T. Hirasawa et al., Adverse effects of an active fragment of parathyroid hormone on rat hippocampal organotypic cultures, BR J PHARM, 129(1), 2000, pp. 21-28
1 Adverse effects of an active fragment of parathyroid hormone (PTH1-34), a
blood Ca2+ level-regulating hormone, were examined using rat hippocampal s
lices in organotypic culture.
2 Exposure of cultured slice preparations to 0.1 mu M PTH1-34 for 60 min re
sulted in a gradual increase in the intracellular Ca2+ concentration ([Ca2](i)); this effect was most obvious in the apical dendritic region of CA1 s
ubfield.
3 When PTH1-34 at a lower concentration (1 nM) was added to the culture med
ium and its toxic effects examined using a propidium iodide intercalation m
ethod, significant toxicity was seen 3 days after exposure and increased wi
th time. Cells in the CA1 region seemed more vulnerable to the hormone than
cells in other regions. At 1 week of exposure, the toxic effects were dose
-dependent over the range of 0.1 pM to 0.1 mu M, the minimum effective dose
being 10 pM.
4 The adverse effects were not induced either by the inactive fragment, PTH
39-84, Or by an active fragment of PTH-related peptide (PTHrP(1-34)), an in
trinsic ligand of the brain PTH receptor.
5 The PTH1-34-induced adverse effects were significantly inhibited by co-ad
ministration of 10 mu M nifedipine, an L-type Ca2+ channel blocker, but not
by co-administration of blockers of the other types of Ca2+ channel.
6 The present study demonstrates that sustained high levels of PTH in the b
rain might cause degeneration of specific brain regions due to Ca2+ overloa
ding via activation of dihydropyridine-sensitive Ca2+ channels, and suggest
s that PTH may be a risk factor for senile dementia.