Adverse effects of an active fragment of parathyroid hormone on rat hippocampal organotypic cultures

1 Adverse effects of an active fragment of parathyroid hormone (PTH1-34), a blood Ca2+ level-regulating hormone, were examined using rat hippocampal slices in organotypic culture. 2 Exposure of cultured slice preparations to 0.1 mu M PTH1-34 for 60 min resulted in a gradual increase in the intracellular Ca2+ concentration ([Ca2+](i)); this effect was most obvious in the apical dendritic region of CA1 subfield. 3 When PTH1-34 at a lower concentration (1 nM) was added to the culture medium and its toxic effects examined using a propidium iodide intercalation method, significant toxicity was seen 3 days after exposure and increased with 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, PTH39-84, Or by an active fragment of PTH-related peptide (PTHrP(1-34)), an intrinsic ligand of the brain PTH receptor. 5 The PTH1-34-induced adverse effects were significantly inhibited by co-administration 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 brain might cause degeneration of specific brain regions due to Ca2+ overloading via activation of dihydropyridine-sensitive Ca2+ channels, and suggests that PTH may be a risk factor for senile dementia.