Research report
Zinc, magnesium and NMDA receptor alterations in the hippocampus of suicide victims

https://doi.org/10.1016/j.jad.2013.08.009Get rights and content

Abstract

Background

There is evidence for an association between suicidal behavior and depression. Accumulating data suggests that depression is related to a dysfunction of the brain's glutamatergic system, and that the N-methyl-d-aspartate (NMDA) receptor plays an important role in antidepressant activity. Zinc and magnesium, the potent antagonists of the NMDA receptor complex, are involved in the pathophysiology of depression and exhibit antidepressant activity.

Methods

The present study investigated the potency of Zn2+ and Mg2+ to [3H] MK-801, which binds to the NMDA receptor channel in the hippocampus of suicide victims (n=17) and sudden death controls (n=6). Moreover, the concentrations of zinc and magnesium (by flame atomic absorption spectrometry) and levels of NMDA subunits (NR2A and NR2B) and PSD-95 protein (by Western blotting) were determined.

Results

Our results revealed that there was a statistically significant decrease (by 29% and 40%) in the potency of zinc and magnesium (respectively) to inhibit [3H] MK-801 binding to NMDA receptors in the hippocampus in suicide tissue relative to the controls. These alterations were associated with increased NR2A (+68%) and decreases in both the NR2B (−46%) and PSD-95 (−35%) levels. Furthermore, lower concentrations (−9%) of magnesium (although not of zinc) were demonstrated in suicide tissue.

Conclusions

Our findings indicate that alterations in the zinc, magnesium and NMDA receptor complex in the hippocampus are potentially involved in the pathophysiology of suicide-related disorders (depression), which may lead to functional NMDA receptor hyperactivity.

Introduction

Depression is a serious psychiatric illness affecting approximately 17% of the population at some point in their lives and is the leading cause of disability worldwide (Duman and Voleti, 2012). Depression is associated with an increased number of suicide attempts and increased lethality. It is estimated that mood disorders, principally major depressive disorder and bipolar disorder, are associated with about 60% of all suicides (Brådvik, 2002, Brådvik and Berglund, 2005, Gibbons et al., 2005, Martinez et al., 2005). Moreover, suicide accounts for almost 2% of the world's deaths (WHO, 2000). The World Health Organization (WHO) estimates that over 120 million people worldwide suffer from depression and has, in turn, predicted that by 2020 unipolar major depression will be the second leading cause of disease or injury after ischemic heart disease (Mathews et al., 2012).

Almost 4 decades of intensive research have sought to elucidate the neurobiological basis of depression. However, a study of the biological bases of depression is still overdue. The principal aims are to increase the knowledge of the basis of the disease in order to better define its pathogenic process and to identify predictive biomarkers or, at least, markers able to support the diagnosis.

The data gathered during recent years suggests that abnormalities within glutamatergic transmission, especially NMDA (N-methyl-d-aspartate) receptor overactivation, are associated with more generalized mechanisms of brain dysfunction that may underlie various psychiatric disorders, including major depressive disorder. The accumulated evidence demonstrated that the functional and structural pathology of excitatory neurotransmitters have been observed in animal models of depression and clinical trials (Hansen et al., 1983, Kugaya and Sanacora, 2005, Petrie et al., 2000, Sanacora et al., 2003, Zarate et al., 2002, Hashimoto, 2009, Pilc et al., 2013). Furthermore, there is evidence that NMDA receptor ligands (functional antagonists) interacting with different components of the NMDA receptor–ionophore complex produced antidepressant-like effects (Lopes et al., 1997, Panconi et al., 1993, Poleszak et al., 2007, Przegalinski et al., 1998, Trullas and Skolnick, 1990, Szewczyk et al., 2012). Furthermore, there are some clinical reports suggesting augmentation of antidepressant therapy by NMDA receptor antagonists (ketamine and CP-101,606/traxoprodil) in refractory depression (Berman et al., 2000, Zarate et al., 2006, Preskorn et al., 2008).

During the last few years, many articles have been presented indicating the important role of zinc and magnesium (inorganic NMDA receptors antagonists) in the mechanism of antidepressant therapy and/or the pathophysiology of depression (Murck, 2013, Swardfager et al., 2013). In the preclinical experiments, zinc and magnesium produced antidepressant-like activity in both tests (Decollogne et al., 1997, Kroczka et al., 2000, Kroczka et al., 2001, Poleszak et al., 2004, Poleszak et al., 2005a, Rosa et al., 2003) and some models of depression (Cieslik et al., 2007, Nowak et al., 2003a, Sowa-Kucma et al., 2008). Besides, both cations enhanced the activity of antidepressant drugs (Kroczka et al., 2001, Szewczyk et al., 2002, Szewczyk et al., 2009, Cieslik et al., 2007, Poleszak et al., 2005b, Poleszak et al., 2007).

Clinical observations demonstrated a significant reduction in the serum zinc concentration in depressed patients (Hansen et al., 1983, Maes et al., 1994, Maes et al., 1997, Maes et al., 1999, Nowak et al., 1999, Siwek et al., 2010), which was normalized by successful antidepressant therapy (Maes et al., 1994, McLoughlin and Hodge, 1990, Siwek et al., 2010). Also, data concerning the blood magnesium concentration in depressed patients is inconsistent, since both increases (Frazer et al., 1983, Kirov et al., 1994, Widmer et al., 1992, Widmer et al., 1995) and decreases (Banki et al., 1985, Hashizume and Mori, 1990, Rasmussen et al., 1989, Zięba et al., 2000, Ruljancic et al., 2013) have been observed.

Since a considerable percentage of suicide victims had suffered from depression (Bottlender et al., 2000, Hawton and van Heeringen, 2009, Pawlak et al., 2013), we hypothesized that an alteration in zinc and magnesium homeostasis might occur in brain tissue. Moreover, because hippocampal zinc and/or magnesium homeostasis in particular might be involved in the pathophysiology of affective disorders (e.g. Murck, 2002, Nowak et al., 2003c, Takeda, 2011), this brain structure was chosen for the present examination.

The main aim of the present study was to examine zinc and magnesium concentration and their potency to inhibit [3H] MK-801 binding to NMDA receptors in the hippocampus of suicide victims and sudden death controls. The second aim of the study was to investigate the level of relevant subunits of the NMDA complex (NR2A, NR2B) and PSD-95 protein.

Section snippets

Tissue collection

Brain tissue from 17 suicide victims and six unexpected sudden death controls (mean age±SEM, 35.8±4.3 years for suicide and 34.3±6.0 for controls) was obtained as discarded tissue at the time of autopsy by the Department of Forensic Medicine, Jagiellonian University Medical College [Grant no. 6P05B 142 20 from the State Committee for Scientific Research, approved by the Ethics Committee (2001–2004)]. According to the available medical history, both suicide and control subjects included in the

The effect of zinc or magnesium on [3H] MK-801 binding to the NMDA complex

The radioligand receptor binding assay was used to examine the potency of Zn2+ and Mg2+ on [3H] MK-801 binding to the NMDA receptor channel. [3H] MK-801 is a well-characterized NMDA receptor channel antagonist and it is widely used in receptor binding studies. We used extensively washed neuronal membrane preparations from the human hippocampus. The present data demonstrated a significant increase in the IC50 value of zinc [by 29±7%; from 0.343±0.016 mM to 0.441±0.025 mM; t(21)=2.244, and P

Discussion

In recent years, there has been an increasing interest in the involvement of zinc and magnesium in the pathophysiology of depression. Moreover, both of these ions appear to have therapeutic potential in clinical depression. It was found that depressed patients showed a significantly lower serum zinc level than psychiatrically normal controls (Maes et al., 1994, Maes et al., 1997, Nowak et al., 1999, McLoughlin and Hodge, 1990, Siwek et al., 2010). The beneficial effect of zinc supplementation

Role of funding source

The funding source had no role in study design, in the collection, analysis and interpretation of data, in writing of the report and in the decision to submit the paper for publication.

Conflict of interest

All authors declare that there are no actual or potential conflicts of interest that could inappropriately influence this work.

Acknowledgments

This study was partially supported by the Grant no. 6P05B 142 20 from the State Committee for Scientific Research, Warszawa, Poland and funds for statutory activity from the Institute of Pharmacology PAS and Jagiellonian University Medical College, Krakow, Poland.

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