Distribution of myo-inositol in the cat cochlear nucleus.

The distribution of myo-inositol, a substance that has been implicated in synaptic transmission, has been mapped within sections of the cat cochlear nucleus as well as some nearby regions. Highest values in the cochlear nucleus were found in regions of granule cells along the periphery of the anteroventral subdivision of the nucleus. Highest values overall were found in the molecular layer of the cerebellar flocculus. A fairly good correlation was found between myo-inositol levels and activities of the enzymes of acetylcholine metabolism in the cat cochlear nucleus, supporting the possibility that myo-inositol may be involved in cholinergic synaptic transmission. No positive correlation was found between myo-inositol levels and the levels of glutamate, aspartate, glycine, or gamma-aminobutyric acid (GABA). The most striking gradient of myo-inositol levels within a region was found in the auditory nerve, where different myo-inositol levels might be related to nerve fibers innervating different parts of the cochlea. The distribution of scyllo-inositol, a stereoisomer of myo-inositol, was also examined, and found to parallel closely the distribution of myo-inositol, with levels 4--5% as high.

Evidence that lithium alters phosphoinositide metabolism: chronic administration elevates primarily D-myo-inositol-1-phosphate in cerebral cortex of the rat.

The administration of LiCl (3.6 mequiv./kg/day) to adult male rats for 9 days results in an increase in the cerebral cortex level of myo-inositol-1-phosphate (M1P) to 4.43 +/- 0.52 mmol/kg (dry weight) compared with a control level of 0.24 +/- 0.02 mmol/kg. This establishes that the previously observed acute effect of lithium on M1P (Allison et al., 1976) is both prolonged and augmented by repeated doses of lithium. Larger doses of LiCl over a 3-5 day period result in even larger increases in M1P and a 35% decrease in myo-inositol. In each case, 90% of the increase is due to the D-enantiomer, evidence that lithium is largely producing this effect via phospholipase C-mediated phosphoinositide metabolism. Data are presented showing that lithium is an uncompetitive inhibitor of the hydrolysis of both D- and L-M1P by M1P'ase.

Human diabetic endoneurial sorbitol, fructose, and myo-inositol related to sural nerve morphometry.

Fascicles of the sural nerve from each of 20 diabetic patients, mostly with maturity-onset diabetes, were studied by biochemical and pathological techniques, and results were compared to values found in nerve specimens from 15 healthy persons. The sorbitol and fructose content was much more variable in diabetic than in healthy nerves. More than one-third of the diabetic nerves had sorbitol and fructose values above the highest levels for controls. myo-Inositol and scyllo-inositol content was not reduced in diabetic nerves. The sorbitol, fructose, and inositol concentrations could not be related to clinical, neurophysiological, or pathological severity of neuropathy. A comparison of scored symptoms and signs and clinical neurophysiological studies against morphometric and teased fiber studies of sural nerve demonstrated that the former three provide sensitive and reliable measures of severity of neuropathy that can be used for controlled clinical trials of diabetic neuropathy. The presence and type of teased fiber abnormalities could be related to the duration of diabetes and to symptoms of neuropathy. In untreated diabetics without symptoms of neuropathy, a higher than normal frequency of teased fibers showing segmental demyelination and remyelination was found. Untreated diabetics with symptomatic neuropathy showed two kinds of abnormalities: fibers with segmental demyelination and remyelination and fibers undergoing axonal degeneration. In treated diabetics, who often had longstanding neuropathy, the most common abnormalities were fibers undergoing axonal degeneration.

The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain.

myo-Inositol-1-phosphatase has been partially purified from bovine brain. The enzyme has a molecular weight of about 58,000. Both L-myo-inositol 1-phosphate and D-myo-inositol 1-phosphate are hydrolyzed by the enzyme as well as (-)-chiro-inositol 3-phosphate and 2'-AMP. Triphosphoinositide is not a substrate. The phosphatase is completely dependent on Mg2+, which has a Km of 1 mM. Calcium and manganese ions are competitive inhibitors of Mg2+ binding with Ki values of 18 microM and 2 microM, respectively. Lithium chloride inhibits the hydrolysis of both L- and D-myo-inositol 1-phosphate to the extent of 50% at a concentration of 0.8 mM. The phosphatase from testis is similarly inhibited by lithium. Lithium ion is a noncompetitive inhibitor of Mg2+ binding and an uncompetitive inhibitor of myo-inositol 1-phosphate binding. Because lithium chloride administration elicits both an increase in the levels of myo-inositol 1-phosphate and a decrease in the levels of myo-inositol in rat brain (Allison, 1978), and because these actions are blocked by anticholinergic agents, we examined the effects of cholinergic agonists and antagonists on the enzyme and found none. The possibility that the inhibition of this enzyme by lithium ion is related to the pharmacological actions of lithium is discussed.