title: Neuroprotective effects of hibernation-regulating substances against low-temperature-induced cell death in cultured hamster hippocampal neurons.
abstract: The neuroprotective effects of hibernation-regulating substances (HRS) such as adenosine (ADO), opioids, histamine and thyrotropin-releasing hormone (TRH) on low-temperature-induced cell death (LTCD) were examined using primary cultured hamster hippocampal neurons. LTCD was induced when cultures were maintained at <22 degrees C for 7 days. ADO (10-100 microM) protected cultured neurons from LTCD in a dose-dependent manner. The neuroprotective effects of ADO were reversed by both 8-cyclopenthyltheophilline (CPT; A(1) receptor antagonist) and 3,7-dimethyl-1-propargylxanthine (DMPX; A(2) receptor antagonist). Morphine (a non-selective opioid receptor agonist) was also effective in attenuating LTCD at an in vitro dose range of 10-100 muM. The neuroprotective effects of morphine were antagonized by naloxone (a non-selective opioid receptor antagonist). In addition, although [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin (DAMGO; mu-opioid receptor agonist), [D-Pen(2,5)]-enkephalin (DPDPE; delta-opioid receptor agonist) and U-69593 (kappa-opioid receptor agonist) were also effective, LTCD of cultured hippocampal neurons was not affected by TRH. Furthermore, histamine produced hypothermia in Syrian hamsters and protected hippocampal neurons in vitro at 100 microM. The neuroprotective effect of histamine was reversed by pyrilamine (H(1) receptor antagonist). Apoptosis was probably involved in LTCD. These results suggest that ADO protected hippocampal neurons in vitro via its agonistic actions on both A(1) and A(2) receptors, whereas morphine probably elicited its neuroprotective effects via agonistic effects on the mu-, delta- and kappa-opioid receptors. In addition, histamine also protected hippocampal neurons via its agonistic action on the H(1) receptor. Thus, HRS-like adenosine-, opioid- and histamine-like hypothermic actions would most likely induce neuroprotective effects against LTCD in vitro.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tamura
authors.forename: Mayuko
authors.initials: M
authors.lastname: Monden
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Shintani
authors.forename: Ami
authors.initials: A
authors.lastname: Kawai
authors.forename: Hirohito
authors.initials: H
authors.lastname: Shiomi
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006605:Hibernation / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism*; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D007036:Hypothermia, Induced / Q000009:adverse effects*; D007276:Injections, Intraventricular; D009292:Narcotic Antagonists / Q000494:pharmacology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D006634:Histamine H1 Antagonists; D009292:Narcotic Antagonists; D018696:Neuroprotective Agents; D058915:Purinergic P1 Receptor Antagonists; D011957:Receptors, Opioid; D018047:Receptors, Purinergic P1; D013973:Thyrotropin-Releasing Hormone; D006632:Histamine; D000241:Adenosine