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The influence of benzamil hydrochloride on the evolution of hyponatremic brain edema as assessed by in vivo MRI study in rats

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Abstract

Objective

The present study was undertaken to reveal the influence of intracerebroventricular (ICV) benzamil on the dynamics of brain water accumulation in hyponatremic rats. Parameters of brain water homeostasis were continuously monitored, using in vivo magnetic resonance imaging (MRI) methods. The results were compared with those obtained in a previous study by tissue desiccation.

Methods

A 3-T MRI instrument was applied to perform serial diffusion-weighted imaging to measure the apparent diffusion coefficient (ADC) and MR spectroscopy to determine water signal. A decrease of ADC is thought to represent an increase of intracellular water, whereas water signal is used to quantify brain water content. Five groups of male Wistar rats were studied as follows: normonatremic, native animals (group NN, n = 7), hyponatremic animals (group HN, n = 8), hyponatremic animals treated with ICV benzamil (group HNB, n = 8), hyponatremic animals treated with ICV saline (group HNS, n = 5) and normonatremic animals treated with ICV benzamil (group NNB, n = 5). Hyponatremia was induced by intraperitoneal administration of 140 mmol/l dextrose solution in a dose of 20% of body weight. Benzamil hydrochloride (4 μg) was injected ICV to the treated animals.

Results

During the course of hyponatemia, ADC declined steadily from the baseline (100%) to reach a minimum of 92.32 ± 3.20% at 90 min (p < 0.0005). This process was associated with an increase in water signal to a maximum of 5.95 ± 2.62% at 100 min (p < 0.0005). After pretreatment with benzamil, no consistent changes occurred either in ADC or in water signal.

Conclusions

These findings suggest that sodium channel blockade with ICV benzamil has an immediate protective effect against the development of hyponatremic brain edema. Sodium channels, therefore, appear to be intimately involved in the initiation and progression of brain water accumulation in severe hyponatremia.

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Acknowledgements

This study was supported by the following grants: Marie Curie Research Training Networks Aquaglyceroporins (MRTN-CT-2006-035995); Hungarian Science Founds (OTKA PD 72240); “Save what can be saved”—Applied neurological research using high-field magnetic resonance imaging HU0114; “Visible pain”—New fMRI methods in pain research and treatment. S.A. and J.J. were supported by Bolyai fellowship of the Hungarian Academy of Science.

Conflicts of interest

None.

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Authors and Affiliations

  1. Department of Neurosurgery, Faculty of Medicine, University of Pécs, Rét Street 2, 7623, Pécs, Hungary

    Roy Steier, Mihály Aradi, József Pál, Péter Bukovics, Attila Schwarcz & Tamás Dóczi

  2. Pécs Diagnostic Center, University of Pécs, Rét Street 2, 7623, Pécs, Hungary

    Roy Steier, Mihály Aradi, Péter Bukovics, Gábor Perlaki, Gergely Orsi & Attila Schwarcz

  3. Department of Neurology, Faculty of Medicine, University of Pécs, Rét Street 2, 7623, Pécs, Hungary

    József Janszky

  4. Faculty of Health Sciences, University of Pécs, Vörösmarty Street 4, 7621, Pécs, Hungary

    Endre Sulyok

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  1. Roy Steier
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Correspondence to Roy Steier.

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Comment

The authors present further data supporting the use of benzamil in the treatment of cerebral edema. Their data offer encouraging evidence that the intraventricular administration of benzamil halts the evolution of cerebral edema that would otherwise accompany acute hyponatremia. While the data generated here are something of a reiteration of past studies demonstrating reductions in water content post induction of hyponatremia and benzamil infusion in rodents, they have expanded their studies to note that the effects of ENac modulation via benzamil may be tracked by magnetic resonance imaging. There remains much work to be done before such a drug could be considered clinically viable, but these data make significant steps towards that end.

Markus Bookland,

Christopher M. Loftus

Philadelphia, USA

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Steier, R., Aradi, M., Pál, J. et al. The influence of benzamil hydrochloride on the evolution of hyponatremic brain edema as assessed by in vivo MRI study in rats. Acta Neurochir 153, 2091–2097 (2011). https://doi.org/10.1007/s00701-011-0996-3

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