Long-Term Lithium Treatment Increases cPLA2 and iPLA2 Activity in Cultured Cortical and Hippocampal Neurons.

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.

Chronic Lithium Treatment Increases Telomere Length in Parietal Cortex and Hippocampus of Triple-Transgenic Alzheimer's Disease Mice.

Telomere length (TL) is a biomarker of cell aging, and its shortening has been linked to several age-related diseases. In Alzheimer's disease (AD), telomere shortening has been associated with neuroinflammation and oxidative stress. The majority of studies on TL in AD were based on leucocyte DNA, with little information about its status in the central nervous system. In addition to other neuroprotective effects, lithium has been implicated in the maintenance of TL. The present study aims to determine the effect of chronic lithium treatment on TL in different regions of the mouse brain, using a triple-transgenic mouse model (3xTg-AD). Eighteen transgenic and 22 wild-type (Wt) male mice were treated for eight months with chow containing 1.0 g (Li1) or 2.0 g (Li2) of lithium carbonate/kg, or standard chow (Li0). DNA was extracted from parietal cortex, hippocampus and olfactory epithelium and TL was quantified by real-time PCR. Chronic lithium treatment was associated with longer telomeres in the hippocampus (Li2, p = 0.0159) and in the parietal cortex (Li1, p = 0.0375) of 3xTg-AD compared to Wt. Our findings suggest that chronic lithium treatment does affect telomere maintenance, but the magnitude and nature of this effect depend on the working concentrations of lithium and characteristics of the tissue. This effect was observed when comparing 3xTg-AD with Wt mice, suggesting that the presence of AD pathology was required for the lithium modulation of TL.

A inibição da atividade da fosfolipase A2 no hipocampo de ratos prejudica a formação da memória de curta e de longa duração: implicações para a doença de Alzheimer / Inhibition of phospholipase A2 activity in rat hippocampus impairs short and long term memory formation: implications for Alzheimer's disease

Na doença de Alzheimer (DA) leve há prejuízo da memória de curta (MCD) e de longa duração (MLD) episódica, em correlação com a hipofunção do hipocampo. A atividade da fosfolipase A2 (PLA2) foi encontrada reduzida no hipocampo de pacientes com DA. A inibição da PLA2 na região CA1 de fatias hipocampais de ratos impede a indução da potenciação de longa duração, um mecanismo neuronal da MLD. Neste estudo, investigou-se os efeitos de injeções de inibidores da PLA2 na região CA1 do hipocampo de ratos sobre a formação da MCD e da MLD. A inibição da atividade da PLA2 prejudicou a formação da MCD e da MLD, sugerindo que a atividade reduzida da PLA2 pode contribuir para o prejuízo de memória na DA./In mild Alzheimer’s disease (AD) there is impairment of episodic short-term (STM) and long-term memory (LTM), in correlation with the hypofunction of the hippocampus. Phospholipase A2 (PLA2) activity was found to be reduced in the hippocampus of AD patients. PLA2 inhibition in the CA1 region of rat hippocampal slices prevents the induction of long-term potentiation, a neuronal mechanism of LTM. In this study, we investigated the effects of injections of PLA2 inhibitors into the CA1 region of rat hippocampus on STM and LTM formation. PLA2 inhibition impaired STM and LTM formation, suggesting that reduced PLA2 activity may contribute to memory impairment in AD...