Protein kinase C signaling in the brain: Molecular transduction of mood stabilization in the treatment of manic-depressive illness

被引:188
作者
Manji, HK
Lenox, RH
机构
[1] Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Mol Pathophysiol Lab, Detroit, MI 48201 USA
[2] Wayne State Univ, Sch Med, Clin Neurobiol Program, Detroit, MI 48201 USA
[3] Univ Penn, Sch Med, Dept Psychiat, Mol Neuropsychopharmacol Program, Philadelphia, PA USA
[4] Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA USA
[5] Univ Penn, Sch Med, Dept Neurosci, Philadelphia, PA USA
关键词
manic-depressive; lithium; valproate; protein kinase C; MARCKS; AP-1;
D O I
10.1016/S0006-3223(99)00235-8
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Understanding the biology of the pharmacological stabilization of mood will undoubtedly serve to provide significant insight into the pathophysiology of manic-depressive illness (MDI). Accumulating evidence from our laboratories and those of other researchers has identified the family of protein kinase C isozymes as a shared target in the brain for the long-term action of both lithium and valproate. In rats chronically treated with lithium, there is a reduction in the hippocampus of the expression of two protein kinase isozymes, alpha and epsilon, as well as a reduction in the expression of a major PKC substrate, MARCKS, which has been implicated in long-term neuroplastic events in the developing and adult brain. In addition, we have been invesigating the down-stream impact of these mood stabilzizers on another kinase system, GSK-3 beta and on the AP-1 family of transcription factors. Further studies have generated promising preliminary data in support of the antimanic action of tamoxifen, and antiestrogen that is also a PKC inhibitor. Future studies must address the therapuetic relevance of these protein targets in the brain using innovative strategies in both animal and clinical investigations to ultimately create opportunities for the discovery of the next generations of mood stabilizers for the treatment of MDI. Biol Psychiatry 1999;46: 1328-1351 (C) 1999 Society of Biological Psychiatry.
引用
收藏
页码:1328 / 1351
页数:24
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