PKC, MAP kinases and the bcl-2 family of
proteins as long-term targets for mood stabilizers

by
Manji HK, Chen G.
Laboratory of Molecular Pathophysiology,
National Institute of Mental Health,
Bethesda, MD 20892, USA.
manjih@intra.nimh.nih.gov
1: Mol Psychiatry 2002;7 Suppl 1:S46-56


ABSTRACT

The complexity of the unique biology of bipolar disorder--which includes the predisposition to episodic, and often progressive, mood disturbance--and the dynamic nature of compensatory processes in the brain, coupled with limitations in experimental design, have hindered our ability to identify the underlying pathophysiology of this fascinating neuropsychiatric disorder. Although we have yet to identify the specific abnormal genes in mood disorders, recent studies have implicated critical signal transduction pathways as being integral to the pathophysiology and treatment of bipolar disorder. In particular, a converging body of preclinical data has shown that chronic lithium and valproate, at therapeutically relevant concentrations, regulate the protein kinase C signaling cascade. This has led to the investigation of the antimanic efficacy of tamoxifen (at doses sufficient to inhibit protein kinase C), with very encouraging preliminary results. A growing body of data also suggests that impairments of neuroplasticity and cellular resilience may also underlie the pathophysiology of bipolar disorder. It is thus noteworthy that mood stabilizers, such as lithium and valproate, indirectly regulate a number of factors involved in cell survival pathways--including cAMP response element binding protein, brain derived neurotrophic factor, bcl-2 and mitogen-activated protein kinases--and may thus bring about some of their delayed long-term beneficial effects via under-appreciated neurotrophic effects. The development of novel treatments, which more directly target molecules involved in critical central nervous system cell survival and cell death pathways, has the potential to enhance neuroplasticity and cellular resilience, thereby modulating the long-term course and trajectory of these devastating illnesses.
Mania
Tamoxifen
Protein kinase C
Bipolar disorders
Drugs for bipolars
Lithium prophylaxis
The manic spectrum
Schizoaffective disorder
The many faces of mania
The ERK signaling cascade
Mania: lithium versus divaplroex
Dysthymia, hyperthymia and cyclothymia


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