Differential Uptake of Lithium Isotopes by Rat Cerebral Cortex and Its Effect on Inositol Phosphate Metabolism

Abstract

Twenty hours following the subcutaneous administration of 5 mEq/kg doses of 6LiCl and 7LiCl to two groups of rats, the cerebral cortex molar ratio of 6Li+/7Li+ is 1.5. The effects of the lithium isotopes on cortex myo-inositol and myo-inositol-l-phosphate levels are the same as we have reported earlier: a Li+ concentration-dependent lowering of myo-inositol and increase in myo-inositol-1-phosphate. Thus 6LiCl, when administered at the same dose as 7LiCl, produces the larger effect on inositol metabolism. When the 6LiCl and 7LiCl doses were adjusted to 5 mEq/kg and 7 mEq/kg, respectively, the cortical lithium myo-inositol and myo-inositol-1-phosphate levels of each group of animals became approximately equal, suggesting that the isotope effect occurs at the level of tissue uptake, but not on inositol phosphate metabolism. The inhibition of myo-inositol-1-phosphatase by the two lithium isotopes in vitro showed no differential effect. The isotope effect on cerebral cortex uptake of lithium is in the same direction as that reported by others for erythrocytes and for the CSF/plasma ratio, but of larger magnitude.

Lithium isotopes: differential effects on renal function and histology

“…Lithium isotopes show differential effects on maternal behaviors and on development and learning in rat pups (11). Twenty hours after subcutaneous administration of equimolar amounts of each isotope to rats, the molar ratio of 6 Li to 7 Li in cerebral cortex is 1.5, with a resulting larger differential effect on brain inositol metabolism (12) and the speed with which these isotopes diffuse through an aqueous solution (13). These data are consistent with the possibilities that 6 Li crosses cell membranes and the blood-brain barrier faster than 7 Li, with resulting different effects on tissue function.…”

“…6 Li passively diffuses through aqueous solutions more rapidly than 7 Li (13) and achieves higher erythrocyte concentrations than 7 Li when red cells are incubated in lithium-containing solutions (6 -8). 6 Li apparently crosses the gut membrane faster than 7 Li, resulting in higher plasma 6 Li concentrations (10), and can achieve higher cerebrospinal fluid (10) and cerebral cortex (12) concentrations after single equimolar doses of the two isotopes. Therefore, concentration differences at the renal tubule may well be present, and may be related to the difference in functional renal effects of the two lithium isotopes.…”

Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation

“…It is of interest that 6 Li and natural Li, which contains about 93% 7 Li, showed no difference in their potency for inducing neuroprotection and neurotoxic effects. 6 Li and 7 Li have been shown to have a signi®cant difference in their NMR spectra (Riddell 1991), rate of intracellular uptake (Sherman et al 1984), lethality dose (Alexander et al 1982), and potency to inhibit inositol monophosphatase (Sherman et al 1984). 6 Li and 7 Li were found in a subsequent study, however, not to differ in the latter two properties (Parthasarathy et al 1992).…”

“…It is of interest that 6 Li and natural Li, which contains about 93% 7 Li, showed no difference in their potency for inducing neuroprotection and neurotoxic effects. 6 Li and 7 Li have been shown to have a significant difference in their NMR spectra (Riddell 1991), rate of intracellular uptake (Sherman et al . 1984), lethality dose (Alexander et al .…”

“…1984), lethality dose (Alexander et al . 1982), and potency to inhibit inositol monophosphatase (Sherman et al . 1984).…”