**3.2.1 Interaction with neurotransmitters**

Various Hg species presynaptically blocks sodium and calcium channels and thus inhibits the uptake of some neurotransmitters, especially *glutamate* into astrocytes, which increases their extracellular concentration, thus increasing the sensitivity of neighbouring neurons for *stimulating excitotoxic effects* (Aschner et al., 2007; Brookes, 1996; Castoldi et al., 2001; Sirois & Atchison, 1991; Trotti et al., 1997). Many studies reviewed by Mottet et al. in 1997 showed

Elemental Mercury Exposure and Sleep Disorder 53

particularly CNS. Se that binds with Hg in CNS in a molecular ratio of 1:1 into a nontoxic complex, which in lysosomes represents the last stage of detoxification of Hg (Falnoga et al.,

It is evident from the study of ex-mercury miners that the Hg accumulated in the pineal gland and bound to Se did not impair its function, while the blood melatonin level was still high, probably due to the slow release of Hg from the gland and the adaptive response to free radical production induced by Hg (Kobal et al., 2004). Melatonin and free radicals form stable secondary and tertiary products, biogene amines, which also enter into reactions with free radicals. So melatonin inhibits the excessive formation of NO and its free radicals, peroxinitrites, and in this way also reduces the excitotoxic effects of glutamate (Sener et al.,

The main enzymes that provide cellular protection against damage by reactive oxygen species mediated by Hg++ are Cu/Zn superoxide dismutase, catalase and the selenoenzyme glutathion peroxides, which transform the superoxide anion radical into hydrogen peroxide and then into oxygen and water (Lund et al., 1993). It is evident from some studies that repeated-intermittent occupational Hg° exposure induced an adaptive response and increase of GSH and catalase activity in erythrocytes, as well as the melatonin level in blood. The actual levels of GSH and catalase in erythrocytes depend on the actual level of blood Hg, both of these decreasing at higher blood Hg concentrations during actual exposure

A study conducted by Qiu and colleagues in 2010 presented the main overall neurobiological activity of basal ganglia neurons associated with the sleep-wake state. The differences in firing patterns across the basal ganglia suggest multiple input sources, such as the cortex, thalamus, and the dopamine system, as well as some other intra basal ganglia inputs, such as the globus pallidus-subtalamic nucleus, and striatum-globus pallidus interactions. The largest nucleus striatum of the basal ganglia is mostly comprised of aminobutiric acid ergic spiny neurons, whose activity is influenced by excitatory glutaminergic projection from the neocortex and thalamus, and dopaminergic projection from the midbrain ventral tegmental area and other known parts. The striatum receiving cortical inputs projects to the globus pallidus, which then projects to the cerebral cortex directly ore by the thalamus (mainly the mediodorsal thalamic nucleus). It was suggested that the lesion of globus pallidus produced a higher increase in wakefulness and frequent sleep-wake transitions, as well as a concomitant decrease in non-REM sleep duration. The results of the study also suggest that the cortico-striato-pallidal loop may be critically

There are four stages of sleep, which include the brain-active period associated with rapid eye movements called REM sleep (emergent stage 1 EEG), preceded by progressively deeper sleep stages (stages 2, 3, 4) graded on the basis of increasingly slower EEG patterns, called non-REM sleep. Stages 3 and 4 are referred to as slow-wave sleep (SWS) characterized by delta waves (high amplitude and low-frequency). REM sleep and wakefulness are characterized by increased activity in the cerebral cortex with low-amplitude and highfrequency EEG (alpha waves) and in REM by the inhibition of peripheral neurons displayed in the postural muscle atonia. Increased cerebral activity during REM sleep is associated with higher oxygen consumption, blood flow and neural firing (Madsen et al., 1991).

**4. Some basic neurobiological characteristics of sleep-wake cycles** 

2002; Kosta et al., 1975;).

2003; Tan et al., 2000).

(Kobal, 1991; Kobal et al., 2004, 2008).

involved in the basal ganglia control of arousal.

that astrocytes, which accumulate a high level of Hg++, play a fundamental role in regulating glutamate level. In cases of methyl-Hg exposure, it seems that the Hg++ ions formed after the demethylation of methyl-Hg may also be responsible for the disruption of normal Ca++ ion channels.

Hg may affect sleep because it can: (i) increase extra-cellular glutamate concentrations associated with the activation of some cytokines, which can reduce the serotonin level by lowering the availability of its precursor, tryptophan, through the activation of its metabolizing enzyme, indoleamine 2,3-dioxigenase (McNally et al., 2008); (ii) increase the production of nitrogen oxide (NO) (Ikeda et al., 1999), which can directly, or in interaction with melatonin, decrease the active form of serotonin (Fossier et al., 1999; Kopczak et al., 2007); and (iii) Hg can also increase the consumption of serotonin and melatonin because of its potential oxidation in interaction with the increased production of free radicals observed in microglial cell cultures (Huether et al., 1997; Tan et al., 2000).

It is suggested that inorganic Hg potentiate and inhibite the neuronal nicotinic acetylcholine receptors, depending on its concentration (Mirzoian & Luetje, 2002). Another animal study shows that up-regulation of cerebral acetylcholine receptor can occur in chronic methyl-Hg exposure to compensate the early stage reduction of brain acetylcholine, as a consequence of acetylcholinesterase inhibition (Basu et al., 2006). It is evident from some studies on occupationally and environmentally Hg-exposed subjects that Hg enhances the *dopaminergic effect* in CNS, which otherwise leads to cortical hyperexcitability and changes in the control of locomotor function, emotions, and behaviour (Burbure et al., 2006; Entezari-Taher et al., 1999; Lucchini et al., 2003; Missale et al., 1998).

#### **3.2.2 Subcellular protective mechanism**

Particularly significant in reducing the effects of Hg binding with SH groups of GSH and its biochemical precursors, cystine and cysteine, as well as its binding with MTs a cysteine rich low molecular weight proteins and with selenium (Se) an essential element and an integral part of a type of Se-proteins. The two major thiols, GSH and MTs, appear to be most important in regulating the accumulation and detoxification of Hg in CNS. The induction of GSH and MTs in astrocytes leads to greater detoxification of Hg and protection of CNS. Astrocytes represent the first line of CNS's defence against Hg (Aschner et al., 2007; Dringen et al., 2000). GSH (L--glutamyl-L-cysteinyl-glycine) is synthesized from its precursors, glutamate, cysteine and glycine, in the cytosol of cells by the ATP-requiring enzymes glutamilcysteine ligase and GSH synthetase (Meister & Andersen, 1983). Most of the free intracellular GSH (98%) is in thiol-reduced form (GSH) rather than in disulfide form (GSSG). From the cytosol, GSH is delivered into the mitochondria, endoplasmatic reticulum and nucleus, but much of it is delivered to extracellular spaces, where its degradation begins to occur on the surface of cells that express the enzyme -glutamil transpeptidase. GSH, as a nonenzymatic antioxidant, participates in a variety of detoxification, transport, and metabolic processes (Ballatri et al., 2009; Rossi et al., 2002). It is speculated that GSH may also function as a neuromodulator and neurotransmitter, since the degradation of extracellular GSH by -glutamil transpeptidase liberates glutamate and, subsequently, the hydrolysis of cysteinylglicine liberates cysteine and glycine, which function as a source of neuroactive amino acid (Oja et al., 2000).

Some other protective mechanisms, such as Se, antioxidative enzymes and melatonin, are also important in the detoxification of Hg and its peroxidative effect on the body, and

that astrocytes, which accumulate a high level of Hg++, play a fundamental role in regulating glutamate level. In cases of methyl-Hg exposure, it seems that the Hg++ ions formed after the demethylation of methyl-Hg may also be responsible for the disruption of

Hg may affect sleep because it can: (i) increase extra-cellular glutamate concentrations associated with the activation of some cytokines, which can reduce the serotonin level by lowering the availability of its precursor, tryptophan, through the activation of its metabolizing enzyme, indoleamine 2,3-dioxigenase (McNally et al., 2008); (ii) increase the production of nitrogen oxide (NO) (Ikeda et al., 1999), which can directly, or in interaction with melatonin, decrease the active form of serotonin (Fossier et al., 1999; Kopczak et al., 2007); and (iii) Hg can also increase the consumption of serotonin and melatonin because of its potential oxidation in interaction with the increased production of free radicals observed

It is suggested that inorganic Hg potentiate and inhibite the neuronal nicotinic acetylcholine receptors, depending on its concentration (Mirzoian & Luetje, 2002). Another animal study shows that up-regulation of cerebral acetylcholine receptor can occur in chronic methyl-Hg exposure to compensate the early stage reduction of brain acetylcholine, as a consequence of acetylcholinesterase inhibition (Basu et al., 2006). It is evident from some studies on occupationally and environmentally Hg-exposed subjects that Hg enhances the *dopaminergic effect* in CNS, which otherwise leads to cortical hyperexcitability and changes in the control of locomotor function, emotions, and behaviour (Burbure et al., 2006; Entezari-

Particularly significant in reducing the effects of Hg binding with SH groups of GSH and its biochemical precursors, cystine and cysteine, as well as its binding with MTs a cysteine rich low molecular weight proteins and with selenium (Se) an essential element and an integral part of a type of Se-proteins. The two major thiols, GSH and MTs, appear to be most important in regulating the accumulation and detoxification of Hg in CNS. The induction of GSH and MTs in astrocytes leads to greater detoxification of Hg and protection of CNS. Astrocytes represent the first line of CNS's defence against Hg (Aschner et al., 2007; Dringen et al., 2000). GSH (L--glutamyl-L-cysteinyl-glycine) is synthesized from its precursors, glutamate, cysteine and glycine, in the cytosol of cells by the ATP-requiring enzymes glutamilcysteine ligase and GSH synthetase (Meister & Andersen, 1983). Most of the free intracellular GSH (98%) is in thiol-reduced form (GSH) rather than in disulfide form (GSSG). From the cytosol, GSH is delivered into the mitochondria, endoplasmatic reticulum and nucleus, but much of it is delivered to extracellular spaces, where its degradation begins to occur on the surface of cells that express the enzyme -glutamil transpeptidase. GSH, as a nonenzymatic antioxidant, participates in a variety of detoxification, transport, and metabolic processes (Ballatri et al., 2009; Rossi et al., 2002). It is speculated that GSH may also function as a neuromodulator and neurotransmitter, since the degradation of extracellular GSH by -glutamil transpeptidase liberates glutamate and, subsequently, the hydrolysis of cysteinylglicine liberates cysteine and glycine, which function as a source of

Some other protective mechanisms, such as Se, antioxidative enzymes and melatonin, are also important in the detoxification of Hg and its peroxidative effect on the body, and

in microglial cell cultures (Huether et al., 1997; Tan et al., 2000).

Taher et al., 1999; Lucchini et al., 2003; Missale et al., 1998).

**3.2.2 Subcellular protective mechanism** 

neuroactive amino acid (Oja et al., 2000).

normal Ca++ ion channels.

particularly CNS. Se that binds with Hg in CNS in a molecular ratio of 1:1 into a nontoxic complex, which in lysosomes represents the last stage of detoxification of Hg (Falnoga et al., 2002; Kosta et al., 1975;).

It is evident from the study of ex-mercury miners that the Hg accumulated in the pineal gland and bound to Se did not impair its function, while the blood melatonin level was still high, probably due to the slow release of Hg from the gland and the adaptive response to free radical production induced by Hg (Kobal et al., 2004). Melatonin and free radicals form stable secondary and tertiary products, biogene amines, which also enter into reactions with free radicals. So melatonin inhibits the excessive formation of NO and its free radicals, peroxinitrites, and in this way also reduces the excitotoxic effects of glutamate (Sener et al., 2003; Tan et al., 2000).

The main enzymes that provide cellular protection against damage by reactive oxygen species mediated by Hg++ are Cu/Zn superoxide dismutase, catalase and the selenoenzyme glutathion peroxides, which transform the superoxide anion radical into hydrogen peroxide and then into oxygen and water (Lund et al., 1993). It is evident from some studies that repeated-intermittent occupational Hg° exposure induced an adaptive response and increase of GSH and catalase activity in erythrocytes, as well as the melatonin level in blood. The actual levels of GSH and catalase in erythrocytes depend on the actual level of blood Hg, both of these decreasing at higher blood Hg concentrations during actual exposure (Kobal, 1991; Kobal et al., 2004, 2008).
