Effects of Clozapine on Plasma Cytokine and Soluble Cytokine Receptor Levels

Pollmächer, Thomas; Hinze-Selch, D.; Mullington, Janet

doi:10.1097/00004714-199610000-00011

Cited by 214 publications

(131 citation statements)

References 38 publications

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“…It was reported that the plasma levels of sIL-2r and TNF-␣ were significantly increased by clozapine treatment per se; whereas, IL-6 levels were only increased during clozapine-induced fever (Maes et al 1994;Pollmächer et al 1995Pollmächer et al , 1996. At first glance, these results do not seem to be compatible with our in vitro results.…”

Section: Discussioncontrasting

confidence: 93%

“…Independent of such side effects, clozapine treatment consistently increases the plasma levels of cytokines and soluble cytokine receptors that are pivotal immune mediators. In particular, there are consistent reports on increases in the plasma levels of tumor necrosis factor-␣ (TNF-␣ ), soluble TNF-receptor p55 (TNF-Rp55), TNF-Rp75 and soluble interleukin-2 receptor (Maes et al 1994;Pollmächer et al 1995;Pollmächer et al 1996). These effects were already evident after the first week of treatment and persisted for at least 6 weeks .…”

mentioning

confidence: 68%

“…An involvement of the immune system has been discussed for several clozapine-induced side effects, such as transient fever (Blum and Mauruschat 1972;Pollmächer et al 1996), agranulocytosis (Pisciotta and Konings 1994), coagulopathies (Davis et al 1994) and parotitis . Independent of such side effects, clozapine treatment consistently increases the plasma levels of cytokines and soluble cytokine receptors that are pivotal immune mediators.…”

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confidence: 99%

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Effects of Clozapine on In Vitro Immune Parameters A Longitudinal Study in Clozapine-Treated Schizophrenic Patients

Hinze-Selch

Becker

Stein

et al. 1998

Neuropsychopharmacology

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Section: Discussioncontrasting

confidence: 93%

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confidence: 68%

mentioning

confidence: 99%

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Effects of Clozapine on In Vitro Immune Parameters A Longitudinal Study in Clozapine-Treated Schizophrenic Patients

Hinze-Selch

Becker

Stein

et al. 1998

Neuropsychopharmacology

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“…Among them, tumor necrosis factor-a (TNF-a), which can be secreted by astrocytes, is a strong repressor of GLT-1 expression (Su et al, 2003). Interestingly, clozapine raises the plasma levels of TNF-and soluble TNF receptors p55 and p75 in schizophrenic patients (Pollmä cher et al, 1996). Alternatively, the action of clozapine on GLT-1 expression may be the consequence of the blockade of neurotransmitter receptors, such as dopamine and serotonin receptors (Stahl, 1999), which are expressed in astrocytes (Bal et al, 1994;Maxishima et al, 2001).…”

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confidence: 99%

Clozapine reduces GLT-1 expression and glutamate uptake in astrocyte cultures

Vallejo-Illarramendi

Torres-Ramos

Melone

et al. 2005

Glia

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To test the hypothesis that clozapine-induced reduction of glutamate transporter-1 (GLT-1) expression is mediated by astrocytes, we studied the effects of clozapine on Glu transporters and Glu uptake in primary astrocyte cultures of the cerebral cortex. Astrocyte cultures treated for 48 h with clozapine exhibited a reduction in GLT-1 levels of about 50%, whereas glutamate-aspartate transporter (GLAST) levels remained unchanged. Glu uptake was also lowered, and this reduction was dose-dependent. Our findings indicate that clozapine reduces GLT-1 expression and function by a mechanism that directly involves astrocytes. A better understanding of the molecular events by which antipsychotics regulate Glu uptake can contribute to identify new targets for the treatment of schizophrenia. High-affinity uptake is the major mechanism by which the CNS regulates the extracellular levels of glutamate (Glu), the main excitatory neurotransmitter in the cerebral cortex (Conti and Hicks, 1996). To date, five different Glu transporters (GluTs) have been cloned, the neuronal EAAC1 and the astrocytic glutamate aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) being the major subtypes (Conti and Weinberg, 1999;Danbolt, 2001).We showed previously that chronic treatment with clozapine reduces Glu uptake in rat frontal cortex considerably, thereby raising extracellular Glu levels, and that this effect is mediated by a selective reduction of GLT-1 (Melone et al., 2001. The mechanism(s) underlying this novel effect of clozapine is unknown. However, the low levels of GLT-1 expression and function detected in the presence of high Glu levels suggest that the latter effect is secondary to the former, and that the drug's primary site of action are thus the cellular elements expressing GLT-1. Although most studies have shown that GLT-1 is expressed exclusively by astrocytes (Danbolt, 2001), it was recently suggested that, in certain brain regions, some neurons express GLT-1 (see recent data and literature in Chen et al., 2004), raising the possibility that the effects of clozapine may be mediated by a differential action on neuronal or astrocytic GLT-1.The aim of the present experiments was to test the hypothesis that the effects of clozapine on GLT-1 expression and function and on Glu levels are mediated by astrocytes. To do this, we investigated whether the effects of clozapine on GluTs and Glu uptake reported in our previous in vivo studies also take place in primary astrocyte cultures.Primary astrocyte cultures were established from the cerebral cortex of 1-day-old Sprague-Dawley rats and prepared as described (Swanson et al., 1997). To promote astrocyte differentiation, confluent cultures were treated with 200 mM dibutyryl cyclic adenosine monophosphate (dBcAMP) for 6 days. Subsequently, astrocytes were treated with 5-50 mM clozapine for 48 h and used for immunochemistry or uptake

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“…Some studies reported that short-term treatment with clozapine may induce the production of pro-inflammatory cytokines such as IL-6, INF␥ and TNF␣, an effect that tends to disappear upon prolonged treatment. 22,23 Moreover, dysregulation in cytokines production (IL-1, IL-6 and TNF) has also been described in patients with major depressive disorders, Alzheimer's disease, panic disorder, obsessive-compulsive disorder, autism and stress-induced anxiety. [24][25][26][27][28][29] This lack of specificity and the possible biasing influence of the above-mentioned factors weaken the relevance of serum/plasma-based investigations on immune system abnormalities in schizophrenic patients.…”

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confidence: 99%

Association between −G308A tumor necrosis factor alpha gene polymorphism and schizophrenia

et al. 2000

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Dysregulation of the inflammatory response system has been linked to pathophysiology of schizophrenia. 1,2 Evidence of immune activation has derived from the detection of abnormal levels of proinflammatory cytokines and their receptors in peripheral blood and cerebrospinal fluid from schizophrenic patients. 3-7 Cytokines are involved in normal CNS development as well as in the pathogenesis of many neuro-psychiatric disorders, acting directly on neural cells or modulating neurotransmitter and neuropeptide systems. 8,9 In particular tumor necrosis factor ␣ (TNF␣), depending on its concentration, can exert both neurotrophic and neurotoxic effects and influence neural cell growth and proliferation. 10,11 Moreover, TNF␣ gene is located on the small arm of chromosome 6 (6p21.1-21.3), a locus associated with genetic susceptibility to schizophrenia. 12, 13 We studied the distribution of −G308A TNF␣ gene polymorphism in 84 schizophrenic patients and in 138 healthy volunteers. This biallelic base exchange polymorphism directly affects TNF␣ plasma levels. 14-18 Frequency of the TNF2(A) allele is significantly increased in schizophrenic patients as compared to controls (P = 0.0042). Genotype distribution is also significantly different (P = 0.0024). TNF2 homozygotes are represented only in the patient group (P = 0.002). These data suggest a potential role of TNF␣ as a candidate gene for susceptibility to schizophrenia and suggest that immune dysregulation in schizophrenic patients could also have a genetic component. Molecular Psychiatry (2001) 6, 79-82.

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Effects of Clozapine on Plasma Cytokine and Soluble Cytokine Receptor Levels

Cited by 214 publications

References 38 publications

Effects of Clozapine on In Vitro Immune Parameters A Longitudinal Study in Clozapine-Treated Schizophrenic Patients

Effects of Clozapine on In Vitro Immune Parameters A Longitudinal Study in Clozapine-Treated Schizophrenic Patients

Clozapine reduces GLT-1 expression and glutamate uptake in astrocyte cultures

Association between −G308A tumor necrosis factor alpha gene polymorphism and schizophrenia

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