Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: Further evidence for disease course-related immune alterations?

Busse, Stefan; Busse, Mandy; Schiltz, Kolja; Bielau, Hendrik; Gos, Tomasz; Brisch, Ralf; Mawrin, Christian; Schmitt, Andrea; Jordan, Wolfgang; Müller, Ulf; Bernstein, Hans‐Gert; Bogerts, Bernhard; Steiner, Johann

doi:10.1016/j.bbi.2012.08.005

Cited by 172 publications

(128 citation statements)

References 59 publications

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“…Activated M1 microglia produce prostaglandins, chemokines, cytokines, complement proteins, proteinases, reactive oxygen species, and reactive nitrogen species, the sustained production of which can have a deleterious effect on susceptible cell populations by enhancing oxidative stress and activating cell death pathways through stimulation of kinases and caspase cascades [43]. Postmortem evidence is growing: brain microglial activation has been suggested in postmortem and positron emission tomography studies using (R)-[11C]PK11195, a ligand that recognizes the translocator protein [44][45][46][47]. Other postmortem studies have found increased numbers and structural degenerative impairments of human leukocyte antigen-antigen D related+ microglia in schizophrenia [48][49][50].…”

Section: Discussionmentioning

confidence: 99%

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

et al. 2016

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Alterations in the innate inflammatory response may underlie the pathophysiology of psychiatric diseases. Current antipsychotics modulate pro-/anti-inflammatory pathways, but their specific actions on these pathways remain only partly explored. This study was conducted to elucidate the regulatory role of paliperidone (1 mg/kg i.p.) on acute (6 h) and chronic (6 h/day for 21 consecutive days) restraint stressinduced alterations in 2 emerging endogenous anti-inflammatory/antioxidant mechanisms: nuclear factor erythroid-related factor 2 (NRF2)/antioxidant enzymes pathway, and the cytokine milieu regulating M1/M2 polarization in microglia, analyzed at the mRNA and protein levels in prefrontal cortex samples. In acute stress conditions, paliperidone enhanced NRF2 levels, possibly related to phosphoinositide 3-kinase upregulation and reduced kelch-Like ECH-associated protein 1 expression. In chronic conditions, paliperidone tended to normalize NRF2 levels through a phosphoinositide 3-kinase related-mechanism, with no effects on kelch-Like ECH-associated protein 1. Antioxidant response element-dependent antioxidant enzymes were upregulated by paliperidone in acute stress, while in chronic stress, paliperidone tended to prevent stress-induced downregulation of the endogenous antioxidant machinery. However, paliperidone increased transforming growth factor-β and interleukin-10 in favor of an M2 microglia profile in acute stress conditions, which was also corroborated by paliperidone-induced increased levels of the M2 cellular markers arginase I and folate receptor 2. This latter effect was also produced in chronic conditions. Immunofluorescence studies suggested an increase in the number of microglial cells expressing arginase I and folate receptor 2 in the stressed animals pretreated with paliperidone. In conclusion, the enhancement of endogenous antioxidant/anti-inflammatory pathways by current and new antipsychotics could represent an interesting therapeutic strategy for the future.

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Section: Discussionmentioning

confidence: 99%

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

et al. 2016

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“…Saznanje o dva nova subtipa T ćelija -Th17 i T regulatornih ćelija (Tregs), su značajni faktori u rasvetljavanju etiologije ovog oboljenja kao i kontrolnih mehanizama, pogotovo imajući u vidu da povećana produkcija Th-17 intenzivira inflamatornu reakciju i doprinosi oštećenju tkiva [13,14]. Jedna od interesantnih teorija je i " mikroglijalna hipoteza shizofrenije" prema kojoj aktivirana mikroglija oslobadja proinflamatorne citokine i slobodne radikale dovodeći do poremećene neurogeneze, neuralne degradacije, promena u beloj masi, a koje imaju krucijalnu ulogu u patogenezi shizofrenije [15,16].…”

Section: Kratak Sadržajunclassified

Schizophrenia and cytokines

Dunjić-Kostić¹,

Pantović-Stefanović²,

Ivković³

et al. 2015

Engrami

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Razvoj sofisticiranih tehnika detekcije strukturnih i biohemijskih abnormlnosti, u poslednjih nekoliko decenija, odigrao je važnu ulogu u preciznijem sagledavanju brojnih bioloških alteracija kod pacijenata uopšte. Ova činjenica je od posebne važnosti istraživačima u oblasti neuronauka, zbog često nepoznate i/ili multifaktorijalne etiopatogeneze neuropsihijatrijskih poremećaja, te svaki deo spoznaje kompleksnog "algoritma" ima svoje značajno mesto. U poslednje vreme veliku pažnju istraživača privlače eksploracija imunoloških abnormalnosti kod obolelih od shizofrenije, kao i citokinima posredovani mehanizmi koji predstavljaju osnovu za niz hipoteza iznesenih na ovu temu [1][2][3]. U daljem tekstu fokusiraće-mo se na nekoliko najvažnijih teorijskih pravaca koje se tiču inflamacije i imunoloških promena zapaženih u shizofreniji. Jedna od teorija je da je infekcija majke tokom trudnoće (naročito tokom ranog perinatalnog perioda) značajan faktor rizika za dete za razvoj shizofrenije i drugih neurorazvojnih oboljenja [4,5]. Epidemiološke studije su pokazale da infekcija majke virusom influence tokom trudnoće povećava rizik za shizofreniju deteta za 3-7 puta [4,6]. Pored virusa influence i brojni drugi infektivni činioci su povezani sa povećanim rizikom za SCH medju kojima su i varicela zoster virus, polio, difterija, rubela itd [5]. Medjutim, patološki mehanizam odgovoran za povećan rizik za shizofreniju kod dece nakon izloženosti majke infekciji još uvek je nedovoljno jasan. Takodje otvoreno je pitanje, na koji način infekcija majke dovodi do citokinskog disbalansa kod fetusa; da li je u pitnju delovanje infektivnog činioca na specifične receptore koji dovode do produkcije i oslobadjanja različitih medijatora zapaljenja u periferni majčin imuni sistem koji onda prolaze placentu i ulaze u cirkulaciju fetusa [6,7], ili potencijalni iz- Kratak sadržajPoslednjih par decenija pažnju istraživača sve više privlače imunološke abnormalnosti uočene kod obolelih od shizofrenije. U prvom delu teksta prikazan je kratak pregled pojedinih teorijskih konstrukata predloženih u cilju boljeg uvida u povezanost shizofrenije i imunoloških alteracija, u drugom delu je razmotren uticaj citokina na pojedine neurotransmiterske sisteme i finalno izneta su zapažanja dobijena iz istraživanja u realnoj kliničkoj situaciji kao i pravci budućih istraživanja.

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“…5,6 Further, postmor tem studies using messenger RNA (mRNA) expression or im munohistochemical detection have shown increased levels of immune related compounds. [7][8][9] A number of investigations have focused on cytokines, but these studies have not yielded a unanimous picture, possibly because of a number of con founding factors, such as smoking and dietary habits, body mass index (BMI), type and duration of antipsychotic treat ment and drug abuse -all factors potentially affecting the immune system. 10 However, according to recent meta analyses, 11,12 some cytokines are significantly associated with schizophrenia (e.g., interleukin [IL] 6).…”

Section: Introductionmentioning

confidence: 99%

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

Schwieler

Larsson

Skogh

et al. 2015

jpn

188

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IntroductionThe role of immune activation in schizophrenia has received increasing interest in recent years. Epidemiological studies have shown that infections and autoimmune diseases are clin ic ally important risk factors for the development of schizo phrenia. [1][2][3] Furthermore, a recent study integrating results from a meta analysis of genome wide association studies in schizophrenia found that the most significant changes were observed in genetic loci related to the immune system. 4 Also, patients with schizophrenia show microglial activation, as re vealed by positron emission tomography. 5,6 Further, postmor tem studies using messenger RNA (mRNA) expression or im munohistochemical detection have shown increased levels of immune related compounds. 7-9 A number of investigations have focused on cytokines, but these studies have not yielded a unanimous picture, possibly because of a number of con founding factors, such as smoking and dietary habits, body mass index (BMI), type and duration of antipsychotic treat ment and drug abuse -all factors potentially affecting the Background: Accumulating evidence indicates that schizophrenia is associated with brain immune activation. While a number of reports suggest increased cytokine levels in patients with schizophrenia, many of these studies have been limited by their focus on peripheral cytokines or confounded by various antipsychotic treatments. Here, well-characterized patients with schizophrenia, all receiving olanzapine treatment, and healthy volunteers were analyzed with regard to cerebrospinal fluid (CSF) levels of cytokines. We correlated the CSF cytokine levels to previously analyzed metabolites of the kynurenine (KYN) pathway. Methods: We analyzed the CSF from patients and controls using electrochemiluminescence detection with regard to cytokines. Cell culture media from human cortical astrocytes were ana lyzed for KYN and kynurenic acid (KYNA) using high-pressure liquid chromatography or liquid chromatography/mass spectrometry. Results: We included 23 patients and 37 controls in our study. Patients with schizophrenia had increased CSF levels of interleukin (IL)-6 compared with healthy volunteers. In patients, we also observed a positive correlation between IL-6 and the tryptophan:KYNA ratio, indicating that IL-6 activates the KYN pathway. In line with this, application of IL-6 to cultured human astrocytes increased cell medium concentration of KYNA. Limitations: The CSF samples had been frozen and thawed twice before analysis of cytokines. Median age differed between patients and controls. When appropriate, all present analyses were adjusted for age. Conclusion: We have shown that IL-6, KYN and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-d-aspartate receptor antagonist KYNA in patients with schizophrenia.

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Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: Further evidence for disease course-related immune alterations?

Cited by 172 publications

References 59 publications

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

Schizophrenia and cytokines

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

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