The impact of neuroimmune dysregulation on neuroprotection and neurotoxicity in psychiatric disorders--relation to drug treatment.
An inflammatory pathogenesis has been postulated for schizophrenia and major depression (MD). In schizophrenia and depression, opposing patterns of type-7 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 schizophrenia. 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 neurotoxic 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 inflammatory state combined with increased prostaglandin E2 production and increased cyclo-oxygenase-2 (COX-2) expression. 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.
Müller
Norbert
N
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Germany. norbert.mueller@med.uni-muenchen.de
Myint
Aye-Mu
AM
Schwarz
Markus J
MJ
D000818:Animals; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D001523:Mental Disorders / Q000188:drug therapy / Q000209:etiology* / Q000276:immunology* / Q000517:prevention & control; D015213:Neuroimmunomodulation / Q000502:physiology*; D018696:Neuroprotective Agents / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000150:complications* / Q000188:drug therapy / Q000276:immunology
D052246:Cyclooxygenase 2 Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents