Translating neurotrophic and cellular plasticity: from pathophysiology to improved therapeutics for bipolar disorder

Soeiro-de-Souza MG, Dias VV, Figueira ML, Forlenza OV, Gattaz WF, Zarate Jr CA, Machado-Vieira R. 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. Conclusion: 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.