Elevated plasma prostaglandin E2 levels in schizophrenia

Kaiya, Hisanobu; Uematsu, Masashi; Ofuji, M; Nishida, Akira; Takeuchi, Koji; Nozaki, Masakatsu; Idaka, Eiichi

doi:10.1007/bf01255817

Cited by 52 publications

(25 citation statements)

References 26 publications

(25 reference statements)

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“…Several studies demonstrated the type-2 inducing effect of PGE 2 -the major product of COX-2, while inhibition of COX-2 is accompanied by inhibition of type-2 cytokines and induction of type-1 cytokines (Pyeon et al, 2000;Stolina et al, 2000). PGE 2 levels in schizophrenia have not been well studied; increased levels of PGE 2 , however, have been described (Kaiya et al, 1989). PGE 2 , however, induces the production of IL-6, a cytokine which is consistently described to be increased in schizophrenia (see above).…”

Section: The Possible Role Of Kyna In Schizophreniamentioning

confidence: 96%

“…In schizophrenia, however, the data on Prostaglandin E 2 (PGE 2 ) are not conclusive: while in several elder studies increased blood levels of PGE 2 were described (Kaiya et al, 1989), a more recent study found no increase of PGE 2 levels in the CSF of schizophrenics (Nishino et al, 1998). There are indications that the PGE 2 level might be related to the actual psychopathology (Kaiya et al, 1989).…”

Section: Pge 2 Inflammation and Immune Dysbalancementioning

confidence: 96%

“…There are indications that the PGE 2 level might be related to the actual psychopathology (Kaiya et al, 1989). However, more data are needed, in particular since there are several methodological pitfalls in the estimation of PGE 2 from blood or CSF.…”

Section: Pge 2 Inflammation and Immune Dysbalancementioning

confidence: 98%

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Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission

2006

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This overview tries to bridge the gap between psychoneuroimmunological findings and recent results from pharmacological, neurochemical and genetic studies in schizophrenia. Schizophrenia is a disorder of dopaminergic neurotransmission, but modulation of the dopaminergic system by glutamatergic neurotransmission seems to play a key role. This view is supported by genetic findings of the neuregulin- and dysbindin genes, which have functional impact on the glutamatergic system. Glutamatergic hypofunction, however, is mediated by the N-methyl-D-aspartate (NMDA)-receptor antagonism. The only endogenous NMDA receptor antagonist identified up to now is kynurenic acid (KYNA). Despite the NMDA receptor antagonism, KYNA also blocks, in lower doses, the nicotinergic acetycholine receptor, i.e., increased KYNA levels can explain psychotic symptoms and cognitive deterioration. KYNA levels are described to be higher in the cerebrospinal fluid (CSF) and in critical central nervous system (CNS) regions of schizophrenics as compared to controls. Another line of evidence suggests that a (prenatal) infection is involved in the pathogenesis of schizophrenia. Due to an early sensitization process of the immune system or to a (chronic) infection, which is not cleared through the immune response, an immune imbalance between the type-1 and the type-2 immune responses takes place in schizophrenia. The type-1 response is partially inhibited, while the type-2 response is over-activated. This immune constellation is associated with inhibition of the enzyme indoleamine dioxygenase (IDO), because IDO - located in astrocytes and microglial cells - is inhibited by type-2 cytokines. IDO catalyzes the first step in tryptophan metabolism, the degradation from tryptophan to kynurenine, as does tryptophan 2,3-dioxygenase (TDO). Due to the inhibition of IDO, tryptophan-kynurenine is predominantly metabolized by TDO, which is located in astrocytes, not in microglial or other CNS cells. In schizophrenia, astrocytes in particular are activated, as increased levels of S100B appear. Additionally, they do not have the enzymatic equipment for the normal metabolism-route of tryptophan. Due to the lack of kynurenine hydroxylase (KYN-OHase) in astrocytes, KYNA accumulates in the CNS, while the metabolic pathway in microglial cells is blocked. Accordingly, an increase of TDO activity has been observed in critical CNS regions of schizophrenics. These mechanisms result in an accumulation of KYNA in critical CNS regions. Thus, the immune-mediated glutamatergic-dopaminergic dysregulation may lead to the clinical symptoms of schizophrenia. Therapeutic consequences, e.g., the use of anti-inflammatory cyclo-oxygenase-2 inhibitors, which can also decrease KYNA directly, are discussed.

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Section: The Possible Role Of Kyna In Schizophreniamentioning

confidence: 96%

Section: Pge 2 Inflammation and Immune Dysbalancementioning

confidence: 96%

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Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission

2006

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“…Elevated serum and/or plasma levels of pro-inflammatory factors like prostaglandin E2 (PGE 2 ) [13], C-reactive protein (CRP) [14], IL-1β and TNF-α [15] have been found in schizophrenic individuals. Furthermore, high microglial activation in the brain of schizophrenic patients has been reported in postmortem studies [16,17].…”

mentioning

confidence: 99%

Tumour necrosis factor - alpha mediated mechanisms of cognitive dysfunction

Baune

Camara²,

Eyre³

et al. 2012

Translational Neuroscience

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Background: Tumour necrosis factor -alpha (TNF-α) is a pro-inflammatory cytokine that combines a plethora of activities in the early stages of an immune response. TNF-α has gained increasing importance given TNF-α upregulation in multiple brain pathologies like neuropsychiatric conditions such as depression, schizophrenia, as well as neuroinflammatory disorder like multiple sclerosis (MS). Aim: The aim of this review is to critically analyse neurobiological, immunological and molecular mechanisms through which TNF-α influences the development of cognitive dysfunction. Principal findings/results: The review presents several lines of original research showing that the immunological properties of TNF-α exacerbate inflammatory responses in the central nervous system such as microglial and endothelial activation, lymphocytic and monocytic infiltration and the expression of downstream pro-inflammatory cytokines and apoptotic factors. Depression, schizophrenia, and MS all manifest symptoms of activated immune response along with cognitive dysfunction, with TNF-α overexpression as a central clinical feature common to these disorders. Furthermore, TNF-α acts negatively on neuroplasticity and the molecular mechanisms of memory and learning (i.e., long-term potentiation and long-term depression). TNF-α also exerts influence over the production of neurotrophins (i.e., nerve growth factor and brain-derived neurotrophic factor), neurogenesis, and dendritic branching. Conclusions/significance: This review outlines that TNF-α and its receptors have a substantial yet underappreciated influence on the development and progression of neuropsychiatric symptoms across several disease entities. An improved understanding of these underlying mechanisms may help develop novel therapeutic targets in the form of drugs specifically targeting downstream products of TNF-α activation within the central nervous system.

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“…To elaborate, elevated levels of PGE 2 , a signalling molecule, were associated with SCZ and symptom severity. 73 In addition, a beneficial effect on treatment outcome of cyclooxygenase-2 (COX-2) inhibitor add-on treatment to risperidone was observed. 74 Inhibition of COX-2, an upstream regulator of PGE 2 , is expected to reduce PGE 2 levels.…”

Section: Drd3 Polymorphisms and Clozapine Responsementioning

confidence: 98%

Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant

et al. 2009

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D2 blockade has been implicated in having a central role in antipsychotic response. However, treatment refractoriness, in spite of complete D2 blockade, as well as the efficacy of clozapine (CLZ) in a portion of this patient population, indicates the involvement of other factors as well. Several lines of evidence suggest a role for D3. Furthermore, an earlier meta-analysis by Jönsson et al. (2003) (n ¼ 233) suggested a role for genetic variation in the D3 gene. Relevant to this study, Jönsson et al. found the Ser allele of the D3 serine-to-glycine substitution at amino acid position 9 (Ser9Gly) polymorphism to be associated with worse CLZ response compared with the Gly allele. In this study, we attempt to validate these findings by performing a meta-analysis in a much larger sample (n ¼ 758). Eight other variants were also tested in our own sample to explore the possible effect of other regions of the gene. We report a negative but consistent trend across individual studies in our meta-analysis for the DRD3 Ser allele and poor CLZ response. A possible minor role for this single-nucleotide polymorphism cannot be disregarded, as our sample size may have been insufficient. Other DRD3 variants and haplotypes of possible interest were also identified for replication in future studies.

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Elevated plasma prostaglandin E2 levels in schizophrenia

Cited by 52 publications

References 26 publications

Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission

Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission

Tumour necrosis factor - alpha mediated mechanisms of cognitive dysfunction

Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant

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