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 microM 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 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 microM, the minimum effective dose being 10 pM. 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 microM 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
Hirasawa
T
T
School of Life Science, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Nakamura
T
T
Mizushima
A
A
Morita
M
M
Ezawa
I
I
Miyakawa
H
H
Kudo
Y
Y
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005456:Fluorescent Dyes; D016257:Fura-2; D006624:Hippocampus / Q000187:drug effects*; D007091:Image Processing, Computer-Assisted; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D009924:Organ Culture Techniques; D010281:Parathyroid Hormone / Q000096:biosynthesis / Q000494:pharmacology / Q000633:toxicity*; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000096:biosynthesis / Q000494:pharmacology / Q000633:toxicity*; D011419:Propidium / Q000494:pharmacology; D011506:Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018016:Receptors, Parathyroid Hormone / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D005456:Fluorescent Dyes; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; D012333:RNA, Messenger; D018016:Receptors, Parathyroid Hormone; C071784:parathyroid hormone-related protein (107-111); D011419:Propidium; D009543:Nifedipine; D002118:Calcium; D016257:Fura-2