Translating neurotrophic and cellular plasticity: from pathophysiology to improved therapeutics for bipolar disorder.
OBJECTIVE
Bipolar disorder (BD) likely involves, at a molecular and cellular level, dysfunctions of critical neurotrophic, cellular plasticity and resilience pathways and neuroprotective processes. Therapeutic properties of mood stabilizers are presumed to result from a restoration of the function of these altered pathways and processes through a wide range of biochemical and molecular effects. We aimed to review the altered pathways and processes implicated in BD, such as neurotrophic factors, mitogen-activated protein kinases, Bcl-2, phosphoinositol signaling, intracellular calcium and glycogen synthase kinase-3.


METHODS
We undertook a literature search of recent relevant journal articles, book chapter and reviews on neurodegeneration and neuroprotection in BD. Search words entered were 'brain-derived neurotrophic factor,''Bcl-2,''mitogen-activated protein kinases,''neuroprotection,''calcium,''bipolar disorder,''mania,' and 'depression.'


RESULTS
The most consistent and replicated findings in the pathophysiology of BD may be classified as follows: i) calcium dysregulation, ii) mitochondrial/endoplasmic reticulum dysfunction, iii) glial and neuronal death/atrophy and iv) loss of neurotrophic/plasticity effects in brain areas critically involved in mood regulation. In addition, the evidence supports that treatment with mood stabilizers; in particular, lithium restores these pathophysiological changes.


CONCLUSIONS
Bipolar disorder is associated with impairments in neurotrophic, cellular plasticity and resilience pathways as well as in neuroprotective processes. The evidence supports that treatment with mood stabilizers, in particular lithium, restores these pathophysiological changes. Studies that attempt to prevent (intervene before the onset of the molecular and cellular changes), treat (minimize severity of these deficits over time), and rectify (reverse molecular and cellular deficits) are promising therapeutic strategies for developing improved treatments for bipolar disorder.
Mood Disorders Unit (GRUDA), Department and Institute of Psychiatry, School of Medicine, University of Sao Paulo (HC-FMUSP), São Paulo, Brazil.
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D018692:Antimanic Agents / Q000627:therapeutic use; D001284:Atrophy / Q000378:metabolism; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006801:Humans; D008094:Lithium / Q000627:therapeutic use; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D018692:Antimanic Agents; D019208:Brain-Derived Neurotrophic Factor; D019253:Proto-Oncogene Proteins c-bcl-2; D008094:Lithium; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium