An investigation of calcium-independent phospholipase A2 (iPLA2) and cytosolic phospholipase A2 (cPLA2) in schizophrenia

Xu, Chuangye; Yang, Xuhan; Sun, Liya; Yang, Tianqi; Cai, Chao; Wang, Peng; Jiang, Jie; Qing, Ying; Hu, Xiaowen; Wang, Dandan; Wang, Pengkun; Cui, Gaoping; Zhang, Juan; Li, Yan; Feng, Jia‐Xun; Liu, Chuanxin; Wan, Chunling

doi:10.1016/j.psychres.2019.01.095

Cited by 16 publications

(10 citation statements)

References 46 publications

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“…In the US dataset, cytosolic phospholipase 2 (Cpla2) was the master regulator for a causal pathway, including ADAMTS2 and GABRA2. Cpla2 is involved in inflammatory responses, and it is increased in schizophrenia and autism [18]. The P2RY11-regulated pathway in the Finnish dataset and the astaxanthin-regulated pathway in the US dataset imply an abnormal purine-related molecular cascade underlying, which is in line with data from small RCTs suggesting beneficial effects for purinergic agents [19].…”

Section: Discussionsupporting

confidence: 74%

Molecular signaling pathways underlying schizophrenia

Tiihonen

Koskuvi

Lähteenvuo

et al. 2020

Preprint

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The molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. Studies using stem cell-derived neurons have investigated differentially expressed genes (DEGs) and GO and KEGG pathways between patients and controls, but not analyzed data-driven causal molecular pathways involved. We used Ingenuity Pathway Analysis (IPA) to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were observed for glutamate receptor signaling, hepatic fibrosis, and glycoprotein 6 (GP6) pathways in the Finnish dataset, and GP6 and hepatic fibrosis pathways in the US dataset. In data-driven causal pathways, ADCYAP1, ADAMTS, and CACNA genes were involved in the majority of the top 10 pathways differentiating patients and controls in both Finnish and US datasets. In contrast, no dopamine-specific genes were consistently involved. Results from a Finnish nation-wide database showed that the risk of schizophrenia relapse was 41% lower among first-episode patients during the use of losartan, the master regulator of an ADCYAP1, ADAMTS, and CACNA -related pathway, compared to those time periods when the same individual did not use the drug. This association was not attributable to general adherence to drug treatments. The results from the two independent datasets suggest that the GP6 signaling pathway, and the ADCYAP1, ADAMTS, and CACNA -related purine, oxidative stress, and glutamatergic signaling pathways are primary pathophysiological alterations in schizophrenia among patients with European ancestry. While no reproducible dopaminergic alterations were observed, the results imply that agents such as losartan, and ADCYAP1/PACAP -deficit alleviators, such as metabotropic glutamate 2/3 agonist MGS0028 and 5-HT7 antagonists -which have shown beneficial effects in an experimental Adcyap1 -/mouse model for schizophrenia -could be potential treatments before the full manifestation of illness involving dopaminergic abnormalities.

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Section: Discussionsupporting

confidence: 74%

Molecular signaling pathways underlying schizophrenia

Tiihonen

Koskuvi

Lähteenvuo

et al. 2020

Preprint

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“… 35 ). In addition, when the plasma levels of different forms of PLA2 were measured, the levels of calcium-independent PLA2 were higher in both schizophrenia patients 49 and ultra-high risk individuals 50 than in controls, whereas the level of cytosolic PLA2 were higher only in individuals with ultra-high risk as compared to controls 50 . Whether the niacin-induced flush abnormality could be attributed to the genetic polymorphisms of other PLA2 genes or the altered levels of PLA2 warrants future investigation.…”

Section: Discussionmentioning

confidence: 99%

Niacin skin flush and membrane polyunsaturated fatty acids in schizophrenia from the acute state to partial remission: a dynamic relationship

Lin

Hsiao

et al. 2022

Schizophr

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Despite the consistent finding of an attenuated niacin-induced flush response in schizophrenia, its long-term stability and relationship to the membrane polyunsaturated fatty acid (PUFA) levels remain unknown. We conducted niacin skin tests and measured the membrane PUFAs using gas chromatography among 46 schizophrenia inpatients and 37 healthy controls at the baseline and the 2-month follow-up. Attenuated flush responses were persistently observed in schizophrenia patients in both acute and partial remission states, whereas an increased flush response was found in the controls. A persistent decrease in both dihomo-gamma-linolenic acid and docosahexaenoic acid and an increased turnover of arachidonic acid (ARA) via endogenous biosynthesis were found in schizophrenia patients. A composite niacin flush score by combining those with a control-to-case ratio of >1.4 (i.e., scores at 5 min of 0.1 M, 0.01 M, and 0.001 M + 10 min of 0.01 M and 0.001 M + 15 min of 0.001 M) at the baseline was correlated positively with ARA levels among controls but not among schizophrenia patients, whereas the flush score at the 2-month follow-up was correlated positively with ARA levels among patients. The 2-month persistence of attenuated niacin-induced flush response in schizophrenia patients implies that the niacin skin test might tap a long-term vulnerability to schizophrenia beyond acute exacerbation.

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“…Messamore et al (288) and Kim et al (289) reported an increase in intracellular calcium concentration, which may result in increased cPLA 2 activity. Instead, (290)(291)(292)(293) suggested that there is increased iPLA 2 and decreased cPLA 2 activity in patients with schizophrenia. The iPLA 2 may be increased as negative feedback by producing an antioxidant that mediates increased oxidative stress, as observed in schizophrenia patients (294)(295)(296).…”

Section: Pla 2 Controversy In Phospholipase Activitymentioning

confidence: 99%

Inflammation and JNK's Role in Niacin-GPR109A Diminished Flushed Effect in Microglial and Neuronal Cells With Relevance to Schizophrenia

Ansarey

2021

Front. Psychiatry

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Schizophrenia is a neuropsychiatric illness with no single definitive aetiology, making its treatment difficult. Antipsychotics are not fully effective because they treat psychosis rather than the cognitive or negative symptoms. Antipsychotics fail to alleviate symptoms when patients enter the chronic stage of illness. Topical application of niacin showed diminished skin flush in the majority of patients with schizophrenia compared to the general population who showed flushing. The niacin skin flush test is useful for identifying patients with schizophrenia at their ultra-high-risk stage, and understanding this pathology may introduce an effective treatment. This review aims to understand the pathology behind the diminished skin flush response, while linking it back to neurons and microglia. First, it suggests that there are altered proteins in the GPR109A-COX-prostaglandin pathway, inflammatory imbalance, and kinase signalling pathway, c-Jun N-terminal kinase (JNK), which are associated with diminished flush. Second, genes from the GPR109A-COX-prostaglandin pathway were matched against the 128-loci genome wide association study (GWAS) for schizophrenia using GeneCards, suggesting that G-coupled receptor-109A (GPR109A) may have a genetic mutation, resulting in diminished flush. This review also suggests that there may be increased pro-inflammatory mediators in the GPR109A-COX-prostaglandin pathway, which contributes to the diminished flush pathology. Increased levels of pro-inflammatory markers may induce microglial-activated neuronal death. Lastly, this review explores the role of JNK on pro-inflammatory mediators, proteins in the GPR109A-COX-prostaglandin pathway, microglial activation, and neuronal death. Inhibiting JNK may reverse the changes observed in the diminished flush response, which might make it a good therapeutic target.

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An investigation of calcium-independent phospholipase A2 (iPLA2) and cytosolic phospholipase A2 (cPLA2) in schizophrenia

Cited by 16 publications

References 46 publications

Molecular signaling pathways underlying schizophrenia

Molecular signaling pathways underlying schizophrenia

Niacin skin flush and membrane polyunsaturated fatty acids in schizophrenia from the acute state to partial remission: a dynamic relationship

Inflammation and JNK's Role in Niacin-GPR109A Diminished Flushed Effect in Microglial and Neuronal Cells With Relevance to Schizophrenia

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