The potential role of iron chelators in the treatment of Parkinson's disease and related neurological disorders.

Neurodegeneration is characterized by a marked accumulation of iron in the affected brain regions. The reason for this is still unknown. In this article we review the available data on the possible involvement of iron and mediated oxidative stress in the aetiology of Parkinson's disease and related disorders.

Mechanism of 6-hydroxydopamine neurotoxicity.

The catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) has recently been found to be formed endogenously in patients suffering from Parkinson's disease. In this article, we highlight the latest findings on the biochemical mechanism of 6-OHDA toxicity. 6-OHDA has two ways of action: it easily forms free radicals and it is a potent inhibitor of the mitochondrial respiratory chain complexes I and IV.

Apomorphine is a highly potent free radical scavenger in rat brain mitochondrial fraction.

Ergoline-derived dopamine receptor agonists, like pergolide or bromocryptine, have recently attracted attention as potential neuroprotective drugs. The classical mixed type dopamine D1 and D2 receptor agonist apomorphine, although used clinically in the therapy of Parkinson's disease, has never been examined for any properties related to neuroprotection. In this paper, we examine the effects of 0.

Effect of human growth hormone (GH)-binding protein in human serum on GH binding to rabbit liver membranes.

The sequence identity of growth hormone-binding protein (GH-BP) with the extracellular domain of GH receptors raised the possibility that circulating GH-BP might affect the binding of human GH (hGH) to its receptors, and thus, its biological effects. To test this hypothesis, we tested the effects of sera with low GH-BP levels (obtained from prepubertal children, girls with anorexia nervosa [AN], and patients with hepatic cirrhosis), normal control sera, and sera with high GH-BP levels (obtained from obese patients) on hGH binding to its receptors. GH-BP activity in patients' sera was measured by incubation with [125I]hGH and the separation of bound hGH from free hGH with dextran-coated charcoal.

Iron-melanin interaction and lipid peroxidation: implications for Parkinson's disease.

The vulnerability of substantia nigral (SN) melaninized dopamine neurons to neurodegeneration in Parkinson's disease and the selective increases of iron and basal lipid peroxidation in SN indicate that iron-melanin interaction could be crucial to the pathogenesis of this disease. The present study describes, for the first time, the identification and characterization of a high-affinity (KD = 13 nM) and a lower affinity (KD = 200 nM) binding site for iron on dopamine melanin. The binding of iron to melanin is dependent on pH and the concentration of melanin.

Prevention of neuroleptic-induced dopamine D2 receptor supersensitivity by chronic iron salt treatment.

The ability of neuroleptics to induce dopamine D2 receptor supersensitivity has been linked to the onset of tardive dyskinesia, the major side-effect of these drugs. Brain iron metabolism has been shown to be involved in the regulation of dopamine D2 receptors. We now examined the effect of chronic treatment with FeCl2 on chlorpromazine-induced D2 receptor supersensitivity.

The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons.

A selective increase in content of iron in the pars compacta of the substantia nigra has been implicated in the biochemical pathology of Parkinson's disease. Iron is thought to induce oxidative stress by liberation of oxygen free radicals from H2O2. Because 6-hydroxydopamine (6-OHDA) is thought to induce nigrostriatal dopaminergic neuronal lesions via metal-catalyzed free radical formation, the effect of the iron chelator desferrioxamine was investigated on 6-OHDA-induced dopaminergic neuron degeneration in the rat.

Inhibition of sympathetic nerve activity by acute administration of the tricyclic antidepressant desipramine.

In rats anesthetized with pentobarbital/chloral hydrate, the i.v. injection of desipramine (0.

Iron in brain function and dysfunction with emphasis on Parkinson's disease.

Metals such as lead, zinc, copper, aluminum and manganese have been implicated in neuropsychiatric disorders. However, until fairly recently the role of iron in brain function was rather obscure, because little attention was paid to its metabolism in the brain. It is now apparent that maintenance of brain iron homoeostasis is important for the normal functioning of his organ.

Identification of growth hormone binding protein in rat serum.

The present report describes the initial characterization of a specific, high-affinity growth hormone binding protein (GH-BP) in adult male rat serum. GH-BP activity was measured by incubation of rat serum with [125I]hGH and [125I]rGH and separation of bound from free GH by dextran-coated charcoal. [125I]hGH binding to rat serum was dependent on serum concentration and incubation time, equilibrium being reached within 10 min both at 4 and 37 degrees C.

Monoamine oxidase (MAO)-A but not MAO-B inhibitors potentiate tyramine-induced catecholamine release from PC12 cells.

The previous report that PC12 (pheochromocytoma) cells have a K(+)-induced, as well as a tyramine-induced, catecholamine release mechanism has been confirmed. Selective monoamine oxidase (MAO)-A (clorgyline and moclobemide) and not MAO-B inhibitors (l-deprenyl, AGN 1135, and Ro 16-6491) potentiate the catecholamine-releasing action of tyramine significantly more than that of K+. The potentiation of tyramine-induced [3H]noradrenaline release from PC12 cells by MAO-A inhibitors has been linked to the presence of MAO-A in these cells, for which tyramine and noradrenaline are substrates.

Selectivity of melaninized nigra-striatal dopamine neurons to degeneration in Parkinson's disease may depend on iron-melanin interaction.

The recent studies on the chemical pathology of Parkinson's disease show selective increases of iron and lipid peroxidation and decreased glutathione (GSH) oxidizing capacity in the substantia nigra (SN). These changes are indicative of oxidative stress, possibly due to the accumulation of iron in the SN. It is the melaninized dopamine neurons that are vunerable to degeneration.

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 (.

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.

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.

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.

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.

Monoamine oxidase B inhibition and the "cheese effect".

The absence of initiation of "cheese effect" (potentiation of sympathomimetic action of tyramine) by 1-deprenyl (selective monoamine oxidase, MAO-B inhibitor) was regarded to be an intrinsic property of this inhibitor. However, availability of other selective MAO-B inhibitors have clearly shown that this is not the case, since the "cheese effect" is associated with the selective inhibition of MAO-A, the enzyme responsible for intraneuronal oxidation of noradrenaline. Following inhibition of neuronal MAO-A, noradrenaline in the cytoplasmic intraneuronal pool can increase to high levels.