TY - JOUR
T1 - Chronic treatment with anti-bipolar drugs causes intracellular alkalinization in astrocytes, altering their functions
AU - Song, Dan
AU - Li, Baoman
AU - Yan, Enzhi
AU - Man, Yi
AU - Wolfson, Marina
AU - Chen, Ye
AU - Peng, Liang
N1 - Funding Information:
Acknowledgments This study was supported by Grants No. 30770667 and No. 31171036 to LP from the National Natural Science Foundation of China. We are grateful to Dr. Barneda Ciurana for permission to quote from parts of his Ph.D. thesis, written under the supervision of Dr. Enrique Claro, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain. We also thankfully acknowledge the intellectual influence, via Leif, by the late Professor Mogens Schou, Statshospitalet ved Risskov, University of Aarhus, Denmark, who introduced general use of lithium treatment in patients and verified its clinical usefulness in careful double-blind experiments, and Professor Robert (Haim) Bel-maker, Department of Psychiatry, Ben Gurion University of the Negev, Beer Sheva, Israel, a world-renowned investigator of myoinositol effects. Leif had the good fortune of working with both, Mogens Schou in his very first research paper, 50 years ago, and Professor Belmaker on sabbaticals decades later.
PY - 2012/11/1
Y1 - 2012/11/1
N2 - 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.
AB - 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.
KW - Alkalinization
KW - Arachidonic acid
KW - Bipolar disorder
KW - Ca2-dependent phospholipase A (cPLA)
KW - Fluorescence activated cell sorting (FACS)
KW - GluK2
KW - Myo-Inositol transporters
UR - http://www.scopus.com/inward/record.url?scp=84871427792&partnerID=8YFLogxK
U2 - 10.1007/s11064-012-0837-7
DO - 10.1007/s11064-012-0837-7
M3 - Review article
AN - SCOPUS:84871427792
SN - 0364-3190
VL - 37
SP - 2524
EP - 2540
JO - Neurochemical Research
JF - Neurochemical Research
IS - 11
ER -