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1.
Curr Alzheimer Res ; 15(7): 637-642, 2018.
Article in English | MEDLINE | ID: mdl-29637859

ABSTRACT

BACKGROUND: It has been postulated that inadequate clearance of the amyloid ß protein (Aß) plays an important role in the accumulation of Aß in sporadic late onset Alzheimer's disease (AD). While the blood brain barrier (BBB) has taken the center stage in processes involving Aß clearance, little information is available about the role of the lymphatic system. We previously reported that Aß is cleared through the lymphatic system. We now assessed lymphatic Aß clearance by treating a mouse model of AD amyloidosis with melatonin, an Aß aggregation inhibitor and immuno-regulatory neurohormone. OBJECTIVE: To confirm and expand our initial finding that Aß is cleared through the lymphatic system. Lymphatic clearance of metabolic and cellular "waste" products from the brain into the peripheral lymphatic system has been known for a long time. However, except for our prior report, there is no additional experimental data published about Aß being cleared into peripheral lymph nodes. METHODS: For these experiments, we used a transgenic mouse model (Tg2576) that over-expresses a mutant form of the Aß precursor protein (APP) in the brain. We examined levels of Aß in plasma and in lymph nodes of transgenic mice as surrogate markers of vascular and lymphatic clearance, respectively. Aß levels were also measured in the brain and in multiple tissues. RESULTS: Clearance of Aß peptides through the lymphatic system was confirmed in this study. Treatment with melatonin led to the following changes: 1-A statistically significant increase in soluble monomeric Aß40 and an increasing trend in Aß42 in cervical and axillary lymph nodes of treated mice. 2- Statistically significant decreases in oligomeric Aß40 and a decreasing trend Aß42 in the brain. CONCLUSION: The data expands on our prior report that the lymphatic system participates in Aß clearance from the brain. We propose that abnormalities in Aß clearance through the lymphatic system may contribute to the development of cerebral amyloidosis. Melatonin and related indole molecules (i.e., indole- 3-propionic acid) are known to inhibit Aß aggregation although they do not reverse aggregated Aß or amyloid fibrils. Therefore, these substances should be further explored in prevention trials for delaying the onset of cognitive impairment in high risk populations.


Subject(s)
Amyloid beta-Peptides/metabolism , Amyloidosis/drug therapy , Lymph Nodes/drug effects , Melatonin/pharmacology , Neuroprotective Agents/pharmacology , Amyloidosis/metabolism , Animals , Brain/drug effects , Brain/metabolism , Disease Models, Animal , Humans , Lymph Nodes/metabolism , Mice, Transgenic
2.
Cent Nerv Syst Agents Med Chem ; 12(3): 189-216, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22640220

ABSTRACT

The CNS is both source and target of melatonin. This methoxyindole formed in the pineal gland is also produced in other CNS regions and additionally enters the brain by uptake from the circulation as well as via the pineal recess. The mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN), not only controls the pineal, but also receives a feedback information on darkness. Two G protein-coupled melatonin receptors, MT1 and MT2, are responsible for the transduction of many melatonergic actions. High receptor densities are especially found in the SCN, but their presence at lower expression levels in other areas is functionally important. Various metabolites and analogs are formed in the CNS, such as N-acetylserotonin, 5-methoxytryptamine, 5-methoxytryptophol, 5-methoxylated kynuramines, and even 6-sulfatoxymelatonin. The chronobiological effects of melatonin go beyond the resetting of a single circadian oscillator. They contribute to phase relationships between oscillatory subsets and are required for robust rhythm amplitudes. CNS effects of melatonin comprise sleep initiation, antiexcitatory, antiepileptic, antinociceptive, anxiolytic, proneurotrophic, antiinflammatory, antioxidant and other neuroprotective actions. The role as a sleep-promoting compound, which is limited by its short half-life in the circulation, has led to the development of controlled-release formulations and of various synthetic agonists, such as ramelteon, agomelatine, tasimelteon, TIK-301, UCM765 and UCM924. Their differences concerning receptor affinities, preferences for receptor subtypes, and pharmacokinetics are discussed, as well as additional antidepressive actions of agomelatine and TIK-301 based on properties as antagonists of the serotonergic 5-HT2C receptor. Indirect antidepressive effects by melatonergic drugs are largely explained by circadian readjustments.


Subject(s)
Central Nervous System/drug effects , Central Nervous System/metabolism , Melatonin/agonists , Melatonin/metabolism , Receptors, Melatonin/agonists , Acetamides/metabolism , Acetamides/pharmacology , Animals , Antidepressive Agents/metabolism , Antidepressive Agents/pharmacology , Humans , Indenes/metabolism , Indenes/pharmacology , Melatonin/pharmacology , Receptors, Melatonin/metabolism , Sleep/drug effects , Sleep/physiology
3.
Br J Dermatol ; 162(5): 1127-31, 2010 May.
Article in English | MEDLINE | ID: mdl-20302576

ABSTRACT

BACKGROUND: Human skin and scalp hair follicles are both a nonclassical target and an extrapituitary source of prolactin (PRL), which is a potent hair growth modulator. However, how the expression of PRL and PRL receptor (PRLR) is regulated in human skin is unknown. OBJECTIVES: To investigate whether two key stimulators of pituitary PRL secretion, thyrotropin-releasing hormone (TRH) and oestrogen, also regulate cutaneous PRL and PRLR expression. METHODS: Female scalp skin and/or microdissected hair follicles were treated for 6 days in serum-free organ culture with oestrogen (100 nmol L(-1)), TRH (1-10 ng mL(-1), 3-30 nm) or vehicle control. Quantitative immunohistomorphometry of skin and hair follicle sections was complemented with quantitative polymerase chain reaction for PRL and PRLR in cultured hair follicles and/or female human outer root sheath (ORS) keratinocytes. RESULTS: Oestrogen treatment significantly upregulated PRL and PRLR immunoreactivity in selected skin and hair follicle compartments, at the gene and protein level (P < 0.05). TRH significantly increased PRL immunoreactivity and transcription in hair follicles (P < 0.05); however, while it also increased PRLR transcription in hair follicles, it downregulated PRLR immunoreactivity in the hair follicle ORS (P < 0.05). CONCLUSIONS: Our pilot study shows that two key endocrine controls of pituitary PRL secretion, oestrogen and TRH, also regulate PRL and PRLR expression in human skin. This provides novel insights into the regulation of extrapituitary PRL and PRLR expression, and invites exploration of oestrogen and TRH as novel therapeutic agents in the management of skin and hair diseases characterized by aberrant PRLR-mediated signalling.


Subject(s)
Estrogens/pharmacology , Prolactin/metabolism , Receptors, Prolactin/metabolism , Skin/drug effects , Thyrotropin-Releasing Hormone/pharmacology , Adult , Female , Gene Expression Regulation/drug effects , Hair Follicle/drug effects , Hair Follicle/metabolism , Humans , Middle Aged , Organ Culture Techniques , Pilot Projects , Prolactin/genetics , Receptors, Prolactin/genetics , Skin/metabolism
4.
Neuroscience ; 148(1): 188-97, 2007 Aug 10.
Article in English | MEDLINE | ID: mdl-17629627

ABSTRACT

The N-methyl-d-aspartate (NMDA) subtype of glutamate receptors plays an important role in brain physiology, but excessive receptor stimulation results in seizures and excitotoxic nerve cell death. NMDA receptor-mediated neuronal excitation and injury can be prevented by high, non-physiological concentrations of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA). Here we report that endogenous KYNA, which is formed in and released from astrocytes, controls NMDA receptors in vivo. This was revealed with the aid of the dopaminergic drugs d-amphetamine and apomorphine, which cause rapid, transient decreases in striatal KYNA levels in rats. Intrastriatal injections of the excitotoxins NMDA or quinolinate (but not the non-NMDA receptor agonist kainate) at the time of maximal KYNA reduction resulted in two- to threefold increases in excitotoxic lesion size. Pre-treatment with a kynurenine 3-hydroxylase inhibitor or with dopamine receptor antagonists, i.e., two classes of pharmacological agents that prevented the reduction in brain KYNA caused by dopaminergic stimulation, abolished the potentiation of neurotoxicity. Thus, the present study identifies a previously unappreciated role of KYNA as a functional link between dopamine receptor stimulation and NMDA neurotoxicity in the striatum.


Subject(s)
Corpus Striatum/metabolism , Corpus Striatum/physiopathology , Kynurenic Acid/metabolism , Neurotoxins/metabolism , Receptors, Dopamine/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Astrocytes/metabolism , Cell Death/drug effects , Cell Death/physiology , Corpus Striatum/drug effects , Dopamine/metabolism , Dopamine Agonists/pharmacology , Excitatory Amino Acid Agonists/metabolism , Excitatory Amino Acid Agonists/toxicity , Female , Glutamic Acid/metabolism , Humans , N-Methylaspartate/metabolism , N-Methylaspartate/toxicity , Nerve Degeneration/chemically induced , Nerve Degeneration/metabolism , Nerve Degeneration/physiopathology , Neurotoxins/toxicity , Quinolinic Acid/metabolism , Quinolinic Acid/toxicity , Rats , Rats, Sprague-Dawley
5.
FEBS J ; 273(13): 2813-38, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16817850

ABSTRACT

Melatonin is a ubiquitous molecule and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as 'neuroendocrine transducers' to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the 'hormone of darkness'. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a number of other cyclical bodily activities. Melatonin is exclusively involved in signaling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronological pacemaker or 'Zeitgeber'. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiological functions through paracrine signaling. Melatonin has also been extracted from the seeds and leaves of a number of plants and its concentration in some of this material is several orders of magnitude higher than its night-time plasma value in humans. Melatonin participates in diverse physiological functions. In addition to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong antiapoptotic signaling function, an effect which it exerts even during ischemia. Melatonin's cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune-enhancing and oncostatic properties. Its 'chronobiotic' properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or shift-work sleep disorder. Melatonin acting as an 'internal sleep facilitator' promotes sleep, and melatonin's sleep-facilitating properties have been found to be useful for treating insomnia symptoms in elderly and depressive patients. A recently introduced melatonin analog, agomelatine, is also efficient for the treatment of major depressive disorder and bipolar affective disorder. Melatonin's role as a 'photoperiodic molecule' in seasonal reproduction has been established in photoperiodic species, although its regulatory influence in humans remains under investigation. Taken together, this evidence implicates melatonin in a broad range of effects with a significant regulatory influence over many of the body's physiological functions.


Subject(s)
Melatonin/chemistry , Animals , Antioxidants/chemistry , Antioxidants/metabolism , Apoptosis , Chronobiology Phenomena , Depression , Free Radical Scavengers , Humans , Models, Chemical , Plant Proteins/chemistry , Receptors, Melatonin/physiology , Signal Transduction , Sleep/physiology
6.
Behav Brain Funct ; 2: 15, 2006 May 04.
Article in English | MEDLINE | ID: mdl-16674804

ABSTRACT

Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-beta toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin, its analogues and kynuric metabolites may have potential value in prevention and treatment of AD and other neurodegenerative disorders.

7.
Biomed Pharmacother ; 59 Suppl 1: S192-202, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16275493

ABSTRACT

An impeccable time series, published in 1930, consisting of hourly observations on colony advance in a fluid culture of E. coli, was analyzed by a periodogram and power spectrum in 1961. While the original senior author had emphasized specifically periodicity with no estimate of period length, he welcomed further analyses. After consulting his technician, he knew of no environmental periodicity related to human schedules other than an hourly photography. A periodogram analysis in 1961 showed a 20.75-h period. It was emphasized that "... the circadian period disclosed is not of exactly 24-h length." Confirmations notwithstanding, a committee ruled out microbial circadian rhythms based on grounds that could have led to a different conclusion, namely first, the inability of some committee members to see (presumably by eyeballing) the rhythms in their own data, and second, what hardly follows, that there were "too many analyses" in the published papers. Our point in dealing with microbes and humans is that analyses are indispensable for quantification and for discovering a biologically novel spectrum of cyclicities, matching physical ones. The scope of circadian organization estimated in 1961 has become broader, including about 7-day, about half-yearly, about-yearly and ex-yearly and decadal periodisms, among others. Microbial circadians have become a field of their own with eyeballing, yet time-microscopy can quantify characteristics with their uncertainties and can assess broad chronomes (time structures) with features beyond circadians. As yet only suggestive differences between eukaryotes and prokaryotes further broaden the perspective and may lead to life's sites of origin and to new temporal aspects of life's development as a chronomic tree by eventual rhythm dating in ontogeny and phylogeny.


Subject(s)
Chronobiology Phenomena , Eukaryotic Cells/physiology , Prokaryotic Cells/physiology , Acetabularia/metabolism , Animals , Circadian Rhythm/physiology , Cyanobacteria/growth & development , Escherichia coli/growth & development , Euglena/growth & development , Humans , Jet Lag Syndrome , Lighting , Oxygen/metabolism , Solar Activity
8.
Biomed Pharmacother ; 59 Suppl 1: S209-12, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16275496

ABSTRACT

A circadian rhythm is documented in duodenal melatonin in rats, peaking 16.8 hours after light onset. This component is more readily detected after log10-transformation of the data. It differs between male and female rats, females having a larger circadian amplitude and an earlier acrophase. The circadian rhythm in duodenal melatonin is also found to lead that of pineal melatonin. The results are qualified by the presence at the start of mapping of the second extremum of a double magnetic storm.


Subject(s)
Chronobiology Phenomena , Circadian Rhythm/physiology , Duodenum/metabolism , Melatonin/metabolism , Animals , Female , Light , Male , Rats , Rats, Wistar , Sex Factors , Solar Activity
9.
Biomed Pharmacother ; 59 Suppl 1: S213-9, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16275497

ABSTRACT

A circadian rhythm is documented for plasma, pineal, and hypothalamic melatonin of male and female rats kept on staggered lighting regimens. Log[_10]-transformation of the data usually normalizes, when need be, the distribution of residuals from the 24-hour cosine curve fits. A tentative circadian acrophase chart is presented that shows a lead in circadian acrophase of duodenal over pineal melatonin. The use of antiphasic lighting regimens facilitates circadian studies that can be carried out for several days, thereby allowing the assessment of infradian components such as a circasemiseptan variation in hypothalamic melatonin documented herein. The results are qualified by the presence of a second extremum of a double magnetic storm at the start of mapping.


Subject(s)
Chronobiology Phenomena , Circadian Rhythm/physiology , Hypothalamus/metabolism , Melatonin/metabolism , Pineal Gland/metabolism , Animals , Female , Lighting , Male , Melatonin/blood , Rats , Rats, Wistar , Reproducibility of Results , Seasons , Sex Characteristics
10.
Biomed Pharmacother ; 59 Suppl 1: S220-4, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16275498

ABSTRACT

In Göttingen, Germany, circadian variations in melatonin had been determined time-macroscopically in pineal glands, blood plasma and duodenum of chicken and rats. When these data were meta-analyzed, they agreed with the results from an independent survey on tissues from rats collected in a laboratory in Pécs, Hungary. In the latter study, tissues were analyzed chemically in Bratislava, Slovakia, and numerically in Minneapolis, MN, USA, all by single- and multiple-component cosinor and parameter tests. In rats and chickens, these inferential statistical procedures clearly demonstrated a lead in phase of the 24-h cosine curves best fitting all of the duodenal vs. those best fitting all of the pineal melatonin values in each species in 2 geographic (geomagnetic) locations. The 24-h cosine curve of circulating melatonin was found to be in an intermediate phase position. Mechanisms of the phase differences and the contribution of gastrointestinal melatonin to circulating hormone concentrations are discussed.


Subject(s)
Chronobiology Phenomena , Circadian Rhythm/physiology , Duodenum/metabolism , Melatonin/metabolism , Pineal Gland/metabolism , Animals , Chickens , Data Interpretation, Statistical , Electromagnetic Fields , Geography , Male , Melatonin/blood , Rats , Rats, Wistar
11.
Biochemistry ; 40(49): 14995-5001, 2001 Dec 11.
Article in English | MEDLINE | ID: mdl-11732920

ABSTRACT

Inheritance of apoE4 is a strong risk factor for the development of late-onset sporadic Alzheimer's disease (AD). Several lines of evidence suggest that apoE4 binds to the Alzheimer Abeta protein and, under certain experimental conditions, promotes formation of beta-sheet structures and amyloid fibrils. Deposition of amyloid fibrils is a critical step in the development of AD. We report here that addition of melatonin to Abeta in the presence of apoE resulted in a potent isoform-specific inhibition of fibril formation, the extent of which was far greater than that of the inhibition produced by melatonin alone. This effect was structure-dependent and unrelated to the antioxidant properties of melatonin, since it could be reproduced neither with the structurally related indole N-acetyl-5-hydroxytryptamine nor with the antioxidants ascorbate, alpha-tocophenol, and PBN. The enhanced inhibitory effects of melatonin and apoE were lost when bovine serum albumin was substituted for apoE. In addition, Abeta in combination with apoE was highly neurotoxic (apoE4 > apoE3) to neuronal cells in culture, and this activity was also prevented by melatonin. These findings suggest that reductions in brain melatonin, which occur during aging, may contribute to a proamyloidogenic microenvironment in the aging brain.


Subject(s)
Amyloid beta-Peptides/metabolism , Apolipoproteins E/metabolism , Melatonin/pharmacology , Peptide Fragments/metabolism , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/ultrastructure , Animals , Apolipoprotein E4 , Apolipoproteins E/genetics , Astrocytes/drug effects , Astrocytes/metabolism , Cells, Cultured , Circular Dichroism , Humans , Mice , Mice, Knockout , Mice, Transgenic , Peptide Fragments/chemistry , Peptide Fragments/ultrastructure , Protein Structure, Secondary , Spectroscopy, Fourier Transform Infrared
12.
J Neural Transm (Vienna) ; 107(2): 203-31, 2000.
Article in English | MEDLINE | ID: mdl-10847561

ABSTRACT

This review summarizes recent advancements in our understanding of the potential role of the amyloid beta protein in Alzheimer's disease. It also discusses the significance of amyloid beta in initiating the generation of partially reduced oxygen species and points out their role in damaging essential macromolecules in the CNS which leads to neuronal dysfunction and loss. Recently acquired experimental data links these destructive oxidative processes with some neurodegenerative aspects of Alzheimer's disease. The experimental findings related to the free radical scavenging and antioxidative properties of melatonin are tabulated and its efficacy and the likely mechanisms involved in its ability to reduce neuronal damage mediated by oxygen-based reactive species in experimental models of Alzheimer's disease are summarized. Besides the direct scavenging properties and indirect antioxidant actions of melatonin, its ability to protect neurons probably also stems from its antiamyloidogenic properties. Melatonin is also unique because of the ease with which it passes through the blood-brain barrier.


Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Antioxidants/metabolism , Melatonin/metabolism , Alzheimer Disease/metabolism , Animals , Antioxidants/pharmacology , Free Radicals/metabolism , Humans , Melatonin/pharmacology , Neuroprotective Agents/metabolism , Neuroprotective Agents/pharmacology
13.
J Pineal Res ; 27(4): 226-9, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10551770

ABSTRACT

Most contemporary progress in Alzheimer's disease (AD) stems from the study of a 42 43 amino acid peptide. called the amyloid beta protein (Abeta), as the main neuropathologic marker of the disorder. It has been demonstrated that Abeta has neurotoxic properties and that such effects are mediated by free-radicals. Exposure of neuronal cells to Abeta results in a spectrum of oxidative lesions that are profoundly harmful to neuronal homeostasis. We had previously shown that Abeta25-35 induces oxidative damage to mitochondrial DNA (mtDNA) and that this modality of injury is prevented by melatonin. Because Abeta25 35 does not occur in AD and because the mode of toxicity by Abeta25-35 may be different from that of Abeta1-42 (the physiologically relevant form of Abeta), we extended our initial observations to determine whether oxidative damage to mtDNA could also be induced by Abeta1-42 and whether this type of injury is prevented by melatonin. Exposure of human neuroblastoma cells to Abeta1-42 resulted in marked oxidative damage to mtDNA as determined by a quantitative polymerase chain reaction method. Addition of melatonin to cell cultures along with Abeta completely prevented the damage. This study supports previous findings with Abeta25-35, including a causative role for Abeta in the mitochondrial oxidative lesions present in AD brains. Most important, the data confirms the neuroprotective role of melatonin in Abeta-mediated oxidative injury. Because melatonin also inhibits amyloid aggregation, lacks toxicity, and efficiently crosses the blood-brain barrier, this hormone appears superior to other available antioxidants as a candidate for pharmacologic intervention in AD.


Subject(s)
Amyloid beta-Peptides/metabolism , DNA Damage , DNA, Mitochondrial/drug effects , DNA, Mitochondrial/metabolism , Melatonin/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/etiology , Alzheimer Disease/metabolism , Antioxidants/pharmacology , Base Sequence , Cell Line , DNA Primers/genetics , Humans , Oxidative Stress
14.
J Biol Chem ; 274(31): 21937-42, 1999 Jul 30.
Article in English | MEDLINE | ID: mdl-10419516

ABSTRACT

Widespread cerebral deposition of a 40-43-amino acid peptide called the amyloid beta-protein (Abeta) in the form of amyloid fibrils is one of the most prominent neuropathologic features of Alzheimer's disease. Numerous studies suggest that Abeta is toxic to neurons by free radical-mediated mechanisms. We have previously reported that melatonin prevents oxidative stress and death of neurons exposed to Abeta. In the process of screening indole compounds for neuroprotection against Abeta, potent neuroprotective properties were uncovered for an endogenous related species, indole-3-propionic acid (IPA). This compound has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. IPA completely protected primary neurons and neuroblastoma cells against oxidative damage and death caused by exposure to Abeta, by inhibition of superoxide dismutase, or by treatment with hydrogen peroxide. In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity. These findings may have therapeutic applications in a broad range of clinical situations.


Subject(s)
Amyloid beta-Peptides/toxicity , Hippocampus/cytology , Indoles/pharmacology , Lipid Peroxidation/drug effects , Melatonin/pharmacology , Neurons/drug effects , Neuroprotective Agents/pharmacology , Animals , Antioxidants/pharmacology , Cell Survival/drug effects , Cells, Cultured , Fetus , Hippocampus/physiology , Humans , Hydroxyl Radical/metabolism , Indoles/metabolism , Neuroblastoma , Neurons/cytology , Neurons/physiology , Oxidants/pharmacology , PC12 Cells , Rats , Tumor Cells, Cultured
15.
Arch Med Res ; 30(2): 125-7, 1999.
Article in English | MEDLINE | ID: mdl-10372446

ABSTRACT

BACKGROUND: The noncompetitive NMDA antagonists phencyclidine (PCP) and dizocilpine (MK-801) have been considered for use as neuroprotective therapeutic agents, although both produce injury in neurons of cingulate and retrosplenial cortices in rodents. The low-affinity, noncompetitive NMDA antagonist dextrorphan has been considered for use as a neuroprotective therapeutic drug. The aim of the present work was to evaluate the neurotoxicity of dextrorphan. METHODS: Sprague-Dawley male rats were used and injected with either saline or dextrorphan (30 mg/kg i.p.). The animals were sacrificed 30 min later, and the brain was examined for histopathological changes. RESULTS: After systemic administration of the drug, hyperchromatic and shrunken nuclei with chromatin condensation and disruption were observed. Also, granular and vacuolated cytoplasm was apparent in pyramidal neurons in the retrosplenial (posterior cingulate) cortex. Status spongiosus (spongy degeneration) of the neuropil was also detected. CONCLUSIONS: Morphological changes are similar to those described previously, which are induced by high-affinity, noncompetitive NMDA antagonists, such as MK-801.


Subject(s)
Dextrorphan/adverse effects , Neuroprotective Agents/adverse effects , Animals , Brain/drug effects , Male , Neurons/drug effects , Rats , Rats, Sprague-Dawley
16.
Brain Res ; 815(2): 382-8, 1999 Jan 09.
Article in English | MEDLINE | ID: mdl-9878843

ABSTRACT

The hydroxyl radical scavenging activity of indole-3-propionate was evaluated by kinetic competition studies with the hydroxyl radical trapping reagent 2,2'-azino-bis-(3-ethyl-benz-thiazoline-6-sulfonic acid) (ABTS) and by measuring hydroxyl radical-initiated lipid peroxidation in the rat striatum. Using ABTS, the indole was shown to act as a potent hydroxyl radical scavenger with a rate constant of 7.8x1010 mol l-1 s-1. Hydroxyl radical-initiated lipid peroxidation, determined by measuring tissue malondialdehyde formation, was inhibited dose-dependently both in vitro and in vivo. Indole-3-propionate reacts with hydroxyl radicals at a diffusion controlled rate and can thereby provide on-site protection against the oxidative damage of biomolecules induced by these highly reactive and toxic oxygen intermediates. While it remains to be established if endogenous brain tissue levels of indole-3-propionate are sufficiently high to have a significant impact on total antioxidative capacity, the compound itself or a structurally related agent may be useful as an antioxidant adjuvant to combat hydroxyl radical-mediated oxidative stress.


Subject(s)
Brain/metabolism , Free Radical Scavengers/pharmacokinetics , Hydroxyl Radical/pharmacokinetics , Indoles/pharmacokinetics , Animals , Benzothiazoles , Cations/antagonists & inhibitors , Corpus Striatum/drug effects , Free Radical Scavengers/antagonists & inhibitors , Indicators and Reagents , Indoles/administration & dosage , Indoles/pharmacology , Injections, Intraperitoneal , Lipid Peroxidation/drug effects , Male , Rats , Rats, Sprague-Dawley , Sulfonic Acids/antagonists & inhibitors
17.
Adv Exp Med Biol ; 467: 113-23, 1999.
Article in English | MEDLINE | ID: mdl-10721048

ABSTRACT

Using in vivo and in vitro paradigms, the regulation and function of the brain metabolite kynurenic acid (KYNA) was examined in rats on postnatal days (PND) 7 and 14. As shown previously in adult rats, glucose removal and d-amphetamine (d-Amph) administration caused decreases in KYNA formation, while exposure to pyruvate up-regulated KYNA synthesis. The effect of glucose deprivation was substantially blunted in immature animals. In PND 14 rats, d-Amph pre-treatment exacerbated the excitotoxic effects of an intrastriatal N-methyl-D-aspartate (NMDA) injection. This potentiation was prevented by m-nitrobenzoylalanine, a kynurenine 3-hydroxylase inhibitor that also antagonized the KYNA reduction caused by d-Amph. These and additional experiments with the competitive NMDA receptor antagonist CGP 40116 indicate the existence of a functionally significant, novel high-affinity receptor for KYNA in the brain.


Subject(s)
Brain/physiology , Kynurenic Acid/metabolism , 2-Amino-5-phosphonovalerate/analogs & derivatives , 2-Amino-5-phosphonovalerate/pharmacology , Aging/metabolism , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Brain/drug effects , Brain/growth & development , Dextroamphetamine/pharmacology , Enzyme Inhibitors/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Glucose/metabolism , Kynurenine 3-Monooxygenase , Male , Microdialysis , Mixed Function Oxygenases/antagonists & inhibitors , N-Methylaspartate/pharmacology , Neurons/drug effects , Neurons/physiology , Pyruvates/pharmacology , Rats , Rats, Sprague-Dawley
18.
Adv Exp Med Biol ; 467: 389-95, 1999.
Article in English | MEDLINE | ID: mdl-10721080

ABSTRACT

Chemiluminescence associated with oxidation by free radicals was investigated in an alkaline, hemin-catalysed hydrogen peroxide system, using the following tryptophan metabolites as radical scavengers: indole-3-pyruvic, indole-3-propionic, kynurenic, xanthurenic and quinaldic acids and 4-hydroxy-quinoline. Light emission from oxidation of the indolic compounds was only partially inhibited by the hydroxyl-radical scavenger DMSO, but strongly suppressed by the superoxide-anion scavenger Tiron, whereas chemi-luminescence generated from kynurenic acid was strongly inhibited by either of these compounds. Light emission from oxidation of kynurenic acid lasts for a surprisingly long period of time: At 0.4 mM and 20 degrees C, luminescence increased for 5 hours and continued at a high rate for more than a day. Comparison of structural analogues indicated that the 4-hydroxyl and carboxyl groups of kynurenic acid are essential for effective light emission, and that an additional 8-hydroxyl residue leading to an intramolecular hydrogen bond diminishes the reaction rate.


Subject(s)
Free Radical Scavengers/chemistry , Indoles/chemistry , Kynurenic Acid/chemistry , Dimethyl Sulfoxide , Indicators and Reagents , Kinetics , Luminescent Measurements , Oxidation-Reduction
19.
Brain Res ; 802(1-2): 111-8, 1998 Aug 17.
Article in English | MEDLINE | ID: mdl-9748528

ABSTRACT

Tissue levels of the endogenous excitatory amino acid receptor antagonist kynurenic acid (KYNA) and of its bioprecursor L-kynurenine were measured in rats of different ages after d-amphetamine administration. In adult animals, extracellular KYNA concentrations were also determined in vivo by hippocampal microdialysis. In the adult brain, d-amphetamine caused a transient, dose-dependent decrease in tissue content and extracellular levels of KYNA, reaching a nadir of approximately 70% of control values after 1 h at 5 mg/kg. Quantitatively similar decrements were observed in four different brain regions. Seven, 14 and 28-day-old pups were particularly sensitive to the drug, showing a reduction in forebrain KYNA levels to 25%, 40% and 35% of control values, respectively, 1 h after the administration of 5 mg/kg d-amphetamine. Notably, no changes in brain L-kynurenine levels and in liver L-kynurenine and KYNA concentrations were found after d-amphetamine administration. Thus, endogenous monoamines released by d-amphetamine may interfere with the transamination of L-kynurenine to KYNA specifically in the brain. These results suggest that d-amphetamine increases excitatory amino acid receptor function temporarily by reducing the levels of endogenous KYNA.


Subject(s)
Brain/metabolism , Central Nervous System Stimulants/pharmacology , Dextroamphetamine/pharmacology , Excitatory Amino Acid Antagonists/metabolism , Kynurenic Acid/antagonists & inhibitors , Animals , Animals, Newborn/growth & development , Animals, Newborn/metabolism , Extracellular Space/metabolism , Kynurenine/metabolism , Liver/metabolism , Male , Rats , Rats, Sprague-Dawley , Tissue Distribution
20.
Dev Neurosci ; 20(2-3): 146-53, 1998.
Article in English | MEDLINE | ID: mdl-9691189

ABSTRACT

This study was designed to examine the effects of d-amphetamine (D-AMPH) and D1- and D2-selective dopaminergic drugs on the concentration of the broad-spectrum excitatory amino acid receptor antagonist kynurenic acid (KYNA) in the striatum of developing and adult rats. At all ages, KYNA levels were significantly reduced 1 h after the systemic administration of D-AMPH (5 mg/kg). SKF 38393 (5 mg/kg) and quinpirole (2 mg/kg) also caused a rapid decrease in striatal KYNA, but only in postnatal day (PND) 7 and 14 rats. All these effects were readily prevented by specific dopamine receptor antagonists. The possible functional significance of the reduction in KYNA levels was tested in PND 14 animals. When pretreated with D-AMPH (5 mg/kg), these rats showed markedly increased vulnerability to an intrastriatal injection of the excitotoxin NMDA. These data suggest that KYNA plays a role as a mediator of dopamine-glutamate interactions in the rat striatum.


Subject(s)
Aging/physiology , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dopamine/pharmacology , Excitatory Amino Acid Agonists/poisoning , Kynurenic Acid/metabolism , N-Methylaspartate/poisoning , Animals , Animals, Newborn/growth & development , Animals, Newborn/physiology , Corpus Striatum/growth & development , Dextroamphetamine/pharmacology , Dopamine Agents/pharmacology , Dopamine Antagonists/pharmacology , Haloperidol/pharmacology , Injections , Ligands , Male , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism
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