Chronic treatment with anti-bipolar drugs causes intracellular alkalinization in astrocytes, altering their functions

Dan Song, Baoman Li, Enzhi Yan, Yi Man, Marina Wolfson, Ye Chen, Liang Peng

Research output: Contribution to journalReview articlepeer-review

16 Scopus citations

Abstract

Bipolar disorder I and II are affective disorders with mood changes between depressive and manic (bipolar I) or hypomanic (bipolar II) periods. Current therapy of these conditions is chronic treatment with one or more of the anti-bipolar drugs, Li+ ('lithium'), carbamazepine and valproic acid. The pathophysiology of bipolar disorder is multifactorial and far from clear. Recent data on the dependence of normal brain function on neuronal-astrocytic interactions raise the possibility of astrocytic involvement. We will discuss our previously published and new results on effects of chronic treatment of primary cultures of normal mouse astrocytes with any of three conventional anti-bipolar drugs. The focus will be on several drug-induced events in relation to therapeutic effects of the drugs, such as myo-inositol uptake, intracellular pH and alkalinization, drug-induced modulation of glutamatergic activity in astrocytes and release of astrocytic 'gliotransmitters'. Finally, we will discuss the importance of phospholipase A2 (PLA2) and arachidonic acid cascade in drug-treated astrocytes, partly based on Dr. Barneda Cuirana's published thesis. All three drugs cause gradual intracellular alkalinization through different mechanisms. Alkalinization inhibit myo-inositol uptake, resulting in reduced inositolphosphate/phospholipid signaling. Accordingly, transmitter-induced increase in free intracellular Ca2+ ([Ca2+]i) becomes inhibited, aborting release of astrocytic 'gliotransmitters'. The reduction of "gliotransmitter" effects on neurons may have therapeutic effects in mania. Alkalinization also up-regulates expression of cPLA2, an enzyme releasing arachidonic acid, and triggered arachidonic acid cascade and production, but perhaps not release, of prostaglandins. Whenever tested, identical effects were observed in freshly isolated astrocytes, but not neurons, from carbamazepine-treated healthy animals.

Original languageEnglish
Pages (from-to)2524-2540
Number of pages17
JournalNeurochemical Research
Volume37
Issue number11
DOIs
StatePublished - 1 Nov 2012

Keywords

  • Alkalinization
  • Arachidonic acid
  • Bipolar disorder
  • Ca2-dependent phospholipase A (cPLA)
  • Fluorescence activated cell sorting (FACS)
  • GluK2
  • Myo-Inositol transporters

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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