Vol 11, N°3 Neurotoxicity and Neuroprotection
Past issues Contributors How to publish Contributions and comments Home
 
here is no doubt that dopaminergic, serotoner- gic,  and/or  noradrenergic neurotransmission play an important role in the pathophysiology of major depres- sion (MD) and schizophrenia. Although the roles of dopamine in schizophrenia and of serotonin and nora- drenaline in depression have been studied intensively, the exact underlying pathological mechanisms of both disorders are still unclear. In MD, glutamatergic hyperfunction seems to be closely related to the lack of serotonergic and noradrenergic neu- rotransmission.  Altered  glutamate  levels  have  been observed in the plasma, serum, cerebrospinal fluid (CSF), and  in  imaging  and  postmortem  studies  of  depressed P h a r m a c o l o g i c a l  a s p e c t s T The impact of neuroimmune dysregulation on neuroprotection and neurotoxicity in psychiatric disorders—relation to drug treatment Norbert Müller, MD, PhD, DipPsych; Aye-Mu Myint, MD, PhD, Markus J. Schwarz, MD, PhD   Keywords: schizophrenia; major depression; kynurenine; inflammation;
therapy Author  affiliations:  Department  of  Psychiatry  and  Psychotherapy, Ludwig-Maximilians-Universit‰t M¸nchen, Germany   Address  for  correspondence: Prof  Dr  med  Dipl-Psych  Norbert  M¸ller, Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universit‰t, Nuflbaumstr. 7, 80336 M¸nchen, Germany (e-mail: norbert.mueller@med.uni-muenchen.de) An inflammatory pathogenesis has been postulated for schizophrenia and major depression (MD). In schizophrenia and depression, opposing patterns of type-1 vs type-2 immune response seem to be associated with differences in the activation of the enzyme indoleamine 2,3-dioxygenase and in the tryptophan-kynurenine metabolism, resulting in increased production of kynurenic acid in schizophrenia and decreased production of kynurenic acid in depression. These differences are associated with an imbalance in the glutamatergic neurotransmission, which may contribute to an excessive agonist action of N-methyl-D-aspartate (NMDA) in depression and of NMDA antagonism in schizophre- nia. Regarding the neuroprotective function of kynurenic acid and the neurotoxic effects of quinolinic acid (QUIN), different patterns of immune activation may also lead to an imbalance between the neuroprotective and the neuro- toxic effects of the tryptophan/kynurenine metabolism. The differential activation of microglia cells and astrocytes may be an additional mechanism contributing to this imbalance. The immunological imbalance results in an inflam- matory state combined with increased prostaglandin E2 production and increased cyclo-oxygenase-2 (COX-2) expres- sion. The immunological effects of many existing antipsychotics and antidepressants, however, partly correct the immune imbalance and the excess production of the neurotoxic QUIN. COX-2 inhibitors have been tested in animal models of depression and in preliminary clinical trials, pointing to favorable effects in schizophrenia and in MD. © 2009, LLS SAS Dialogues Clin Neurosci. 2009;11:319-332. Copyright © 2009 LLS SAS.  All rights reserved www.dialogues-cns.org