Abstract
Background: Experimental evidence supports the neuroprotective properties of lithium, with implications for the treatment and prevention of dementia and other neurodegenerative disorders. Lithium modulates critical intracellular pathways related to neurotrophic support, inflammatory response, autophagy and apoptosis. There is additional evidence indicating that lithium may also affect membrane homeostasis. Objective: To investigate the effect of lithium on cytosolic phospholipase A2 (PLA2) activity, a key player on membrane phospholipid turnover which has been found to be reduced in blood and brain tissue of patients with Alzheimer’s disease (AD). Methods: Primary cultures of cortical and hippocampal neurons were treated for 7 days with different concentrations of lithium chloride (0.02 mM, 0.2 mM and 2 mM). A radio-enzymatic assay was used to determine the total activity of PLA2 and two PLA2 subtypes: cytosolic calcium-dependent (cPLA2); and calcium-independent (iPLA2). Results: cPLA2 activity increased by 82% (0.02 mM; p = 0.05) and 26% (0.2 mM; p = 0.04) in cortical neurons and by 61% (0.2 mM; p = 0.03) and 57% (2 mM; p = 0.04) in hippocampal neurons. iPLA2 activity was increased by 7% (0.2 mM; p = 0.04) and 13% (2 mM; p = 0.05) in cortical neurons and by 141% (0.02 mM; p = 0.0198) in hippocampal neurons. Conclusion: long-term lithium treatment increases membrane phospholipid metabolism in neurons through the activation of total, c- and iPLA2. This effect is more prominent at sub-therapeutic concentrations of lithium, and the activation of distinct cytosolic PLA2 subtypes is tissue specific, i.e., iPLA2 in hippocampal neurons, and cPLA2 in cortical neurons. Because PLA2 activities are reported to be reduced in Alzheimer’s disease (AD) and bipolar disorder (BD), the present findings provide a possible mechanism by which long-term lithium treatment may be useful in the prevention of the disease.
Highlights
Lithium is a first-line drug for the acute and long-term treatment of bipolar disorder (BD)
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Recent findings from our group indicates that decreased independent PLA2 (iPLA2) activity predicts the risk of conversion from mild cognitive impairment (MCI) to dementia within the MCI-Alzheimer’s disease (AD) continuum, and decreased cPLA2 predicts incident MCI in former cognitively unimpaired elders [37]
Summary
Lithium is a first-line drug for the acute and long-term treatment of bipolar disorder (BD). Arachidonic acid (AA) is the most important and abundant free fatty acid released from membrane phospholipids through the catalytic activity of PLA2 [20,21] Both c- and iPLA2 are highly expressed in the central nervous system, with distinct roles and regional specificities, in addition to a distinct sensitivity and pattern of response to the effect of regulatory cascades. We further develop this hypothesis by analyzing the effect of chronic lithium treatment at different working concentrations (0.02, 0.2 and 2 mM) on PLA2 activity in primary cultures of cortical and hippocampal neurons. Recent findings from our group indicates that decreased iPLA2 activity predicts the risk of conversion from MCI to dementia within the MCI-AD continuum, and decreased cPLA2 predicts incident MCI in former cognitively unimpaired elders [37] These abnormalities seem to respond to treatment with the antidementia drug donepezil, restoring homeostatic levels of enzymatic activity [42]. The present findings suggest that lithium treatment may modify a biological abnormality that is found in patients with, or at risk of AD
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