NMDA receptor antagonist prevents cell death in the hippocampal dentate gyrus induced by hyponatremia accompanying adrenal insufficiency in rats

Hisakazu Izumida, Hiroshi Takagi, Haruki Fujisawa, Naoko Iwata, Kohtaro Nakashima, Seiji Takeuchi, Shintaro Iwama, Takashi Namba, Yukio Komatu, Kozo Kaibuchi, Yutaka Oiso, Hiroshi Arima, Yoshihisa Sugimura

Research output: Contribution to journalArticle

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 < 125 mEq/L (moderate hyponatremia), but rarely in those whose serum [Na+] was ≥ 125 mEq/L or in normonatremic rats. Although all hyponatremic ADX rats survived following treatment with corticosterone and saline started 7 days 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.

Original languageEnglish
Pages (from-to)65-74
Number of pages10
JournalExperimental Neurology
Volume287
DOIs
Publication statusPublished - 01-01-2017

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Adrenal Insufficiency
Parahippocampal Gyrus
Hyponatremia
Dentate Gyrus
N-Methyl-D-Aspartate Receptors
Cell Death
Apoptosis
Memantine
Serum
Entorhinal Cortex
Long-Term Potentiation
Adrenalectomy
Therapeutics
Corticosterone
Synaptic Transmission
Synapses
Hippocampus
Central Nervous System

All Science Journal Classification (ASJC) codes

  • Neurology
  • Developmental Neuroscience

Cite this

Izumida, Hisakazu ; Takagi, Hiroshi ; Fujisawa, Haruki ; Iwata, Naoko ; Nakashima, Kohtaro ; Takeuchi, Seiji ; Iwama, Shintaro ; Namba, Takashi ; Komatu, Yukio ; Kaibuchi, Kozo ; Oiso, Yutaka ; Arima, Hiroshi ; Sugimura, Yoshihisa. / NMDA receptor antagonist prevents cell death in the hippocampal dentate gyrus induced by hyponatremia accompanying adrenal insufficiency in rats. In: Experimental Neurology. 2017 ; Vol. 287. pp. 65-74.
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Izumida, H, Takagi, H, Fujisawa, H, Iwata, N, Nakashima, K, Takeuchi, S, Iwama, S, Namba, T, Komatu, Y, Kaibuchi, K, Oiso, Y, Arima, H & Sugimura, Y 2017, 'NMDA receptor antagonist prevents cell death in the hippocampal dentate gyrus induced by hyponatremia accompanying adrenal insufficiency in rats', Experimental Neurology, vol. 287, pp. 65-74. https://doi.org/10.1016/j.expneurol.2016.08.007

NMDA receptor antagonist prevents cell death in the hippocampal dentate gyrus induced by hyponatremia accompanying adrenal insufficiency in rats. / Izumida, Hisakazu; Takagi, Hiroshi; Fujisawa, Haruki; Iwata, Naoko; Nakashima, Kohtaro; Takeuchi, Seiji; Iwama, Shintaro; Namba, Takashi; Komatu, Yukio; Kaibuchi, Kozo; Oiso, Yutaka; Arima, Hiroshi; Sugimura, Yoshihisa.

In: Experimental Neurology, Vol. 287, 01.01.2017, p. 65-74.

Research output: Contribution to journalArticle

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T1 - NMDA receptor antagonist prevents cell death in the hippocampal dentate gyrus induced by hyponatremia accompanying adrenal insufficiency in rats

AU - Izumida, Hisakazu

AU - Takagi, Hiroshi

AU - Fujisawa, Haruki

AU - Iwata, Naoko

AU - Nakashima, Kohtaro

AU - Takeuchi, Seiji

AU - Iwama, Shintaro

AU - Namba, Takashi

AU - Komatu, Yukio

AU - Kaibuchi, Kozo

AU - Oiso, Yutaka

AU - Arima, Hiroshi

AU - Sugimura, Yoshihisa

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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 < 125 mEq/L (moderate hyponatremia), but rarely in those whose serum [Na+] was ≥ 125 mEq/L or in normonatremic rats. Although all hyponatremic ADX rats survived following treatment with corticosterone and saline started 7 days 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.

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