Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: role of nitric oxide as a signal crossing the blood–brain barrier

Kitagami, Tomitsune; Yamada, Kiyofumi; Matsui, Hideki; Hashimoto, Ryo; Nabeshima, Toshitaka; Ohta, Tatsuro

doi:10.1016/s0006-8993(03)02776-8

Cited by 128 publications

(100 citation statements)

References 69 publications

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“…As described above, data in laboratory animals and humans indicate that dopamine is a primary target of the effects of inflammation on the brain. These findings have been manifested by alterations in dopamine metabolism following the administration of inflammatory stimuli as well as the presence of decreased effort-based motivation for reward (Kitagami et al, 2003;Felger et al, 2013bFelger et al, , 2015. In addition, increased peripheral CRP in patients with major depression has been associated with symptoms of anhedonia as well as psychomotor retardation that is mediated by inflammation-induced alterations in functional connectivity between ventral and dorsal striatum and ventromedial prefrontal cortex .…”

Section: Reviewmentioning

confidence: 99%

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

Miller

Haroon

Felger

2016

Neuropsychopharmacol

118

124

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A wealth of data has been amassed that details a complex, yet accessible, series of pathways by which the immune system, notably inflammation, can influence the brain and behavior. These data have opened the window to a diverse array of novel targets whose potential efficacy is tied to specific neurotransmitters and neurocircuits as well as specific behaviors. What is clear is that the impact of inflammation on the brain cuts across psychiatric disorders and engages dopaminergic and glutamatergic pathways that regulate motivation and motor activity as well as the sensitivity to threat. Given the ability to identify patient populations with increased inflammation, the precision of interventions can be further tuned, in conjunction with the ability to establish target engagement in the brain through the use of multiple neuroimaging strategies. After a brief overview of the mechanisms by which inflammation affects the brain and behavior, this review examines the extant literature on the efficacy of anti-inflammatory treatments, while forging guidelines for future intelligent clinical trial design. An examination of the most promising therapeutic strategies is also provided, along with some of the most exciting clinical trials that are currently being planned or underway.

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Section: Reviewmentioning

confidence: 99%

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

Miller

Haroon

Felger

2016

Neuropsychopharmacol

118

124

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“…9 A direct connection between IFN-a and human CNS disorders came from recent clinical observations in which chronic, high-dose IFN-a therapy was frequently found to lead to severe neurotoxicity and neuropsychiatric complications such as agitation, depression, anxiety and memory loss in as high as 30-45% of patients. 10,11 Depression-and anxiety-like behaviors, associated with disturbances in monoamine neurotransmission 12 following systemic IFN-a treatment, have also been reported in rodents. 6,13 In search of the molecular basis for neuromodulatory actions, especially neuropsychiatric complications associated with systemic IFN-a, recent positron emission tomography and functional magnetic resonance imaging have recorded metabolic changes from patients undergoing IFN-a therapy in several parts of the brain.…”

Section: Introductionmentioning

confidence: 97%

Systemic interferon-α regulates interferon-stimulated genes in the central nervous system

2007

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The prime anti-viral cytokine interferon-a (IFN-a) has been implicated in several central nervous system (CNS) disorders in addition to its beneficial effects. Systemic IFN-a treatment causes severe neuropsychiatric complications in humans, including depression, anxiety and cognitive impairments. While numerous neuromodulatory effects by IFN-a have been described, it remains unresolved whether or not systemic IFN-a acts directly on the brain to execute its CNS actions. In the present study, we have analyzed the genes directly regulated in post-IFN-a receptor signaling and found that intraperitoneal administration of mouse IFN-a, but not human IFN-a, activated expression of several prototypic IFN-stimulated genes (ISGs), in particular signal transducers and activators of transcription (STAT1), IFN-induced 15 kDa protein (ISG15), ubiquitin-specific proteinase 18 (USP18) and guanylate-binding protein 3 (GBP3) in the brain. A similar temporal profile for the regulated expression of these IFN-aactivated ISG genes was observed in the brain compared with the peripheral organs. Dual labeling in situ hybridization combined with immunocytochemical staining demonstrated a wide distribution of the key IFN-regulated gene STAT1 transcripts in the different parenchyma cells of the brain, particularly neurons. The overall response to IFN-a challenge was abolished in STAT1 knockout mice. Together, our results indicate a direct, STAT1-dependent action of systemic IFN-a in the CNS, which may provide the basis for a mechanism in humans for neurological/neuropsychiatric illnesses associated with IFN-a therapy.

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“…11,[22][23][24][25][26][27] Divergent results might be attributable to methodological differences. To the best of our knowledge, this report is the first to address both the dose-dependent and the temporal effects of peripherally administered IFN-α on various brain regions.…”

Section: Discussionmentioning

confidence: 99%

“…injection of 10 000 IU/kg IFN-α decreased DA levels in the amygdala and raphe area. 11 They did not feed the experimental animals for 24 h prior to decapitation. This might have acted as a stressor for their experimental animals and could be one reason for the resulting data not being consistent with the present findings.…”

Section: Discussionmentioning

confidence: 99%

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Chronic intraperitoneal injection of interferon‐α reduces serotonin levels in various regions of rat brain, but does not change levels of serotonin transporter mRNA, nitrite or nitrate

Sato¹,

Suzuki²,

Yokoyama³

et al. 2006

Psychiatry Clin Neurosci

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Interferon-α therapy is associated with a high rate of depression, but the pathophysiological mechanisms remain unclear. The purpose of the present study was to investigate the effects of i.p. administered interferon-α on monoaminergic neurotransmission in the brain. The levels of monoamines and associated metabolites were measured in various regions of the rat brain using a high-performance liquid chromatography-electrochemical detection system. The serotonin transporter mRNA levels were also measured using in situ hybridization. After 1 day, dopamine turnover was diminished in the cortex. Norepinephrine turnover was decreased in most regions tested after 4 days. However, these changes were transient. After 14 days, serotonin turnover was increased in the frontal cortex and hippocampus in rats given a dose of 20 000 IU/kg; in the frontal cortex, hippocampus, amygdala, thalamus, hypothalamus and brainstem in those on 200 000 IU/kg; and in the thalamus and hypothalamus in those on 2 000 000 IU/kg (all P < 0.05). However, 14-day treatment did not significantly change serotonin transporter mRNA levels. Next, the question of whether interferon-α affects monoamine levels via induction of nitric oxide (NO), was investigated. However, there were no changes in either NO 2 -or NO 3 -, as markers of NO production, in any brain regions after 14-day treatment. These results suggest that chronic peripheral administration of interferon-α induces metabolic changes in the central serotonin system. Further investigation is needed to determine exactly how this cytokine affects the central serotonin system and to assess whether a central serotonin abnormality is involved in interferon-induced depression.

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Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: role of nitric oxide as a signal crossing the blood–brain barrier

Cited by 128 publications

References 69 publications

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

Systemic interferon-α regulates interferon-stimulated genes in the central nervous system

Chronic intraperitoneal injection of interferon‐α reduces serotonin levels in various regions of rat brain, but does not change levels of serotonin transporter mRNA, nitrite or nitrate

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