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Vink R, Nechifor M, editors. Magnesium in the Central Nervous System [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
Magnesium (Mg) is essential for cell functions such as transport of calcium and potassium ions, and modulates signal transduction, energy metabolism, and cell proliferation. Several studies elucidated a reduced concentration of Mg in patients with Parkinson’s disease (PD), and experimentally, severe loss of dopaminergic neurons exclusively in the substantia nigra in 1-year-old rats that had been subjected to continuously low Mg intake (one-fifth of the normal level) over generations. A study conducted by the authors revealed a significant and striking effect of Mg to prevent neurite and neuron pathology, and also to ameliorate neurite pathology in a rat Parkinson disease (PD) model involving culture of ventral mesencephalic-striatal cells with 1-methyl-4-phenylpyridinium (MPP+). Mg is expected to prevent and ameliorate Parkinson’s disease in cases where it would be able to cross into the brain in a suitable way.
Parkinson’s disease (PD) is a neurodegenerative disease occurring in middle-aged and aged humans characterized by clinical symptoms including tremor and rigidity (Parkinson, 1817). It has been reported that almost 90% of the patients are sporadic and 10% are familial. Sporadic PD shows neuropathological features involving the appearance of Lewy bodies (Lewy, 1912; Tretiakoff, 1919) and loss of neurons in the substantia nigra (Figures 1 and 2) and substantia innominata. After establishment of the disease as an entity, it was revealed that dopaminergic neurons in the ventral tegmental area, noradren- ergic neurons in the locus coeruleus and motor vagal nucleus, serotonergic neurons in the dorsal raphe nucleus, and neurons in the sympathetic ganglia and visceral autonomic nervous system are involved in the disease with neuronal loss and presence of Lewy bodies (Jellinger, 1999). In the present manuscript, the authors review the role of magnesium (Mg) in the pathogenesis and patho- mechanisms in clinical and basic aspects of PD.
Midbrain and upper pons. The substantia nigra and locus coeruleus in the patient with Parkinson’s disease show marked depigmentation as compared with those of controls.
The substantia nigra of a patient with Parkinson’s disease shows severe loss of neurons as compared with a control subject. Some remaining neurons represent Lewy bodies.
Uitti et al., (1989) analysed four brain regions (frontal cortex, caudate nucleus, substantia nigra and cerebellum) for concentrations of 24 metals (Ag, Al, As, B, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Pb, Mg, Mn, Mo, Na, Ni, P, Se, Ti, V, W, Zn) by atomic absorption and atomic emission spectroscopy in brains of 9 patients with PD, 15 patients with other chronic neurological diseases and 12 subjects of controls. The results were that brains of PD and parkinsonism secondary to neurofibrillary tangle disease showed lower concentrations of Mg in the caudate nucleus and copper in the substantia nigra than control brains. Barbiloni et al., (1999) performed in vivo phosphorus magnetic resonance spectroscopy on the occipital lobes of 13 patients with PD, 15 patients with multiple system atrophy and 16 age-matched healthy subjects. They reported that patients with PD showed significantly increased contents of inorganic phosphate (Pi), decreased cytosolic free [Mg2+], and unchanged phosphocreatine and pH. Bocca et al., (2006) examined concentrations of Ca, Cu, Fe, Mg, Si and Zn by inductively coupled plasma atomic emission spectrometry (ICP-AES) in blood, urine and cerebrospinal fluid (CSF) of 91 PD patients and 18 controls. They concluded that Mg concentration in CSF of PD patients decreased with the duration and severity of the disease.
It has been proposed that Mg deficiency is involved in the pathogenesis of parkinsonism- dementia complex (PDC) and amyotrophic lateral sclerosis (ALS) in the Chamorro population on Guam, which is a member of the Mariana Islands in the western Pacific Ocean, as well as in the Kii peninsula of Japan and in West New Guinea (Yase 1978, Garruto et al., 1984). PDC is a disease entity that was established by Hirano et al., (1961a; 1961b) that affects the neurons in the substantia nigra, brainstem, and temporal and frontal cortex. The disease is characterized by the presence of neurofibrillary tangles in the remaining neurons, and disease-specific granular hazy inclusions in the astrocytes (Oyanagi et al., 1997; Oyanagi, 2005), tau-positive fine granules in the cerebral white matter (Yamazaki et al., 2005), and widespread TDP-43-immunopositive inclusions (Hasegawa et al., 2007). Patients exhibit parkinsonism and dementia, and usually die within about 5 years from infectious diseases (Hirano et al., 1961a; 1961b; Chen and Chase, 1985). ALS is a motor neuron disease affecting the Betz cells in the cerebral cortex, and facial and hypoglossal nuclei in the brainstem and anterior horn cells in the spinal cord, and usually patients die of respiratory failure within 5 years after the onset.
Increased expression of 4-hydroxy-2-nonenal (HNE) (Yoritaka et al., 1996), decreased activity of mitochondrial complex I and a decreased amountof alpha-ketoglutarate dehydrogenase complex (KGDHC) in the pigmented neurons of the substantia nigra (Hattori et al., 1991; Mizuno et al., 1994) have been reported in affected patients. In the substantia nigra, decreased activity of catalase and peroxidase (Ambani et al., 1975) and increased amounts of protein carbonyls, 8- hydroxy-2'-deoxyguanosine (8-OHdG)/8-hydroxy- guanine (8-OHG), 4-hydroxynonenal-lysine and malondialdehyde-lysine (MDAL) (Alam et al., 1997a,b; Zhang et al., 1999; Dalfo et al., 2005) have been reported.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was the first human parkinsonian agent to be characterized. It is converted to 1-methyl-4- phenylpyridinium (MPP+) by monoamine oxidase B in astrocytes. MPP+ damages mitochondrial complex I of dopaminergic neurons after transfer by the dopamine transporter, and increased calcium permeability of the mitochondrial membrane induces free radicals (Smeyne et al., 2005). MPP+ has been used to induce selective degeneration of dopaminergic neurons in an experimental model of PD (Nakamura et al., 2000). In addition, rotenone, 6-hydroxydopamine (6-OHDA), paraquat and annonacin have been used as noxious agents to create in vivo models of PD (Fornai et al., 2003; Champy et al., 2004; Bove et al., 2005) (Figure 3). Dopamine and dopamine quinones themselves are considered to be causes of oxidative stress. PINK1 (PTEN-induced putative kinase 1) maintains mitochondrial function and the gene is causative in some familial PD (Valente et al., 2004).
Possible relationship between mito- chondria, rough ER and Lewy body formation.
Alpha-synuclein was found as a main component of the Lewy bodies and the gene was found to be a causative gene of a rare autosomal dominant PD (Polymeropoulos et al., 1997). It has been reported that multiplication of the gene was to be the cause of the disease (Singleton et al., 2003). It has been suggested that aggregates of alpha-synuclein cause potentiation of oxidative stress, possibly with interaction with iron.
Synuclein was considered to be degraded in the proteasome. Knockout of the 26S proteasome in the dopaminergic neurons induced “pale bodies”, which is reported to be a prodrome of the Lewy bodies (Bedford et al., 2008).
Parkin and UCHL-1 are considered essential for ubiquitination of the unfolded proteins, and the gene mutations were found in some familial PD. It is considered that oxidative stress may lead a combination of Parkin and DJ-1, and the combination suffocates unfolded protein degrad- ation (Kitada et al., 1998; Bonifati et al., 2003). Mg has also been reported to inhibit spontaneous and iron-induced aggregation of alpha-synuclein (Golts et al., 2002) (Figure 4).
Scheme of possible pathomechanisms of dopaminergic neuron death in Parkinson’s disease.
In the course of investigations into the patho- genesis of the PDC, the present authors performed an experiment in which rats were exposed to restricted intake of Ca and/or Mg over two generations. This resulted in severe loss of dopaminergic neurons exclusively in the substantia nigra in 1-year-old rats that had been subjected to continuously low Mg intake (one- fifth of the normal level) over generations (Oyanagi et al., 2006). This finding suggested a deep concern of low Mg intake over several generations to the pathogenesis of degeneration of the substantia nigra in humans.
Mg controls cytochrome c release in mito- chondria (Eskes et al., 1998), and decreases the activity of N-methyl-D-aspartate (NMDA) receptors in excitotoxicity (Mayer et al., 1984). Mg treatment has also been shown to decrease cerebral infarct volume in rats in vivo (Lyden et al., 2000). The mechanism responsible for the neuroprotective effect of Mg has been considered to be reduced presynaptic release of the neurotrans-mitter glutamate (Lin et al., 2002), and blockade of the glutamatergic NMDA receptor (Nowak et al., 1984)(Figure 5). A relationship between decreased Mg concentration in serum and migraine has been reported in humans, and it has been suggested that migraine might be caused by hypersensitivity of the NMDA receptor to glutamic acid and certain other neuro-excitatory amino acids due to Mg depletion (Cojocaru et al., 2006). A decrease of cytosolic free Mg in the occipital lobe of PD patients has also been demonstrated by phosphorus magnetic response spectroscopy (Barbiroli et al., 1999).
Metallic elements and neuron conduction.
The present authors conducted a study to clarify the effects of Mg administration in a rat PD model involving culture of ventral mesencephalic- striatal cells with 1-methyl-4-phenylpyridinium (MPP+), based on recent evidence for significant loss of dopaminergic neurons exclusively in the substantia nigra of 1-year-old rats after exposure to low Mg intake over generations (Oyanagi et al., 2006) (Figure 6). The results indicated that Mg might protect dopaminergic neurons in the substantia nigra from degeneration. The concentration of Mg in the culture medium varied from 0.8 mM, corresponding to the control condition, to 4.0 mM. Effects were estimated by counting the number of surviving dopaminergic neurons immunopositive for tyrosine hydroxylase and measuring the length of dopaminergic neurites. An increase in the concentration of Mg to 1.2 mM significantly inhibited the toxicity of MPP+, and a concentration of 4.0 mM completely prevented any decrease in the number of dopaminergic neurons. The length of dopam- inergic neurites was significantly preserved in the presence of Mg at 1.2 and 4.0 mM. An increase in the concentration of Mg to 1.2 and 4.0 mM led to a significant amelioration in the length of dopam- inergic neurites after MPP+ toxicity (Figure 7).
Severe atrophy and selective loss of dopaminergic neurons in the substantia nigra in rats with low Mg over generations (Oyanagi K, et al., 2006).
This was the first report to document a significant and striking effect of Mg for prevention of neurite and neuron pathology, and also amelioration of neurite pathology in a PD model. In addition, an increase in the Mg concentration to 1.2, 2.0, and 4.0 mM did not induce any degenerative features in the cultured dopaminergic cells, suggesting that a Mg concentration of up to 4.0 mM in the extracellular space might not induce any neuron degeneration in humans. Mg oxide per os has often been used as a laxative for patients with PD, but is reportedly not absorbed in the bowels, thus not affecting the serum concentration of Mg (Sakimura et al., 1998). Recent studies by the authors using mice also established that no significant alteration was found in the CSF of B6 mice injected intraperitoneally with Mg, even though the serum Mg concentration was significantly increased (Sun et al., 2009). Further research is necessary to find Mg compounds that can easily be absorbed in the bowels and pass through the blood-brain barrier, like Mg-L- threonate (Slutsky et al., 2010) and besides, via transporters that can carry Mg through the bowel mucosa, blood-brain barrier and plasma membrane of neurons.
The authors are indebted to Dr. M. Yasui, Yasui Clinic, Wakayama, Japan, Dr. K. Nishi, Nishi Clinic, Tokyo, Japan, Dr. J. Nagasao, Ms. E. Kawakami, Dr. L. Sun and Dr. Y. Piao, Department of Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan, Dr. S. Takahama, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan, Ms. Y. Kosugi, Department of Environmental Health and Toxicology, Division of Environmental Health, Tokyo Metropolitan Institute of Public Health, Tokyo, Japan for their valuable advice and technical assistance. This work was supported in part by grants from the Japanese Ministry of Education, Science, Sports and Culture (Basic Research (C) #20500330 to TH), a Yujin Memorial Grant (to KO) and The Salt Science Research Foundation, No. 1028 (to KO).
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