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

Adverse effects of an active fragment of parathyroid hormone (PTH 1–34 ), a blood Ca 2+ level‐regulating hormone, were examined using rat hippocampal slices in organotypic culture. Exposure of cultured slice preparations to 0.1 μ M PTH 1–34 for 60 min resulted in a gradual increase in the intracellular Ca 2+ concentration ([Ca 2+ ] i ); this effect was most obvious in the apical dendritic region of CA1 subfield. When PTH 1–34 at a lower concentration (1 n M ) 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 p M to 0.1 μ M , the minimum effective dose being 10 p M . 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 intrinsic ligand of the brain PTH receptor. The PTH 1–34 ‐induced adverse effects were significantly inhibited by co‐administration of 10 μ M nifedipine, an L‐type Ca 2+ channel blocker, but not by co‐administration of blockers of the other types of Ca 2+ channel. The present study demonstrates that sustained high levels of PTH in the brain might cause degeneration of specific brain regions due to Ca 2+ overloading via activation of dihydropyridine‐sensitive Ca 2+ channels, and suggests that PTH may be a risk factor for senile dementia.British Journal of Pharmacology (2000) 129 , 21–28; doi: 10.1038/sj.bjp.0702949