Portuguese Version

Year:  2003  Vol. 69   Ed. 1 - (18º)

Artigo de Revisão

Pages: 111 to 115

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Zinc ion: its presence in the auditory system

Author(s): Anderson S. Botti,
Maria Cristina L. C. Féres

Keywords: zinc, auditory system, cochlea, cochlear nuclei.

Abstract:
The ion zinc has been studied in the last decades, mainly concerning its presence and role in the Central Nervous System physiology. It has been well described in some cortical, cerebelar and limbic regions, as well as in the cochlea and cochlear nuclei. It seems that the ion acts associated to the neurotransmitter glutamate, as a sinaptic modulator; it also takes part in the protection against free radicals. It is believed that alterations in the systemic levels of zinc can lead to disturbs on the auditory pathways, such as tinnitus or presbiacusis. The authors show a review about this theme.

INTRODUCTION

We first learned about the importance of zinc to live organisms when Rolin, one of Pasteur's disciples, reported in 1869 that zinc was essential to the growth of the Aspergillus niger fungi. Since the beginning of the 20th century, the role of zinc has been studied in Microbiology, Agronomy and Nutrition (Sayers, 1938). Since the 1950s, zinc has also been studied in Neuroscience, once it was demonstrated that the zinc ion, in addition to being an essential nutritional component for vegetal and animal metabolism, has a very specific role in excitatory central nervous transmission in mammals (Peters et al., 1987).

REVIEW OF THE LITERATURE

Bioavailability of zinc, its metabolism and effects of zinc ion deficiency.

Zinc is widely found in nature. Diets with high protein concentrations are rich in zinc, while carbohydrate-rich diets usually have low concentrations of zinc (Halstead et al., 1997). Cereals have reasonable amounts of zinc, and although most of it is stored in fibers and germ, approximately 80% of the total amount of zinc is lost in the grinding process. Zinc concentrations range from 0.02 mg/100g in eggs to 1 mg/100g in chicken white meat, reaching 75 mg/100g in oysters. In the United States, the National Academy of Sciences recommends the following daily intake of zinc: 3 to 5 mg for infants under 12 months; 10 mg for children ages 1 to 10; 15 mg from 11 and older; 20 mg for pregnant women; 25 mg for breastfeeding women. (Hambidge, 1986).

Zinc is absorbed in the small intestine, mainly in the jejunum and ileum. Only small amounts of zinc are absorbed in the stomach and large intestine. Zinc intake is helped by the glucose in intestinal lumen. Zinc absorption by brush border in intestine takes place through a mechanism mediated both by a saturable carrier and a nonsaturable carrier. (Prasad, 1995; Valee and Falchuk, 1993). Zinc concentration increases from 1 to 3 times, since it is added to the zinc present in the digestive juice. It seems to be absorbed by passive diffusion, but mediated by enzyme carriers (Krebs et al., 1996). On the basal-lateral serous surface of intestine cells, zinc is release to the lumen of mesenteric capillaries, taken to the portal system and then to the liver. It is carried mainly bound to albumin, which is the most abundant serum protein in the body, with strong affinity for metals (Cousins and Leinart, 1988). Apparently, no tissue stores zinc. It is believed, however, that the liver seems to have a key role in zinc metabolism and, along with the pancreas and kidneys, the liver can serve as a storage for later transfer and distribution of zinc in the organism (Enche et al., 1990).

Normal zincemia is around 100mg/100ml, varying according to age, gender, pregnancy and time of the day. Plasma zinc accounts for less than 1% of the total zinc concentration in the organism, though cells absorb zinc from the plasma zinc. The total zinc concentration in the organism depends on how efficient the intestines are in absorbing and excreting stored endogenous zinc. Fecal excretion seems to promote a fine counterbalance between retention and metabolic needs (Coppen, 1987).

According to Hambidge (1986), the main excretion route for endogenous zinc is the gastrointestinal tract. From the total concentration provided to the organism orally or intravenously, only 2 to 10% is found in urine and the remainder is lost in feces. Fecal loss of zinc represents an association of non-absorbed zinc from the diet with its endogenous secretion. Pancreatic secretion is the main source of endogenous zinc (2 to 5 mg/day), which is used in the synthesis of digestive enzymes. Other sources are gastric, duodenal and biliary secretions and cell desquamation into the intestinal lumen. Most of the zinc secreted into the intestinal lumen should be absorbed to avoid zinc imbalance in the organism. The enteropancreatic system is key for the maintenance of zinc levels in the body.

Zinc deficiency is the most important pathological state involving a metal-related metabolism. Due to the variety of roles played by zinc, involving several systems in the organism, zinc deficiency can show minor clinical changes, such as a mild anorexia, taste changes, reduction in physical activity and predisposition to infections. However, it can progress to more severe clinical pictures, such as growth retardation and puberty delay, changes in the immune system and sensorineural disorders (Prasad, 1995; Cunha & Cunha, 1998).

Prasad (1995) and Gibson and Ferguson (1998) studied rural populations in Iran and Turkey. They described cases of mild to moderate zinc deficiency in these populations, who ate mainly grains, which have vegetal proteins and are poor in zinc. They are zinc-deficient populations due to the low concentrations of zinc in their diet, both because zinc is lost during food processing and also due to zinc absorption inhibitors (phytates) present in vegetable-rich diets.

Ghishon (1984) studied acrodermatitis enteropathica, a rare hereditary disease associated with a zinc absorption disorder. He described uncommon symptoms, such as pustular dermatitis, affective and emotional disorder (irritability, lethargy and depression), periorificial and acral dermatitis, skeletal abnormalities, changes in the reproductive system, weight loss, anorexia and diarrhea.

Cousins and Leinart (1988) reported that chronic diarrhea can also be related to hypozincemia. Black and Sazawai (1998) highlighted that, in addition to its role in cell functions, zinc has an important role in the structure of the intestinal enterocyte; therefore, while diarrhea can lead to zinc deficiency due to an absorption deficit, hypozincemia can also cause or worsen diarrhea, creating a vicious cycle. Patients with short bowel syndrome, celiac disease, intestinal bypass and Crohn's disease with acute or chronic persistent diarrhea can develop zinc deficiency. According to McClain (1985), patients with Short Bowel Syndrome have a defective zinc absorption mechanism, both due to the reduced area of small intestine and the fast transit there, which further decreases zinc absorption. Zinc re-absorption from the pancreatic juice can be impaired in large intestinal resections. Patients with a history of mesenteric thrombosis have low levels of serum zinc, probably because their absorption ability is changed.

Role of zinc in the Central Nervous System.

Since the second half of the 20th century, the role of some transition metals in biological reactions has become more widely known. These metals take part in the structure of some enzymes and non-enzymatic proteins and also bind to some kinds of biological molecules. Chemical analyses have shown the presence of metals in the Central Nervous System (CNS), requiring the development of investigation protocols using histochemical techniques to better understand how they are distributed in tissues and cells. During the mid 20th century, studies using a zinc chelator - dithizone - revealed the presence of zinc in the hippocampus. In 1958, Timm observed the same thing through histochemical staining using silver sulfide. Other studies followed, finding pronounced zinc staining, particularly in hippocampal mossy fibers (Haug, 1973; Danscher et al., 1985).

The zinc cation is found in some synaptic terminals, sequestered by the terminal buttons of the axon and released in the synaptic cleft following an electrical impulse through a probable mechanism of exocytosis of the cation-containing vesicles. Initially detected in the limbic system structures (hippocampus and amygdala), today it can be found in layers 1-3 and 5 of the cerebral cortex, in pineal gland and also in the cochlear nuclei. It is estimated that 1% of the human genome is related to protein-bound zinc. In the CNS, zinc plays a role in the production of neural activity, as well as in brain chemical reactions. In some regions, the zinc ion is bound to pro-proteins and stabilizes them. It also appears bound to a substance called neuronal growth factor (NGF), mainly to its storing complex, 7S-NGF. It is a neurotrophic factor whose activation follows a loss of afferents in the systems where it is found and it is related to the occurrence of plastic phenomena of neuronal sprouting (Peters et al., 1987; Frederickson et al., 1988; Howell et al., 1991; Frederickson et al., 2000).

Since zinc can always be found in glutamatergic synapses, its importance to neurotransmission is demonstrated. It can act on synaptic vesicles, cleft or post-synaptic neuron. Theoretically, zinc could increase glutamate storage capacity through its polymerization and precipitation or decrease the levels of glutamate release in glutamate-zinc bindings for a long period of time (Easley et al., 1995). Smart et al. (1994) claim that zinc at the synaptic cleft is a powerful modulator of N-Methyl-D-Aspartate glutamatergic receptors and kainate receptors. Zinc also plays a role in the modulation of the gamma-aminobutyric acid (GABA), whose receptors are widely distributed in areas of the hippocampus (Christensen and Geneser, 1995; Sperk et al., 1997).

Correlation between zinc ion and auditory pathways

The relationship between zinc and the auditory system has been extensively studied. Shambaugh Jr. (1985) studied metallic chemical elements in the body and correlated changes in serum levels of zinc with sensorineural hearing loss. He observed a group of patients with symptoms that suggested hypozincemia and progressive hearing loss associated with tinnitus. Zinc supplements were administered and improvement was observed in 25% of the patients with tinnitus, although it was not fully eliminated. Gersdorff (1987) studied a group of 115 patients in an attempt to find a correlation between hypozincemia and tinnitus, but found no direct relationship between these symptoms. However, he did not rule out the possibility of intermittent tinnitus being due to hypozincemia.

Hewett and Tashian (1996) stressed the importance of the role of zinc in the functioning of several metallic enzymes. It is particularly involved in the formation of carbon anhydrase, which plays an important role in fighting free radicals in the vascular stria of cochlear duct. Hypozincemia can alter the role of carbon anhydrase in the metabolism of carbon dioxide in the vascular stria of cochlear duct. Mees (1983) described the role of zinc in calcium channels and in the sodium-potassium pump, which is controlled by the Na-K-ATPase binding and is inhibited by zinc. Consequently, zinc deficiency can lead to changes in the endocochlear potential, altering the electrophysiology of the cochlea and causing tinnitus.

Min et al. (1995) studied the levels of zinc in the perilymph and claimed that changes in zinc concentration could influence the role and structure of hair cells. Gentamicin was administered in ototoxic doses and it was observed, through electrocochleography, that hearing levels were reduced, while zinc levels in the perilymph had significantly increased. These findings can indicate the existence of a homeostatic system involving zinc in the cochlea. Shambaugh Jr. (1985) proposed that zinc could act as a protective element of the cell membrane, especially in hair cells and in epithelial cells of vascular stria, protecting them from attacks and damages caused by free radicals. This zinc increase in the perilymph could be due to compensatory mechanisms in the cochlea.

Rarey and Yo (1996) studied zinc binding with superoxide-dismutase (ZN-SOD) and found high amounts of these elements in the cochlea. The superoxide-dismutase (SOD) radical has powerful action on free radicals which, in excessive amounts, can lead to protein inactivation and cause cell damage. Pierson and Moller (1981) detected high levels of Zn-SOD in the cochlear cytosol, especially in the vascular stria. The authors claim that high levels of aerobic oxidation in the vascular stria are closely related to the high level of energetic activity in ion transport. It is well known that the vascular stria is rich in Na-K-ATPase, whose roles include the transport of potassium to the endolymph, and this mechanism consumes energy. The decrease in Zn-SOD levels can be related to the increase in noise-induced hearing loss, presbycusis and use of ototoxic drugs (Ohlemiller et al., 1999a). Troy et al. (1996) observed an increased formation of hydroxyl and/or peroxinitrite radicals in cells associated with an decrease in ZN-SOD.

In central structures of the auditory system, Danscher (1981) and Frederickson et al. (1987a), using histochemical methods, were able to identify zinc in cochlear nuclei (NNCC). Frederickson (1988) studied neurons of the cochlear nuclei and observed that numerous neurons contained vesicularized zinc and that they had axon fibers spreading towards the molecular layer of the cochlear nucleus.

Frederickson et al. (1987b) stated that, in terminal buttons, zinc could stabilize the structure of pro-protein molecules stored in vesicles. Martinez-Quizarro et al. (1991) suggested that the zinc present in the synapse area may have a moderating effect on glutamatergic neurotransmission, deeply affecting many excitatory synapses.

Danscher (1981) and Casanovas-Aguilar et al. (1998) made clear in their experimental models that zinc contained in the synaptic vesicle in NNCC precipitated 60 minutes after an intraperitoneal injection of sodium selenite. They found functional resemblance between zinc vesicles in the dorsal cochlear nucleus and in different areas of the brain, such as in hippocampal formation, temporal lobe and telencephalon. Rúbio and Juiz (1998) confirmed, through electronic microscopy, the presence of zinc ions in synaptic terminals of granule cells of cochlear nuclei.

It is likely that glutamate and zinc are correlated with the same neurons and that zinc inhibits the response of N-Methyl-D-Aspartate (NMDA) receptors in terminal buttons and it is believed that zinc has a modulating role in the activity of this kind of synapse. The response of non-NMDA receptors is facilitated by the zinc ion, showing the importance of zinc in post-synaptic modulation mechanisms for glutamate. This modulation could be played by an increase in zinc extracellular concentration, by successive excitatory synapse activity, which releases zinc along with the neurotransmitter and leads to a moderating block (Frederickson et al., 1988; Waller et al., 1996).

In the cochlear nuclei, zinc that is identified by histochemical techniques, specially the Neo-Timm technique, can serve as an anatomic marker for changes in the arrangement of glutamatergic synapses, which are secondary to nuclei response plastic phenomena (Féres, 1998).

DISCUSSION

The zinc ion is the most abundant intracellular element, but only 1% of the total zinc in the organism circulates in vessels (Kessalak, 1987). This makes it hard to evaluate what are the real consequences of hypozincemia, once zinc serum levels not necessarily reflect the total zinc concentration in the body. Yet, studies regarding the importance of zinc have shown that its roles in general physiology are multifold and that zinc deficiency could lead to various levels of change in several systems (Prasad, 1995).

Since the mid 20th century, studies have revealed the role of zinc in central neurotransmission, mainly in glutamatergic systems. It seems that zinc has a regulatory role in the excitatory activity of specific receptors. Since glutamate is the major excitatory neurotransmitter in the auditory system, if the zinc ion works as its regulator and moderator, then it plays a key role in the functioning of auditory pathways and its deficiency can indeed affect the auditory physiology and lead to a clinical picture that includes hearing loss and/or tinnitus (Haug, 1973; Shambaugh Jr., 1985; Gersdorff et al., 1987; Peters et al., 1987; Frederickson et al., 1988; Howell et al., 1991).

Since it is anatomically detectable by histochemical techniques, in which zinc granules are stained in brown and its color intensity is directly proportional to zinc ion concentration in the tissue, these techniques are very useful for marking glutamatergic systems that use the zinc ion as a co-factor. On the other hand, markers for zinc are also very useful to study plastic changes and neuronal rearrangements in systems containing the zinc ion, such as the cochlear nuclei (Frederickson et al., 1988; Féres, 1998).

CLOSING REMARKS

Knowing how a metal such as zinc plays a role in the physiology of various neural systems has led to advances in the study of Central Nervous System physiology. Extending this knowledge to auditory pathways has also opened new paths in the research on physiological and pathological states of the auditory system.

In central auditory pathways, it is known that zinc takes part in the neurotransmission of cochlear nuclei, mainly the dorsal subnucleus. In other structures of the auditory pathways, research on zinc detection is still in its early stages. It is very important to conduct further research in order to reveal details of the central auditory physiology.

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1 Master studies in Otorhinolaryngology under course, Medical School of Ribeirão Preto, University of São Paulo.
2 Ph.D., Professor, Discipline of Otorhinolaryngology, Medical School of Ribeirão Preto, University of São Paulo.

Affiliation: Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery.
Hospital das Clinicas, Ribeirão Preto - Campus de Monte Alegre

Address correspondence to: Avenida Bandeirantes, 3900 Ribeirão Preto SP 14049-900. - Tel (55 16) 602-2862/ 602-2863 - Fax (55 16) 602-2860 - E-mail: mariacristina@roo.fmrp.usp.br

This review article is part of the Introduction of the Master dissertation thesis in Otorhinolaryngology submitted

to the Medical School of Ribeirão Preto, University of São Paulo.

Article submitted on September 18, 2001. Article accepted on April 11, 2002.

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