Abstract:Recently, erythropoietin (EPO) receptors and synthesis of EPO have been identified in the brain. To clarify the effects of EPO on neuronal cells, we investigated the effects of EPO on Ca 2ϩ uptake, intracellular Ca 2ϩ concentration, membrane potential, cell survival, release and biosynthesis of dopamine, and nitric oxide (NO) production in differentiated PC12 cells, which possess EPO receptors. EPO (10 Ϫ12 -10 Ϫ10 M) increased 45 Ca 2ϩ uptake and intracellular Ca 2ϩ concentration in PC12 cells in a dose-related manner; these increases were inhibited by nicardipine (1 M) or anti-EPO antibody (1:100 dilution). EPO induced membrane depolarization in PC12 cells. After a 5-day culture without serum and nerve growth factor (NGF), viable cell number decreased to 50% of that of the control cells cultured with serum and NGF. EPO (10 Ϫ13 -10 Ϫ10 M) increased the number of viable cells cultured without serum and NGF; this increase was blunted by nicardipine or anti-EPO antibody. Incubation with EPO (10 Ϫ13 -10 Ϫ10 M) stimulated mitogen-activated protein kinase activity in PC12 cells. EPO (10 Ϫ13 -10 Ϫ10 M) increased dopamine release from PC12 cells and tyrosine hydroxylase activity; these increases were sensitive to nicardipine or anti-EPO antibody. Following a 4-h incubation with EPO (10 Ϫ14 -10 Ϫ10 M), NO production was increased, which was blunted by nicardipine and anti-EPO antibody. In contrast, maximal NO synthase activity was not changed by EPO. These results suggest that EPO stimulates neuronal function and viability via activation of Ca 2ϩ channels. Key Words: Erythropoietin-PC12 cells-Ca 2ϩ channels-Cell survivalDopamine release -Nitric oxide.

Effects of aging and sex on total plasma IGF-I levels were studied in 207 normal adults (103 males and 104 females), aged 21 to 80 years. Plasma IGF-I concentrations were measured by specific radioimmunoassay after extraction with acid-ethanol. Plasma IGF-I levels ranged from 50.8 to 480.6 \ g=m\ g/ l with a mean (\m=+-\sd)value of 200.7\m=+-\81.9 \g=m\g/l in these normal adults. The mean plasma IGF-I levels were higher in females than in males in the second decade (332.6\m=+-\63.9 vs 252.4\m=+-\45.2\g=m\g/l,p<0.01), whereas there was no sex difference in plasma IGF-I levels in elderly subjects. In both sexes, plasma IGF-I levels declined with age. In females, the slope of the regression line was much steeper in the young group (aged 21 to 40 years) than in the middle-aged and elderly group (aged 41 to 80 years) (y=\m=-\11.3x+641.7, r=\m=-\0.538, p<0.005 and y=\m=-\1.97x+289.3, r=\m=-\0.308,p<0.01). In males, plasma IGF-I linearly declined with age and the slope of the regression line (y=\m=-\2.36x+322.2, r=\m=-\0.480, p<0.005) was not considerably different from that of the middle-aged and elderly group in females.

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Growth hormone (GH) secretion from anterior pituitary is regulated by the hypothalamus and the mediators of GH actions. Major regulatory factors include GHreleasing hormone (GHRH), somatostatin (SRIF), GHreleasing peptide (ghrerin) and insulin-like growth factor (IGF-I). The principal physiological regulation mechanisms of GHsecretion are neural endogenousrhythm, sleep, stress, exercise, and nutritional and metabolic signals. GHdeficiency results from various hereditary or acquired causes, which may be isolated or combined with other pituitary hormone deficiencies. GHdeficiency can be treated with recombinant humanGH, which results in accelerating growth in children and normalization of intermediary metabolism in adults. GHhypersecretion mostly results from a pituitary tumor and causes acromegaly or gigantism. Hypersecretion of GHcan be treated by transshenoidal surgery. Medical treatment with octreotide and analogs is also effective to reduce GHsecretion in combination with or without the surgery. (Internal Medicine 41: 7-13, 2002)

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