title: NMDA receptor antagonist prevents cell death in the hippocampal dentate gyrus induced by hyponatremia accompanying adrenal insufficiency in rats.
abstract: Selective apoptosis of granule cells in the hippocampal dentate gyrus (DG) of rats with bilateral adrenalectomy (ADX) and in patients who died of adrenal insufficiency has been reported. Although adrenal insufficiency is a common disease and is usually associated with hyponatremia, its effect on the central nervous system and in apoptosis in the hippocampus remain to be elucidated. Using rat models to represent clinical hyponatremia accompanying adrenal insufficiency, we show that reduced serum [Na+] was associated with selective apoptosis in the DG. Nine days after ADX, apoptotic cells were observed in the DG of rats whose serum [Na+] was <125mEq/L (moderate hyponatremia), but rarely in those whose serum [Na+] was ≥125mEq/L or in normonatremic rats. Although all hyponatremic ADX rats survived following treatment with corticosterone and saline started 7days after ADX when apoptosis had not yet occurred, selective apoptosis on day 9 was not prevented in moderately hyponatremic rats. Interestingly, treatment with memantine, a noncompetitive NMDAR antagonist, prevented the selective apoptosis in the DG in moderately hyponatremic, ADX rats, and improved electrophysiological dysfunction, including impaired basal synaptic transmission and long-term potentiation at the entorhinal cortex-DG synapses. These results demonstrated that in adrenal insufficient rats, hyponatremia was associated with apoptosis in the DG, and that memantine prevented the apoptosis and improved cell function. Our data imply the importance of assessing the possibility of neurological impairments after treatment with CORT in patients with moderate or severe hyponatremia accompanying adrenal insufficiency and that memantine may represent a beneficial therapeutic strategy to prevent neurological impairments in such patients.
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Izumida
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takagi
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Fujisawa
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Nakashima
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Takeuchi
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Iwama
authors.affiliation: Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Namba
authors.affiliation: Department of Neuroscience, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-0814, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Komatu
authors.affiliation: Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oiso
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arima
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: sugiyosi@med.nagoya-u.ac.jp.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Sugimura
mesh_terms: D000309:Adrenal Insufficiency / Q000150:complications / Q000473:pathology*; D000315:Adrenalectomy / Q000009:adverse effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003345:Corticosterone / Q000008:administration & dosage; D018891:Dentate Gyrus / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D004334:Drug Administration Schedule; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007010:Hyponatremia / Q000150:complications / Q000473:pathology*; D008297:Male; D008559:Memantine / Q000494:pharmacology* / Q000627:therapeutic use; D008840:Microfilament Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009479:Neuropeptides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000009:adverse effects; D013997:Time Factors
chemical_list: C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D000089622:Doublecortin Domain Proteins; D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D012965:Sodium Chloride; D008559:Memantine; D003345:Corticosterone
keywords: Adrenal insufficiency; Apoptosis; Basal synaptic transmission; Cell death; Hippocampal dentate gyrus; Hyponatremia; Long term potentiation; Memantine; NMDA receptor antagonist