency on brain biochemistry and behavior.
An animal model of nutritional iron deficiency (ID) is described that demonstrates a reduction of brain nonheme iron. The most prominent feature of ID is the significant and selective diminution of central dopamine neurotransmission resulting from the decreased number of dopamine D2 receptors in the caudate nucleus, nucleus accumbens, pituitary, and in all probability the frontal cortex. The consequences of diminished dopaminergic neurotransmission is a modification of dopamine-dependent behaviors and biochemical reactions, the most important of which is the reduction in learning processes. The role of iron in maintaining the homeostasis of normally functioning dopamine neurons and their involvement in cognitive processes cannot be excluded. An interference with iron metabolism at an early age can result in irreversible damage to developing dopamine neurons, with consequences that may manifest themselves in adult life.
Animals↗
Brain iron: a lesson from animal models.
Brain and blood iron deficiency (ID) can be nutritionally induced. Significant behavioral and brain-biochemical changes are observed in rats rendered iron deficient, including complete reversal of the circadian cycles of motor activity, changes in thermoregulation and stereotyped behavior, and an increased pain threshold. The increase in pain threshold is affected by diurnal factors and peripheral treatment with beta-endorphin has a significant analgesic effect, implicating selective changes in the blood-brain barrier. These effects along with modifications in responses to dopaminergic drugs, interactions of ID with neuroleptic drugs, and modifications in behavior as a result of selective brain lesions, lead to two conclusions: this animal model is appropriate for human anemia and the best explanation for the variety of behavioral and brain biochemical changes in ID rats is that the principal effect of brain ID is a selective decrease in the functional level of the dopaminergic D2 system.
Amphetamine↗
Steroid regulation of monoamine oxidase activity in the adrenal medulla.
Administration of different steroid hormones in vivo has distinct and specific effects on the MAO activity of the adrenal medulla. In an effort to reconstitute these effects in defined cells, we have isolated endothelial cells and chromaffin cells from the bovine adrenal medulla and tested each cell type for sensitivity to these steroids. As in the intact animal, we found that endothelial cell MAO activity was stimulated 1.5- 2.5-fold by 10 microM progesterone, hydrocortisone, and dexamethasone, inhibited by ca. 50% by 17-alpha-estradiol, but unaffected by testosterone. The type of MAO in the endothelial cells was found to be exclusively of the A type. The chromaffin cells had MAO B exclusively and were inert to treatment with dexamethasone. The mode of action of the various steroids on MAO A activity in endothelial cells seemed to be that of affecting the number of MAO molecules, as binding of [3H]pargyline, an MAO inhibitor, changed in proportion to changes in enzyme activity. Consistently, the kinetic parameters for MAO A showed changes in Vmax but not Km under all conditions. The specificity of steroid action on MAO A activity was also supported by the fact that steroid-induced changes in total cell division ([14C]thymidine incorporation) and total protein synthesis ([14C]leucine incorporation) were seen after changes in MAO A. We conclude that the differential effects of steroids on MAO activity in the intact adrenal medulla can be reproduced in cultured adrenal medullary endothelial cells but not in chromaffin cells. Therefore we suggest that the action of these steroid hormones on the intact adrenal medulla may be restricted to the endothelial cell component of this tissue.
Adrenal Medulla↗
The novel neuropsychotropic agent milacemide is a specific enzyme-activated inhibitor of brain monoamine oxidase B.
The novel neuropsychotropic agent milacemide hydrochloride (2-n-pentylaminoacetamide HCl) is a highly selective substrate of the B form of monoamine oxidase (EC 1.4.3.4; MAO). Under the in vitro conditions used in the present study, milacemide acts as an enzyme-activated, partially reversible inhibitor of MAO-B. A reversible inhibition of MAO-A activity is also observed at high concentrations. The inhibitory activity of milacemide is significantly greater for MAO-B. In vivo, after single or repeated oral administration, a specific inhibition of MAO-B is apparent in brain and liver, with a lack of inhibition of the MAO-A activity. In contrast to the irreversible inhibitory action of L-deprenyl, the recovery of MAO-B activity in vivo after milacemide administration is significantly faster, a result suggesting that it is a partially reversible inhibitor. The selective inhibitory effect of milacemide for MAO-B in vivo is confirmed by its potentiation of phenylethylamine-induced stereotyped behavior, whereas vasopressor responses to tyramine were not affected. These observations suggest that milacemide could enhance dopaminergic activity in the brain and could be used as therapy for Parkinson's disease in association with L-3,4-dihydroxyphenylalanine.
Acetamides↗
Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains.
The regional distributions of iron, copper, zinc, magnesium, and calcium in parkinsonian brains were compared with those of matched controls. In mild Parkinson's disease (PD), there were no significant differences in the content of total iron between the two groups, whereas there was a significant increase in total iron and iron (III) in substantia nigra of severely affected patients. Although marked regional distributions of iron, magnesium, and calcium were present, there were no changes in magnesium, calcium, and copper in various brain areas of PD. The most notable finding was a shift in the iron (II)/iron (III) ratio in favor of iron (III) in substantia nigra and a significant increase in the iron (III)-binding, protein, ferritin. A significantly lower glutathione content was present in pooled samples of putamen, globus pallidus, substantia nigra, nucleus basalis of Meynert, amygdaloid nucleus, and frontal cortex of PD brains with severe damage to substantia nigra, whereas no significant changes were observed in clinicopathologically mild forms of PD. In all these regions, except the amygdaloid nucleus, ascorbic acid was not decreased. Reduced glutathione and the shift of the iron (II)/iron (III) ratio in favor of iron (III) suggest that these changes might contribute to pathophysiological processes underlying PD.
Aged↗
Monoamine oxidase activity and triiodothyronine biosynthesis in human cultured thyroid cells.
1. The proposal that monoamine oxidase (MAO) is a source of peroxide in thyroid hormone biosynthesis has been examined by use of isolated cultured human thyroid cells which retain the ability to secrete triiodothyronine (T3) in response to thyroid stimulating hormone (TSH). 2. The results demonstrated the presence of MAO A and B in human thyroid cells which oxidized 5-hydroxytryptamine and 2-phenylethylamine, respectively, and were selectively inhibited by the MAO inhibitors clorgyline and (-)-deprenyl. 3. Addition of propylthiouracil to the culture system induced a 61% reduction in TSH-stimulated T3 secretion, indicating that the bulk of such secretion apparently derives from de novo iodothyronine synthesis. 4. The MAO A and B substrate, tyramine, was ineffective in stimulating T3 secretion. 5. The selective MAO inhibitors, clorgyline and (-)-deprenyl, alone and in combination, and in the presence and absence of tyramine, failed to inhibit basal as well as TSH-stimulated T3 secretion in cultured human thyrocytes. 6. It is therefore apparent that even though thyroid MAO A and B enzyme reactions result in the generation of H2O2, this H2O2 does not seem to play a significant role in T3 biosynthesis.
Cells, Cultured↗
Neurochemical perspectives to the function of monoamine oxidase.
Dopamine (DA) is degraded in part by MAO, an intraneuronal and glial enzyme localized at the outer mitochondrial membrane. DA is a good substrate for MAO-B and selegiline enhances DA-transmission and improves akinesia of Parkinson's disease (PD) by selective MAO-B blockade. Immunocytochemistry (ICC) and histochemistry (HC) demonstrate that neurons of substantia nigra (SN) lack MAO near totally (but see Moll et al 1988). Consequently, inhibition of MAO-B in this brain area occurs mainly in glial cells. Therefore an increase of DA in glia seems to be of long-lasting therapeutic benefit in PD. In addition, synthesis of hydrogen peroxide generated via MAO-B is blocked by selegiline. By this toxicity by endogenous free radicals is diminished. Furthermore, exogenous neurotoxicity by MAO-B substrates can be prevented by inhibition of MAO-B, while such MAO-A substrates are metabolized at the level of the MAO-A containing endothelium of capillaries. As conclusion, selegiline is a safe inhibitor of MAO-B that reduces neurotoxicity possibly triggering PD. (Table: see text).
Brain↗
Is Parkinson's disease a progressive siderosis of substantia nigra resulting in iron and melanin induced neurodegeneration?
Razor sharp and high iron deposits are present in the substantia nigra (SN). Although the function of such high iron content is not known, the homeostasis of brain iron is important for normal brain function. The participation of free tissue iron in oxidative stress (OS), resulting in the formation of cytotoxic hydroxyl radical (.OH) from H2O2 (Fenton reaction) and promotion of membrane lipid peroxides by .OH can no longer be questioned as a biological phenomenon. The highly selective increase of Fe2+ and Fe3+ and lipid peroxidation observed in parkinsonian SN points to OS in such brains. Lipid peroxidation proceeds with either Fe2+ or Fe3+ provided a mechanism exists to facilitate the interconversion of iron between its redox states. Indeed H2O2 derived from MAO B reaction and autooxidation of dopamine to melanin in the SN can drive the iron dependent Fenton reaction. Furthermore, interaction of iron with melanin may be even more important considering that melanin avidly binds Fe3+ and reduce it to Fe2+, resulting in .OH generation. Thus, without evoking environmental neurotoxins, the excessive accumulation of free iron in the SN and "melanin-trap" could be the trigger for accelerated cell death and Parkinsonism.
Humans↗
Adaptation of liver membrane somatogenic and lactogenic growth hormone (GH) binding to the spontaneous pulsation of GH secretion in the male rat.
The secretory pattern of GH is pulsatile in both man and experimental animals. The present study was undertaken to investigate the effect of the endogenous pulsatility of serum GH on the dynamics of plasma membrane GH binding sites. In order to characterize somatogenic and total specific binding, male rats 45 days old were decapitated at 15-min intervals, and rat liver membranes were prepared. Binding studies were done in parallel with and without excess ovine PRL, 1 microgram/tube. Removal of endogenous ligand was performed by exposing the membranes to 3 M MgCl2. A composite picture of serum GH showed relatively good synchronization of the secretory episodes among the animals. Peak levels of the spontaneous secretion pulse of rat GH were followed by an immediate decrease in free somatogenic binding. Two hours later the binding activity returned to presecretion levels, essentially resetting the cell for another cycle. The kinetics of desaturated somatogenic binding were similar. The occupancy of liver GH somatogenic binding sites was maximal at the time of peak serum GH. High levels of the endogenous hormone caused an immediate sharp down-regulation of lactogenic desaturated binding. Up-regulation of the binding sites occurred about 90 min later. Scatchard analysis showed that binding activity of the membranes was a result of the altered number of binding sites, while the binding affinity remained fairly constant. Thus, the centrally regulated GH secretion in the male rat is complemented by appropriate dynamics of the GH receptor turnover, which in turn recognizes individual pulses and allows individual pulse-related responses to occur.
Activity Cycles↗
The dynamics of somatogenic and lactogenic growth hormone binding: internalization to Golgi fractions in the male rat.
Rapid turnover of the GH receptor has previously been shown, and its turnover (t1/2) has been estimated to be 30-85 min. In a companion study, we found that lactogenic and somatogenic GH binding sites on rat liver membranes were down-regulated immediately after an episode of GH secretion and reappeared at the plasma membrane in time for the next secretory surge of the hormone. In the present in vivo study, we followed the fate of the down-regulated membrane GH binding sites in the Golgi membranes. Male rats were killed at 1000, 1100, and 1200 h, and their livers were removed for preparation of Golgi membranes. Lactogenic and somatogenic [125I]human GH binding to Golgi membranes was measured. The results of the present study show that Golgi receptors are related to the endogenous pulsation of serum GH. After the GH surge, an increase in the capacity of the lactogenic and somatogenic receptors in the Golgi membranes takes place. Most of these receptors were occupied by ligand and represent, therefore, internalized receptors. Two hours after the GH secretory peak, the occupied receptors had disappeared from the Golgi membranes and appeared in the plasma membrane, suggesting that receptors were recycled to the plasma membrane, awaiting the next GH surge. The following model is proposed: A surge of GH secretion causes immediate down-regulation of the plasma membrane receptors to GH. The receptors that disappear from the plasma membrane are internalized to the Golgi complex. A fraction of the Golgi receptors is recycled to the membrane, along with newly synthesized receptors, awaiting the next GH pulse.
Activity Cycles↗
Increase in central and peripheral benzodiazepine receptors following surgery.
[3H]Flunitrazepam, [3H]PK 11195, [3H]quinuclidinyl benzilate (QNB) and monoamine oxidase (MAO) A and B activity were measured in male rats 1, 3 and 7 days following laparotomy. The surgery resulted in the up-regulation of central benzodiazepine (BZ) receptors in cerebral cortex and of peripheral BZ binding sites in brain and kidney on the first and third days after operation. This increase was followed by a decrease to normal range 7 days after the surgical procedure. [3H]QNB binding to muscarinic receptors in the cerebral cortex as well as MAO A and B activity in rat cerebral cortex and kidney were not affected by the surgical manipulation. The modulatory effect of surgery on BZ receptors corresponds to stages of the healing process in surgical wounds.
Animals↗
The glycine-prodrug, milacemide, increases the seizure threshold due to hyperbaric oxygen; prevention by 1-deprenyl.
The novel glycine-prodrug anticonvulsant, milacemide (2-N-pentylaminoacetamide) (500 mg/kg), significantly increased (greater than 400% the seizure threshold induced by hyperbaric oxygen (4.5 atmosphere). This effect was significantly reduced by the selective inhibition of monoamine oxidase B by 1-deprenyl (2.0 mg/kg). 1-Deprenyl alone hardly affected the seizure threshold. These results suggest that, in the brain, milacemide is oxidized to glycine and that this reaction is mediated primarily by monoamine oxidase B. However, the interaction of milacemide metabolites (glycine amide, pentanoate and glycine) as antagonists of receptors of the glutamate NMDA (N-methyl-D-aspartate) subtype cannot be excluded.
Acetamides↗
Platelet monoamine oxidase B: use and misuse.
The human platelet in addition to having serotonin (5-HT) receptors, uptake carriers (receptor) and transmitter storage vesicles, primarily possesses mitochondrial monoamine oxidase (MAO) type B. Similar to the major form of MAO in the human brain, this enzyme actively oxidizes A-B and B substrates (tyramine, dopamine, phenylethylamine) as well as the novel secondary amine anticonvulsant, milacemide and dopaminergic neurotoxin, MPTP. 5-HT oxidation is hardly affected by the platelet enzyme and MAO inhibitors have no net effect on its accumulation. MAO-B is selectively inhibited by 1-deprenyl and thus the platelet enzyme may be useful to monitor the anti-Parkinson activity of such drugs, as related to their ability to inhibit brain MAO-B. The oxidation of the anticonvulsant, milacemide, to glycine in vitro and in vivo by MAO-B, may herald new prospects for the development of inert prodrugs capable of being metabolized to neuroactive substances by MAO-B. The plasma levels of their metabolites may be an index of MAO-B activity found in the platelet and brain.
Animals↗
Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain.
Significant differences in the content of iron (III) and total iron were found in post mortem substantia nigra of Parkinson's disease. There was an increase of 176% in the levels of total iron and 225% of iron (III) in the substantia nigra of the parkinsonian patients compared to age matched controls. In the cortex (Brodmann area 21), hippocampus, putamen, and globus pallidus there was no significant difference in the levels of iron (III) and total iron. Thus the changes in total iron, iron (III) and the iron (II)/iron (III) ratio in the parkinsonian substantia nigra are likely to be involved in the pathophysiology and treatment of this disorder.
Aged↗
Monoamine oxidase B; a misunderstood and misjudged enzyme.
Explore the source record for details and available documents.
Animals↗
Selective alteration in blood-brain barrier and insulin transport in iron-deficient rats.
Nutritional iron deficiency induced in rats causes a significant reduction in level of brain nonheme iron and is accompanied by selective reduction of dopamine D2 receptor Bmax. Our previous studies have clearly demonstrated that these alterations can be restored to normal by supplementation with ferrous sulfate; however, neither brain nonheme iron level nor dopamine D2 receptor Bmax can be increased beyond control values even after long-term iron therapy. The possibility that iron deficiency can induce the breakdown of the blood-brain barrier (BBB) was examined. A 70 and 100% increase in brain uptake index (BUI) for L-glucose and insulin, respectively, were noted in iron-deficient rats. However, the BUI for valine was decreased by 40%, and those for L-norepinephrine and glycine were unchanged. In addition, it was demonstrated that in normal rats insulin is transported into the brain. The data show that iron deficiency selectively affects the integrity of the BBB for insulin, glucose, and valine transport. Whether the effect of iron deficiency on the BBB is at the level of the capillary endothelial cell tight junction is not yet known. However, this study has shown that an important nutritional disorder (iron-deficiency anemia) has a profound effect on the BBB and brain function.
Anemia, Hypochromic↗