Valproate activates the Notch3/c-FLIP signaling cascade: a strategy to attenuate white matter hyperintensities in bipolar disorder in late life?

摘要

ObjectivesIncreased prevalence of deep white matter hyperintensities (DWMHs) has been consistently observed in patients with geriatric depression and bipolar disorder. DMWHs are associated with chronicity, disability, and poor quality of life. They are thought to be ischemic in their etiology and may be related to the underlying pathophysiology of mood disorders in the elderly. Notably, these lesions strikingly resemble radiological findings related to the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy (CADASIL) syndrome. CADASIL arises from mutations in Notch3, resulting in impaired signaling via cellular Fas-associated death domain-like interleukin-1-beta-converting enzyme-inhibitory protein (c-FLIP) through an extracellular signal-regulated kinase (ERK)-dependent pathway. These signaling abnormalities have been postulated to underlie the progressive degeneration of vascular smooth muscle cells (VSMC). This study investigates the possibility that the anticonvulsant valproate (VPA), which robustly activates the ERK mitogen-activated protein kinase (MAPK) cascade, may exert cytoprotective effects on VSMC through the Notch3/c-FLIP pathway.