RESUMO
BACKGROUND: Early life trauma is an important risk factor for many psychiatric and somatic disorders in adulthood. As a growing body of evidence suggests that brain plasticity is disturbed in affective disorders, we examined the short-term and remote effects of early life stress on different forms of brain plasticity. METHODOLOGY/PRINCIPAL FINDINGS: Mice were subjected to early deprivation by individually separating pups from their dam in the first two weeks after birth. Distinct forms of brain plasticity were assessed in the hippocampus by longitudinal MR volumetry, immunohistochemistry of neurogenesis, and whole-cell patch-clamp measurements of synaptic plasticity. Depression-related behavior was assessed by the forced swimming test in adult animals. Neuropeptides and their receptors were determined by real-time PCR and immunoassay. Early maternal deprivation caused a loss of hippocampal volume, which returned to normal in adulthood. Adult neurogenesis was unaffected by early life stress. Long-term synaptic potentiation, however, was normal immediately after the end of the stress protocol but was impaired in adult animals. In the forced swimming test, adult animals that had been subjected to early life stress showed increased immobility time. Levels of substance P were increased both in young and adult animals after early deprivation. CONCLUSION: Hippocampal volume was affected by early life stress but recovered in adulthood which corresponded to normal adult neurogenesis. Synaptic plasticity, however, exhibited a delayed impairment. The modulation of synaptic plasticity by early life stress might contribute to affective dysfunction in adulthood.
Assuntos
Plasticidade Neuronal/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Comportamento Animal , Regulação para Baixo , Feminino , Hipocampo/patologia , Hipocampo/fisiopatologia , Resposta de Imobilidade Tônica , Potenciação de Longa Duração/fisiologia , Masculino , Privação Materna , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese , Neuropeptídeos/metabolismo , Substância P/metabolismo , NataçãoRESUMO
Early life stress predisposes to the development of psychiatric disorders. In this context the hippocampal formation is of particular interest, because it is affected by stress on the structural and cognitive level. Since little is known how early life stress is translated on the molecular level, we mimicked early life stress in mouse models and analyzed the expression of the glycoprotein Reelin, a master molecule for development and differentiation of the hippocampus. From postnatal day 1 (P1) to P14, mouse pups were subjected to one of the following treatments: nonhandling (NH), handling (H), maternal separation (MS), and early deprivation (ED) followed by immediate (P15) or delayed (P70) real time RT-PCR analysis of reelin mRNA expression. We show that at P15, reelin mRNA levels were significantly increased in male H and ED groups when compared with the NH group. In contrast, no stress-induced alterations of reelin mRNA expression were found in female animals. This sex difference in stress-mediated stimulation of reelin expression was maintained into adulthood, since at P70 intergroup differences were still found in male, but not in female mice. On the cellular level, however, we did not find any significant differences in cell densities of Reelin-immunolabeled neurons between treatment groups or sexes, but an overall reduction of Reelin-expressing neurons in the adult hippocampus when compared to P15. To address the question whether corticosterone mediates the stress-induced up-regulation of reelin gene expression, we used age-matched hippocampal slice cultures derived from male and female mouse pups. Quantitative determination of mRNA levels revealed that corticosterone treatment significantly up-regulated reelin mRNA expression in male, but not in female hippocampi. Taken together, these results show a sex-specific regulation of reelin gene expression by early life experience, most likely mediated by corticosterone.
Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Corticosterona/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Hipocampo/metabolismo , Privação Materna , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/metabolismo , Estresse Psicológico/metabolismo , Animais , Moléculas de Adesão Celular Neuronais/genética , Contagem de Células , Corticosterona/farmacologia , Proteínas da Matriz Extracelular/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína Reelina , Serina Endopeptidases/genética , Fatores Sexuais , Estresse Psicológico/genéticaRESUMO
Associative long-term depression (LTD) in the hippocampus is a form of spike time-dependent synaptic plasticity that is induced by the asynchronous pairing of postsynaptic action potentials and EPSPs. Although metabotropic glutamate receptors (mGluRs) and postsynaptic Ca(2+) signaling have been suggested to mediate associative LTD, mechanisms are unclear further downstream. Here we show that either mGluR1 or mGluR5 activation is necessary for LTD induction, which is therefore mediated by group I mGluRs. Inhibition of postsynaptic phospholipase C, inositol-1,4,5-trisphosphate, and PKC prevents associative LTD. Activation of PKC by a phorbol ester causes a presynaptic potentiation of synaptic responses and facilitates LTD induction by a postsynaptic mechanism. Lithium, an inhibitor of the PKC pathway, inhibits LTD and the presynaptic and postsynaptic effects of the phorbol ester. Furthermore, LTD is sensitive to the postsynaptic application of synthetic peptides that inhibit the interaction of AMPA receptors with PDZ domains, suggesting an involvement of protein interacting with C-kinase 1 (PICK1)-mediated receptor endocytosis. Finally, enhanced PKC phosphorylation, induced by behavioral stress, is associated with enhanced LTD. Both increased PKC phosphorylation and stress-induced LTD facilitation can be reversed by lithium, indicating that this clinically used mood stabilizer may act on synaptic depression via PKC modulation. These data suggest that PKC mediates the expression of associative LTD via the PICK1-dependent internalization of AMPA receptors. Moreover, modulation of the PKC activity adjusts the set point for LTD induction in a behavior-dependent manner.
Assuntos
Hipocampo/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Transdução de Sinais/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , Inositol 1,4,5-Trifosfato/antagonistas & inibidores , Compostos de Lítio/farmacologia , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Domínios PDZ/efeitos dos fármacos , Ésteres de Forbol/farmacologia , Fosforilação/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Proteína Quinase C/fisiologia , Ratos , Ratos Wistar , Receptores de Glutamato Metabotrópico/agonistas , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/metabolismo , Fatores de Tempo , Fosfolipases Tipo C/antagonistas & inibidoresRESUMO
There is evidence from human and animal studies that substance P (SP) is involved in the etiopathology of depression and anxiety. Furthermore, animal studies have shown effects of SP on memory. In a double-blind, randomized cross-over study, 13 healthy young men received SP (1.5 pmol/kg/min) or placebo (NaCl) intravenously over 90 min at two different days. Before and during the infusion, symptoms of anxiety and depression were assessed by different self-rating questionnaires and cognitive functioning by the Auditory-Verbal Learning Test (AVLT) as well as by two subtests of the Test for Attentional Performance (TAP). Infusion of SP caused an increase of symptoms of inner tension and of anxiety as assessed by the Acute Panic Inventory (API) and a disturbance of short-term memory in the AVLT. The results may be interpreted as evidence for an anxiogenic and memory-disturbing effect of SP. Further studies will focus on the effects of SP in patients with depression, anxiety and cognitive disorders.
Assuntos
Afeto/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Substância P/farmacologia , Adulto , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Atenção/efeitos dos fármacos , Sistema Nervoso Autônomo/efeitos dos fármacos , Estudos Cross-Over , Depressão/induzido quimicamente , Depressão/psicologia , Método Duplo-Cego , Humanos , Infusões Intravenosas , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Testes Neuropsicológicos , Inventário de Personalidade , Vasodilatação/efeitos dos fármacosRESUMO
The neuropeptide substance P (SP) has been found to be possibly involved in the etiology of affective and anxiety disorders. However, the molecular mechanisms underlying this involvement are still poorly understood. In this study, we used macroarrays to investigate the differential gene expression profile induced by SP, particularly of genes which have been shown to be involved in the pathophysiology of affective disorders. As a model system, we used the human astrocytoma cell line U373 MG as well as primary rat astroglial cells, which both are known to express functional neurokinin-1 receptors (NK-1-R) and to secret various cytokines upon stimulation with SP. Among several regulated genes, we found that SP (100 and 1000 nM) induced the expression of the corticotropin-releasing factor receptor 1 (CRF1 receptor). Further analyses revealed that this induction was mediated (a) via NK-1-R, as the selective NK-1-R-antagonist L-733,060 (1 microM) strongly inhibited SP-induced CRF1 receptor expression, and (b) intracellularly, by protein kinase C, p42/44 and p38 mitogen-activated protein kinases (MAPK), as shown by using specific inhibitors of signal transduction pathways. In conclusion, this study demonstrates that SP induces CRF1 receptor expression in cells of the CNS, which may be of potential interest for a better understanding of the interplay between SP and the stress hormone axis and, thus, diseases like affective or anxiety disorders. Further studies are needed to substantiate this link in vivo.
Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores da Neurocinina-1/metabolismo , Substância P/farmacologia , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Astrocitoma , Western Blotting/métodos , Células Cultivadas , Relação Dose-Resposta a Droga , Interações Medicamentosas , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Imidazóis/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Piperidinas/farmacologia , Piridinas/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fatores de TempoRESUMO
Psychosocial stress has been shown to induce inflammatory reactions, followed by the release of immunosuppressive glucocorticoids. This may be mediated by catecholamines or other stress reactive substances such as neuropeptides or cytokines. We here set out to explore the effects of acute psychosocial stress on plasma levels of substance P (SP), a possible mediator of stress-induced inflammatory reactions, and interleukin-1 receptor antagonist (IL-1ra). Twelve healthy male subjects (mean age 27 yrs.) were subjected to the psychosocial stress test "Trier Social Stress Test" (TSST) and a resting control condition. Blood and saliva samples were taken before, as well as 1, 20, 45, and 90 min after TSST or rest, respectively. Salivary cortisol and plasma SP and IL-1ra were measured using immunoassays, salivary alpha-amylase (sAA) was measured by an enzyme kinetic method, and plasma epinephrine (E) and norepinephrine (NE) were measured by HPLC. The TSST induced immediate increases of E, NE, and sAA, and a delayed increase of free cortisol. Plasma IL-1ra showed an even further delayed peak at 90 min after stress. Plasma levels of SP did not respond to stress. No significant associations between changes of stress hormones and IL-1ra or SP were found. We conclude that substance P, epinephrine, and norepinephrine are probably not involved in mediating peripheral inflammation following psychosocial stress, at least with respect to IL-1ra. Further studies have to reveal the mechanisms involved in the stress-induced up regulation of IL-1ra.
Assuntos
Sialoglicoproteínas/sangue , Estresse Psicológico/metabolismo , Substância P/sangue , Doença Aguda , Adulto , Afeto/fisiologia , Área Sob a Curva , Biomarcadores , Glândulas Endócrinas/fisiopatologia , Epinefrina/sangue , Humanos , Hidrocortisona/sangue , Inflamação/sangue , Inflamação/metabolismo , Proteína Antagonista do Receptor de Interleucina 1 , Masculino , Norepinefrina/sangue , Saliva/enzimologia , Meio Social , alfa-Amilases/metabolismoRESUMO
The neuropeptide substance P (SP) and its receptor, the neurokinin receptor-1 (NK-1), have been associated with some aspects of the pathophysiology of depression. There is limited information available about the effects of antidepressant treatment on serum and cerebrospinal fluid (CSF) concentrations of SP. We measured serum levels of SP in 78 depressed patients after a 6-day medication washout period, as well as after 14 and 35 days of antidepressant treatment with either paroxetine or amitriptyline. In 11 patients, SP was determined in CSF both before and after treatment. Eleven healthy male subjects served as controls. Baseline SP concentrations were independent of age, gender and severity of depression. Neither the total group nor subgroups showed significant differences in SP serum concentrations. SP concentrations in CSF did not change significantly in the patients during treatment, but there was a trend for an increase in paroxetine-treated patients. Serum SP concentrations were not related to treatment response or the class of antidepressant administered. Our data do not support the hypothesis that changes in SP levels in serum or CSF are related to antidepressant response.
Assuntos
Amitriptilina/uso terapêutico , Antidepressivos Tricíclicos/uso terapêutico , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior , Substância P/sangue , Substância P/líquido cefalorraquidiano , Adulto , Idoso , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Receptores da Neurocinina-1/metabolismo , Índice de Gravidade de DoençaRESUMO
Some studies have demonstrated antidepressant activity of neurokinin-1-receptor antagonists (NK-1-RA) in major depressive disorder. However, the underlying mechanisms of this antidepressant effect are largely unknown. Preclinical studies in rats and mice have suggested that NK-1-RA do increase the neuronal release of serotonin (5-HT). This, however, seems to be compensated by an increased 5-HT reuptake, indicating that NK-1-RA have no inhibitory effect on the 5-HT transporter in rodents. Given the possibility that modulation of neurotransmitter release and reuptake may differ between species, with major differences found between rodents and humans, we investigated for the first time the possible modulatory effect of NK-1-RA on 5-HT uptake in human brain synaptosomes and compared it with the situation in rat cortex. We found that the specific human NK-1-RA L-733060, in contrast to the SSRI fluvoxamine (IC50=10(-7.96)M) did not inhibit 5-HT uptake in human brain synaptosomes and did not modulate fluvoxamine-induced 5-HT uptake inhibition at 1 muM. Furthermore, substance P as well as Sar9Met(O2)11SP, as the major agonists at the NK-1-R, did not modulate 5-HT uptake in human brain synaptosomes. Similar results were found in rat cortex synaptosomes by using the rat-specific NK-1-RA WIN51708. These results show that in humans, as in rodents, inhibition of the 5-HT transporter is probably not the underlying mechanism of the assumed antidepressant activity of NK-1-RA.
Assuntos
Química Encefálica/efeitos dos fármacos , Antagonistas dos Receptores de Neurocinina-1 , Serotonina/metabolismo , Sinaptossomos/metabolismo , Adolescente , Adulto , Idoso , Androstanos/farmacologia , Animais , Benzimidazóis/farmacologia , Western Blotting , Criança , Pré-Escolar , Feminino , Fluvoxamina/farmacologia , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Neocórtex/efeitos dos fármacos , Neocórtex/metabolismo , Ratos , Ratos Wistar , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Substância P/metabolismo , Sinaptossomos/efeitos dos fármacosRESUMO
Increasing evidence suggests that substance P (SP) and its receptor (neurokinin [NK]-1 receptor [NK1R]) might play an important role in the modulation of stress-related, affective and/or anxious behaviour. First, SP and NK1R are expressed in brain regions that are involved in stress, fear and affective response (e.g. amygdala, hippocampus, hypothalamus and frontal cortex). Second, the SP content in these areas changes upon application of stressful stimuli. Third, the central administration of SP produces a range of fear-related behaviours. In addition, the SP/NK1R system shows significant spatial overlap with neurotransmitters such as serotonin and noradrenaline (norepinephrine), which are known to be involved in the regulation of stress, mood and anxiety. Therefore, it was hypothesised that blockade of the NK1R might have anxiolytic as well as antidepressant effects. Preclinical studies investigating the effects of genetic or pharmacological NK1R inactivation on animal behaviour in assays relevant to depression and anxiety revealed that the behavioural changes resemble those seen with reference antidepressant or anxiolytic drugs. Furthermore, antagonism or genetic inactivation of the NK1R causes alterations in serotonin and norepinephrine neuronal transmission that are likely to contribute to the antidepressant/anxiolytic activity of NK1R antagonists but that are--at least partially--distinct from those produced by established antidepressant drugs. This underlines the conceivable unique mechanism of action of this new class of compounds. In three independent clinical trials with three different compounds (aprepitant [MK-869], L-759274 and CP-122721), an antidepressant effect of NK1R antagonists could be demonstrated. These results, however, have been challenged by recent failed studies with aprepitant. There are numerous indications from preclinical studies that, in addition to SP and NK1R, other neurokinins and/or neurokinin receptors might also be involved in the modulation of stress-related behaviour and that exclusive blockade of the NK1R might not be sufficient to produce consistent anxiolytic and antidepressant effects. One such candidate is the neurokinin-2 receptor (NK2R), and clinical trials to assess the antidepressant effects of NK2R antagonists are currently underway. Of special interest might also be substances that block more than one receptor type such as NK1/2R antagonists or NK1/2/3R antagonists. These compounds may be more efficacious in antagonising the effects of SP than compounds that only block the NK1R.
Assuntos
Ansiolíticos/uso terapêutico , Antidepressivos/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Antagonistas dos Receptores de Neurocinina-1 , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Antidepressivos/química , Antidepressivos/farmacologia , Humanos , Transtornos Mentais/psicologia , Receptores da Neurocinina-1/fisiologiaRESUMO
In behavioural screens, mice lacking functional NK1 receptors (NK1-/-) resemble wildtypes (NK1+/+) that have been given an antianxiety/antidepressant drug. Most, if not all, antidepressants increase noradrenergic transmission in the brain. Here, we have used in vivo microdialysis to compare the concentrations of extracellular noradrenaline ('efflux') in the cerebral cortex of anaesthetised NK1-/- and NK1+/+ mice. The effects of systemic administration of the antidepressant, desipramine, with and without local infusion of the alpha(2)-adrenoceptor antagonist, RX821002, were also evaluated. Finally, we compared the effects of desipramine on behaviour of NK1+/+ and NK1-/- mice in an activity chamber and in a light/dark exploration box. Basal noradrenaline efflux was increased 2 to 4-fold in NK1-/- mice compared with NK1+/+ mice but there was no difference in the effects of desipramine. RX821002 increased noradrenaline efflux in all vehicle-injected mice but, in desipramine-pretreated mice, noradrenaline efflux was increased in NK1+/+ mice, only. All behaviours in the light/dark exploration box differed in the two genotypes. Furthermore, with the exception of 'grooming', the effects of desipramine on behaviour of NK1-/- mice could be explained by the effects of this antidepressant on locomotor activity. Finally, alpha(2)-adrenoceptors are possibly desensitised in NK1-/- mice. We have yet to establish whether this is a cause or a consequence of the increased noradrenaline efflux.
Assuntos
Córtex Cerebral/metabolismo , Comportamento Exploratório/fisiologia , Espaço Extracelular/metabolismo , Idazoxano/análogos & derivados , Camundongos Knockout/fisiologia , Norepinefrina/metabolismo , Receptores da Neurocinina-1/deficiência , Antagonistas Adrenérgicos alfa/administração & dosagem , Análise de Variância , Animais , Área Sob a Curva , Comportamento Animal/fisiologia , Córtex Cerebral/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Desipramina/administração & dosagem , Interações Medicamentosas , Eletroquímica/métodos , Inibidores Enzimáticos/administração & dosagem , Comportamento Exploratório/efeitos dos fármacos , Espaço Extracelular/efeitos dos fármacos , Idazoxano/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microdiálise/métodos , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Tempo de Reação/efeitos dos fármacos , Fatores de TempoRESUMO
The neuropeptide substance P (SP) has been suggested to be involved in several physiological and pathological conditions including learning and memory and the processing of pain. This study investigated for the first time acute effects of SP and the neurokinin-1 (NK-1) receptor antagonist L-733060 on long term potentiation (LTP) in the hippocampus. Electrically evoked fEPSP was tested under the influence of SP in the CA1 region of the guinea pig hippocampus. Concentrations of 1 and 10 microM SP increased fEPSP slopes to 114.3+/-4.5% and 115.8+/-2.7%, respectively. A threshold concentration was found at 0.1 microM SP. The SP-specific NK-1 receptor antagonist L-733060 did not influence fEPSP in a concentration of 1 microM. In experiments with LTP, a significant increase of potentiations after 60 min was seen with 1 microM SP. Even if the initial baseline increase due to SP (1 microM) was subtracted, potentiations were bigger compared to controls. L-733060 (1 microM) suppressed the excitatory effects of 1 microM SP nearly complete and subsequent induced LTP was not increased. In conclusion, SP has excitatory effects in the hippocampus and is able to facilitate LTP via activation of the NK-1 receptor.
Assuntos
Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/farmacologia , Substância P/farmacologia , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Estimulação Elétrica/métodos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos da radiação , Feminino , Cobaias , Hipocampo/fisiologia , Técnicas In Vitro , Potenciação de Longa Duração/efeitos da radiação , Substância P/antagonistas & inibidores , Fatores de TempoRESUMO
Substance P (SP) is a neuropeptide which is widely distributed in the periphery and the central nervous system (CNS), where it is co-localised with other neurotransmitters such as serotonin or dopamine and where it acts as a neuromodulator. SP has been proposed to play a role in the aetiopathology of asthma, inflammatory bowel disease, emesis, psoriasis, as well as neuropsychiatric disorders including pain syndromes (e.g. migraine and fibromyalgia) and affective disorders, anxiety disorders, schizophrenia and Alzheimer's disease. This review focuses on the role of SP in the pathogenesis of affective disorders. It summarises the current knowledge on measurements of SP in the CSF and serum in patients with depressive disorders or fibromyalgia, effects of SP-application in humans, SP-receptor expression in postmortem brains and the modulation of SP levels in the course of antidepressant treatment. It also discusses the promise of substance P-receptor antagonists (SPA) for the treatment of affective disorders and their proposed mechanism of action. In summary, much more research is needed to elucidate the role of SP in the pathogenesis of depression. SPA are promising as future drugs for the treatment of affective disorders, but current clinical trials have yet to be completed to draw a firm conclusion. Key words: substance P, neurokinin1-receptor, affective disorders, depression, review.
Assuntos
Antidepressivos/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/metabolismo , Antagonistas dos Receptores de Neurocinina-1 , Substância P/fisiologia , Animais , Humanos , Polimorfismo Genético , Renina/genética , Renina/metabolismo , Substância P/metabolismoRESUMO
Low density lipoprotein (LDL) oxidation within the artery wall likely represents a key event in the formation of atherosclerotic lesions. Oxidatively modified LDL particles exert chemotactic properties on macrophages, and the uncontrolled uptake of modified LDL by macrophages leads to the formation of lipid-loaded foam cells, a hallmark of early stage atherosclerosis. Human macrophages stimulated by interferon-gamma generate reactive oxygen species (ROS), neopterin, and 7,8-dihydroneopterin. Higher concentrations of neopterin were found in atherosclerosis, and earlier studies have provided evidence that these neopterin derivatives are able to interfere with reactive species. We therefore investigated whether they also modulate LDL oxidation mediated by Cu(II) and/or peroxynitrite (ONOO-). By means of UV-absorption recording the formation of conjugated dienes in the course of lipid oxidation as well as by measuring the relative electrophoretic mobility of oxidized LDL, we found that neopterin is capable of enhancing ONOO- - as well as Cu(II)-mediated LDL oxidation, whereas 7,8-dihydroneopterin mainly protects LDL from oxidation. However, in case of Cu(II)-mediated LDL oxidation, an initial prooxidative effect of 7,8-dihydroneopterin could be observed. We hypothesize that 7,8-dihydroneopterin may chemically reduce Cu(II) to Cu(I) thereby increasing its oxidative capacity. After total reduction of Cu(II), excess 7,8-dihydroneopterin may block the oxidative potential of Cu(I) and thus decrease the oxidation of LDL. These findings confirm the general behavior of pteridines in redox processes and suggest an in vivo contribution to the process of LDL oxidation.