Glycogen synthesis in brain and astrocytes is inhibited by chronic lithium treatment

Abstract

Lithium is a drug widely used to treat bipolar disorder. It has been shown to inhibit the total activity of phosphoglucomutase (PGM) from rat brains. In this work, we show that lithium inhibits in vitro PGM activity in the cortex, hippocampus, striatum, brainstem and cerebellum. As a compensatory effect, chronic lithium treatment of Wistar rats for 6 weeks caused a 1.6-fold upregulation of cortex PGM activity. No difference was observed in the other areas tested. Another effect of chronic lithium administration was a drastic reduction of glycogen content in rat brains, as PGM activity is essential for its synthesis. In a primary culture of astrocytes, which are the main cellular components of the brain that produce glycogen, administration of 1mM lithium for 3 days markedly reduced the steady state of glycogen content. In agreement with this result, lithium did not cause insulin-like effects as previously observed in hepatocytes where lithium activated glycogen synthesis. Reduction of glycogen content was due to inhibition of glycogen synthesis, as incorporation of [(14)U(-)C]-glucose into glycogen was impaired by lithium. Consistent with these results, incubation of glucose-starved astrocytes with lithium did not stimulate dephosphorylation of glycogen synthase, which normally occurs with re-feeding of glucose. Furthermore, in a chronically treated astrocyte culture, glycogen synthase was phosphorylated constitutively. Our results indicate that chronic lithium treatment can inhibit glycogen synthesis in brain suggesting that this effect might contribute to lithium's therapeutic effect.

Inhibition of GSK3β by pharmacological modulation of sphingolipid metabolism occurs independently of ganglioside disturbance in a cellular model of Alzheimer's disease

“…In addition, we found that the Ser641phosphorylated form of GS, which is another PP1 substrate (Delibegovic et al, 2003;Suzuki et al, 2001), accumulated in PDMPtreated cells, suggesting that GS was not dephosphorylated under these conditions. Moreover, similar conclusions were drawn by others to explain the lack of GS dephosphorylation they observed when GSK3β was inhibited by the well-known GSK3 inhibitor lithium chloride (LiCl) in cultured astrocytes and L6 myocytes, respectively (Choi and Sung, 2000;de Almeida Souza et al, 2010). Together, our results in conjunction with the data from the literature suggest that in our conditions, both pGSK3βSer9 and pGSSer641 remained elevated after PDMP treatment because both enantiomers reduced the long-chain ceramide species production, which in turn blocked the stimulation of PP1 activity, resulting in a lesser dephosphorylation of GSK3β and GS.…”

Quantitative Study of Volumetric Changes of Cerebellum in Male Adult Rat Following Lithium Administration

“…De Almeida Souza et al, showed that Lithium therapy led to a marked decrease in glycogen content in whole brain. Glycogen metabolism might be implicated in the pathogenesis of bipolar disorder and its diminished synthesis by Lithium can be relevant to treated patients (20). Our study showed that white matter volume in Lithium treated group decreased compared to control group.…”

The Erythrocytic Hypothesis of Brain Energy Crisis in Sporadic Alzheimer Disease: Possible Consequences and Supporting Evidence

“…In addition to ATP, other important energy substrates, for example, lactate produced by glucose metabolism are used by neurons as an additional energy substrate when metabolic activity is high [148,149]. Glucose carbon can be included in lipids [150], proteins [151], and glycogen [152] and is also a precursor of some neurotransmitters such as γ-aminobutyric acid, GABA [153], glutamate [154], and acetylcholine [155] as well as nicotinamide adenine dinucleotide phosphate reduced (NADPH) essential for maintaining brain antioxidant capacity [156].…”