MEDICATIONS CYTOKINES ETC

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J Biol Chem 2002 Mar 8;277(10):7713-9 Related Articles, Books, LinkOut

Lithium induces NF-kappa B activation and interleukin-8 production in human

intestinal epithelial cells.

Nemeth ZH, Deitch EA, Szabo C, Fekete Z, Hauser CJ, Hasko G.

Department of Surgery, UMD-New Jersey Medical School, Newark, New Jersey

07103, USA.

Lithium has been documented to regulate apoptosis and apoptotic gene

expression via NF-kappa B and mitogen-activated protein (MAP)

kinase-dependent mechanisms. Since both NF-kappa B and MAP kinases are also

important mediators of inflammatory gene expression, we investigated the

effect of lithium on NF-kappa B- and MAP kinase-mediated inflammatory gene

expression. Incubation of human intestinal epithelial cells with lithium

induced both enhanced NF-kappa B DNA binding and NF-kappa B-dependent

transcriptional activity. In addition, lithium stimulated activation of both

the p38 and p42/44 MAP kinases. This lithium-induced up-regulation of

NF-kappa B and MAP kinase activation was associated with an enhancement of

interleukin-8 mRNA accumulation as well as an increase in interleukin-8

protein release. These proinflammatory effects of lithium were, in large

part, mediated by activation of Na(+)/H(+) exchangers, because selective

blockade of Na(+)/H(+) exchangers prevented the lithium-induced intestinal

cell inflammatory response. These results demonstrate that lithium

stimulates inflammatory gene expression via NF-kappa B and MAP kinase

activation.

PMID: 11756416 [PubMed - indexed for MEDLINE]

Biol Chem 2001 Aug 24;276(34):31674-83 Related Articles, Books, LinkOut

The mood stabilizer valproic acid activates mitogen-activated protein

kinases and promotes neurite growth.

Yuan PX, Huang LD, Jiang YM, Gutkind JS, Manji HK, Chen G.

Laboratory of Molecular Pathophysiology, Department of Psychiatry and

Behavioral Neurosciences, Wayne State University School of Medicine,

Detroit, Michigan 48201, USA.

The mood-stabilizing agents lithium and valproic acid (VPA) increase DNA

binding activity and transactivation activity of AP-1 transcription factors,

as well as the expression of genes regulated by AP-1, in cultured cells and

brain regions involved in mood regulation. In the present study, we found

that VPA activated extracellular signal-regulated kinase (ERK), a kinase

known to regulate AP-1 function and utilized by neurotrophins to mediate

their diverse effects, including neuronal differentiation, neuronal

survival, long term neuroplasticity, and potentially learning and memory.

VPA-induced activation of ERK was blocked by the mitogen-activated protein

kinase/ERK kinase inhibitor PD098059 and dominant-negative Ras and Raf

mutants but not by dominant-negative stress-activated protein kinase/ERK

kinase and mitogen-activated protein kinase kinase 6 mutants. VPA also

increased the expression of genes regulated by the ERK pathway, including

growth cone-associated protein 43 and Bcl-2, promoted neurite growth and

cell survival, and enhanced norepinephrine uptake and release. These data

demonstrate that VPA is an ERK pathway activator and produces neurotrophic

effects.

PMID: 11418608 [PubMed - indexed for MEDLINE]

Clin Exp Med 2001 Sep;1(3):133-6 Related Articles, Books, LinkOut

Effect of anticonvulsant drugs on interleukins-1, -2 and -6 and monocyte

chemoattractant protein-1.

Verrotti A, Basciani F, Trotta D, Greco R, Morgese G, Chiarelli F.

Department of Medicine, University of Chieti, Ospedale Policlinico, Italy.

averrott@...

In order to evaluate whether treatment with valproic acid or carbamazepine

can modify interleukins and monocyte chemoattractant protein-1, we studied

40 epileptic children and adolescents. We evaluated the patients before and

after 1 year of therapy. At the end of follow-up, the patients showed a

significant increase of the production of interleukin-1alpha,

interleukin-1beta, interleukin-6, and monocyte chemoattractant protein-1;

interleukin-2 production was significantly higher only in patients receiving

carbamazepine. In conclusion, antiepileptic drugs can influence the immune

system by modifying interleukin and chemokine concentrations; these changes

seem to be independent of the serum concentrations of these drugs.

PMID: 11833849 [PubMed - in process]

Biol Psychiatry 2001 Aug 1;50(3):217-24 Related Articles, Books, LinkOut

The effects of lithium on ex vivo cytokine production.

Rapaport MH, Manji HK.

Psychopharmacology Research Program, Department of Psychiatry, University of

California, San Diego, California 92037, USA.

BACKGROUND: Studies suggest that lithium may have profound immunomodulatory

effects in animal models as well as in humans. METHODS: In this study, whole

blood cultures from normal control subjects were established for 5 days and

the effects of lithium on cytokine production were investigated. Because

many of lithium's actions have been postulated to be modulated through

phosphoinositide (PI), protein kinase C (PKC) and cyclic adenosine

monophosphate (c-AMP) signaling pathways, the effects of myo-inositol and

prostaglandin E(2), alone or in combination with lithium, were also

investigated. RESULTS: We found that lithium caused an increase in

interleukin-4 and interleukin-10 levels, traditionally classified as

T-helper lymphocyte type-2 cytokines, and a decrease in interleukin-2 and

interferon-gamma levels, traditionally classified as T-helper lymphocyte

type-1 (TH-1) cytokines. This shift cannot be fully explained by lithium's

actions on the PI, PKC, or c-AMP messenger systems. CONCLUSIONS: Monocytes

exposed to lithium in the presence of a mitogen for 5 days produced a shift

toward the production of TH-2 cytokines and away from the production of TH-1

cytokines. The study suggests that lithium may have complex time-dependent

effects on immune function.

PMID: 11513821 [PubMed - indexed for MEDLINE]

Fortschr Neurol Psychiatr 2001 Sep;69 Suppl 2:S65-74 Related Articles,

Books, LinkOut

[On the clinical relevance of clozapine-triggered release of cytokines and

soluble cytokine-receptors]

[Article in German]

Pollmacher T, Schuld A, Kraus T, Haack M, Hinze-Selch D.

Max Planck Institut fur Psychiatrie, Munchen. topo@...

Cytokines are pivotal mediators of the interaction between immunocompetent

cells. Moreover, they mediate the interaction between the immune system and

other physiological systems, including the CNS. It has been shown recently

that the antipsychotic drug clozapine stimulates in vivo the release of

cytokines and soluble cytokine receptors. This holds true for the tumor

necrosis factor(TNF)-system, the interleukin(IL)-2-system, IL-6, and

granulocyte colony-stimulating factor (G-CSF). The present paper discusses

the clinical relevance of these findings for the pathophysiology of

clozapine-induced side-effects. It is very probable that TNF-alpha plays an

important role in clozapin-induced fever and in the hematopoetic side

effects, including agranulocytosis. Moreover, it is likely that TNF-alpha

and other cytokines are involved in metabolic (weight gain, diabetes),

cardiac (myocarditis), CNS (sedation) and other rare side effects. The

mechanisms underlying clozapine-induced immunomodulation are unknown. Hence,

further studies are very important to enhance our understanding of

clozapins's side effects and to develop strategies for prevention and

treatment.

Publication Types:

Review

Review, Tutorial

PMID: 11533853 [PubMed - indexed for MEDLINE]

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volume 26, Issue 1

January 2002

Pages 33-39

PII: S0278584601002214

Cytokine profiles in schizophrenic patients treated with risperidone: A

3-month follow-up study

Carlo L. Cazzullo a, Emilio Sacchetti b, Alessandro Galluzzo bA, Adelaide

Panariello b, Adorni b, Marco Pegoraro b, Simona Bosis c, Fulvia

Colombo c, Daria Trabattoni c, Arianna Zagliani c and Clerici c

[a]Association for the Research on Schizophrenia (A.R.S.), Fondazione

Legrenzi, Milan, ItalyUniversity Psychiatric Service, Brescia University

School of Medicine and Spedali Civili, Pz. le Spedali Civili 1, 25130

Brescia, Italy[c]Chair of Immunology, DISP LITA Vialba, University of Milan,

Milan, Italy

A Corresponding author

Abstract

An increasing body of evidence suggests a role for the immune system in the

pathogenesis of schizophrenia. The information concerning the effects of

antipsychotics on cytokine profiles are limited and often controversial in

particular regarding novel antipsychotics. The authors first investigated

the production of various cytokines [interleukin (IL)-2, IL-4, IL-10,

interferon (INF)-] in drug-free (n=12) and drug-naive (n=3) schizophrenic

patients and in healthy controls (n=33) and then the modifications of

cytokines values during a 3-month period of treatment with risperidone. In

the baseline condition, the production of IL-2 and INF- was significantly

higher (P=.023 and .026, respectively) in patients than in controls. In the

same patients, the use of risperidone was associated with augmented IL-10 (a

suppressor of Type 1 cytokines) and decreased INF- production. This

modification suggests that clinical improvement is associated with a

reduction in the inflammatory-like situation present in not currently

treated schizophrenic patients.

© 2001 Elsevier Science Inc. All rights reserved.

Int J Exp Pathol 2001 Dec;82(6):337-48 Related Articles, Books, LinkOut

Ultrastructure of Purkinje cell perikarya and their dendritic processes in

the rat cerebellar cortex in experimental encephalopathy induced by chronic

application of valproate.

Sobaniec-Lotowska ME.

Department of Pathomorphology, Medical Academy of Bialystok, Waszyngtona,

Poland.

Long-term intragastric administration of the antiepileptic drug sodium

valproate (Vuprol Polfa) to rats for 1, 3, 6, 9 and 12 months, once daily at

the effective dose of 200 mg/kg body weight showed morphological evidence of

encephalopathy, manifested by numerous nonspecific changes within Purkinje

cell perikarya and their dendritic processes. The first ultrastructural

abnormalities appeared after 3 months. They became more severe in animals

with longer survival and were most pronounced after 12 months. The changes

were maintained both 1 and 3 months after drug withdrawal. Mitochondria of

Purkinje cell perikarya were most severely affected. Damage to mitochondria

was accompanied by disintegration and fragmentation of granular endoplasmic

reticulum, dilation of channels and cisterns of Golgi apparatus, enlargement

of smooth endoplasmic reticulum elements including submembranous cisterns,

and accumulation of profuse lipofuscin deposits. Frequently, Purkinje cells

appeared as dark ischemic neurones, with focally damaged cellular membrane

and features of disintegration. Swollen Bergmann's astrocytes were seen

among damaged Purkinje cells or at the site of their loss. The general

pattern of submicroscopic alterations of Purkinje cell perikarya suggested

severe disorders in several intercellular biochemical extents, including

inhibition of oxidative phosphorylation and abnormal protein synthesis, both

of which could lead to lethal damage. Ultrastructural abnormalities within

dendrites were characterized by damage to elements of smooth endoplasmic

reticulum, which was considerably enlarged, with formation of large vacuolar

structures situated deep in the dendroplasm. Mitochondrial lesions and

alterations in cytoskeletal elements--disintegration of microtubules or even

their complete loss--were also observed. The general pattern of

abnormalities within the organelles and cytoskeletal elements of dendritic

processes in Purkinje cells in the VPA chronic experimental model imply that

there are disturbances in detoxication processes. Furthermore these changes

were irreversible, as they were maintained after drug withdrawal.

PMID: 11846840 [PubMed - in process]

Neuropsychopharmacology 2001 Nov;25(5):729-36 Related Articles, Books,

LinkOut

Tetraspan protein CD151: a common target of mood stabilizing drugs?

Hua LV, Green M, Wong A, Warsh JJ, Li PP.

Section on Biochemical Psychiatry, Centre for Addiction and Mental Health,

e Site, 250 College Street, Toronto, Ontario, Canada, M5T 1R8.

The latency in onset of antimanic and mood stabilizing effects of lithium

suggest that long-term neuronal adaptations mediated by changes in gene

expression may be important to the therapeutic action of lithium treatment.

Using differential display-polymerase chain reaction, several novel,

hitherto unexpected lithium-regulated genes have been isolated, all of which

would not have been predicted with the candidate gene approach. During the

process of characterizing one of these novel genes, we have identified a

cDNA clone, a homolog of human/mouse transmembrane-4-superfamily (also known

as tetraspan) protein, CD151, the expression of which was significantly

decreased in rat frontal cortex following chronic (five weeks) lithium

treatment. The reduction of CD151 mRNA levels was also observed following

chronic administration of carbamazepine and valproate. Conversely, the

expression of CD151 was not altered by short-term (one week) lithium

treatment and by chronic administration of the tricyclic antidepressant,

imipramine, or the typical antipsychotic, haloperidol, further demonstrating

time dependence and pharmacological specificity of this effect. Our studies,

thus, indicate that CD151 may represent a therapeutically relevant target

common to lithium and the anticonvulsant mood stabilizing drugs,

carbamazepine and valproate.

PMID: 11682256 [PubMed - indexed for MEDLINE]

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