ROLE OF NATURAL SUBSTANCES AND VITAMIN SUPPLEMENTATION IN TINNITUS PREVENTION AND TREATMENT

Abstract

The aim of this review is to refer a possibility of using natural substances for treating or reducing the symptoms of tinnitus. Tinnitus is a sensation of sound without an external source. It often manifests as a ringing in the ears, but it may also sound like a buzzing, hissing, whistling or even roaring in the head. Tinnitus is a symptom of an underlying condition. It can be linked to hearing loss, stress, ear damage, blood pressure, tumours and atherosclerosis. Exposure to loud noise is one major cause of tinnitus, since it wears down the delicate hair cells in inner ear that translate sounds into nerve impulses. Potential therapy of tinnitus is a pharmacological treatments. Fortunately, there are many effective natural alternatives to drugs that can bring considerable relief and help cope. The potential form of treatment is vitamins and natural flavonoids therapy. Low levels of melatonin and vitamin B12 in body have a significant correlation with the development of tinnitus. It was reported that melatonin is useful in the treatment of tinnitus, even in cases associated with sleep disturbance. There are relationship between vitamin B12 deficiency and dysfunction of the auditory pathway. Antioxidants are another substances which have a promising effect in the treatments of tinnitus. The constituents of G. biloba are potent scavengers of free radicals and has been prescribed their positive effect on treat of central nervous system disorders and cognitive deficits. Positive antioxidant effects have vitamin C, hesparidin and diosmin also.

Full text

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ROLE OF NATURAL SUBSTANCES AND VITAMIN SUPPLEMENTATION IN TINNITUS PREVENTION AND
TREATMENT
Tomáš Slanina*1, Lenka Petrovičová2, Peter Massányi1
Address(es): MSc. Tomáš Slanina, PhD.,
1Department of Animal Physiology, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovak
Republic, phone number: +421 37 641 4288.
2Department of Biochemistry and Biotechnology, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76
Nitra, Slovak Republic.
*Corresponding author: tomas.slanina@uniag.sk
ABSTRACT
Keywords: Tinnitus, vitamins, antioxidants, bioflavonoids, natural substances
INTRODUCTION
Tinnitus
Tinnitus is defined as the perception of sound in the absence of external auditory
stimulation (Hoekstra, 2013). Although the experience of short bursts of noise is
almost universal, tinnitus is typically defined as noise that lasts at least 5 minutes
(Davis, 1995).This is the most common statement among researchers in
audiology and related fields, stemming from basic neurosciences (Kaltenbach,
2011) to applied psychophysiology (Kropp et al., 2012), audiology (Caffier et
al., 2006), and behavioural psychology (Westin et al., 2008). Among severe
sufferers, tinnitus causes disability associated with concentration deficits,
insomnia, hypersensitivity to sounds, anxiety and depression. Often a
combination of several complaints leads to a diminished quality of life
(Erlandsson and Hallberg, 2000; Bauch et al., 2003). It poses a significant
clinical problem for millions of people and is proportionally problematic in
countries where epidemiological data have been reported (Henry et al., 2005;
Erlandsson and Dauman, 2013).
The overall prevalence of tinnitus in adult populations ranges from 7 % to 19 %.
The prevalence of tinnitus increases with age and seems to attain a plateau or
even decrease at around 60–80 years (Henry et al., 2005). Within the group of
treatment-seeking patients, the male-female ratio is 2:1. In up to 5% of the adult
population, tinnitus interferes negatively with the ability to lead a normal daily
life, and in 2%, it has a severe effect on daily life (Nondahl et al., 2002). The
most common additional complaints are sleep problems, depression and anxiety
(Zoger et al., 2006). Patients report limitations in activity and restrictions to
participation in work and employment, and in social and civic life (Tyler and
Baker, 1983). The distress can become so intense as to drive patients to suicide
(Pridmore et al., 2012).
Hearing loss is presumably the most important risk factor for tinnitus, but the
association is complex. Tinnitus is reported in individuals with apparently normal
hearing, and only some hearing-impaired persons report tinnitus (Aarhus et al.,
2015, Tyler, 2006).
For those whose tinnitus has significant clinical impact, a number of therapeutic
approaches have been described and employed, from cognitive-behavioral
therapies and sound enrichment, to drug approaches. Some studies have shown
favorable results, while others did not result in benefits (Baguley et al., 2013).
Treatments proffered for tinnitus can be grouped into four main classes:
pharmacological, acoustic–physical, psychological, and some combination of
elements from at least two of these three. Pharmacological and physical
treatments principally aim to affect the tinnitus itself, ideally to eliminate it or
reduce its prominence to the point that it is no longer troublesome (Noble,
2008).Various substances have been used and tested as drug treatments. Among
them, antioxidants have appeared promising (Polanski et al., 2016). Oxidative
stress is a consequence of the inefficient utilization of molecular oxygen (O2) by
cells (Reiter et al., 2004). ROS including the superoxide anion radical (O2•−) and
hydroxyl radical (•OH), hydrogen peroxide (H2O2), and singlet oxygen (IO2) are
generated as by-products of cellular respiration and other metabolic processes.
They damage cellular macromolecules including DNA, proteins, and lipids
(Kozina et al., 2007). Additionally, however, there are also highly devastating
agents which are nitrogen based e.g. nitric oxide (NO•) and especially the
peroxynitrite anion (ONOO−) (Tengattini et al., 2008). Oxidative stress is
thought to play an important role in atherosclerotic vascular disease. Thus,
dietary antioxidants such as ascorbate (vitamin C) can protect against the
development and progression of atherosclerosis in experimental models.
Numerous observational studies have shown an inverse association between
antioxidant intake of body status and the risk of cardiovascular diseases (Cares et
al., 2000). Antioxidant vitamins may reduce risks of cardiovascular disease has
been the subject of considerable research attention in recent years. Basic research
studies have provided evidence of possible mechanisms for an effect of
antioxidants on atherosclerosis, and several observational epidemiologic studies
have suggested that risk of coronary heart disease (CHD) may be 20 – 40 %
lower among those with high dietary intake or serum levels of antioxidant
The aim of this review is to refer a possibility of using natural substances for treating or reducing the symptoms of tinnitus. Tinnitus is a
sensation of sound without an external source. It often manifests as a ringing in the ears, but it may also sound like a buzzing, hissing,
whistling or even roaring in the head. Tinnitus is a symptom of an underlying condition. It can be linked to hearing loss, stress, ear
damage, blood pressure, tumours and atherosclerosis. Exposure to loud noise is one major cause of tinnitus, since it wears down the
delicate hair cells in inner ear that translate sounds into nerve impulses. Potential therapy of tinnitus is a pharmacological treatments.
Fortunately, there are many effective natural alternatives to drugs that can bring considerable relief and help cope. The potential form of
treatment is vitamins and natural flavonoids therapy. Low levels of melatonin and vitamin B12 in body have a significant correlation
with the development of tinnitus. It was reported that melatonin is useful in the treatment of tinnitus, even in cases associated with sleep
disturbance. There are relationship between vitamin B12 deficiency and dysfunction of the auditory pathway. Antioxidants are another
substances which have a promising effect in the treatments of tinnitus. The constituents of G. biloba are potent scavengers of free
radicals and has been prescribed their positive effect on treat of central nervous system disorders and cognitive deficits. Positive
antioxidant effects have vitamin C, hesparidin and diosmin also.
ARTICLE INFO
Received 15. 9. 2016
Revised 14. 10. 2016
Accepted 17. 11. 2016
Published 1. 12. 2016
Review
doi: 10.15414/jmbfs.2016/17.6.3.987-994

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vitamins. CHD remains the leading cause of death in the United States, as well as
most developed countries, accounting for approximately one of every four deaths.
For this reason, even the modest reductions in CHD risk suggested by studies to
date, if real, could yield substantial public health benefits. Due to the changing
environment including a lot of noise pollution is very important (Ayepola et al.,
2014). Hearing protection is very important as the hearing right after eyesight is
one of the most important senses. Numerous neurological, vascular and other
somatic disorders have been linked to the development of the tinnitus. Therefore
no single treatment will be effective for treating all tinnitus patients (Loockwood
et al., 2002). It was reported that the several natural substances have a potential
benefit effect on the cause of this disorders.
Effects of selected natural substances at the cell level
Melatonin
Melatonin is an evolutionally phylogenic old molecule, which can be traced back
to the ancient photosynthetic prokaryotes. It is a tryptophan derivative that was
first isolated from bovine pineal glands (Lerner et al., 1958). Melatonin was
later found to be also present or synthesized in extrapineal tissues such as retina,
Harderian gland, gastrointestinal tract, testes and lymphocytes (Reiter et al.,
2013). Melatonin is a functionally diverse molecule (Reiter et al., 2010), its
originally described mission was the regulation of circadian and circannual cycles
(Marczynski et al., 1964; Reiter, 1991, 1993; Zhang and Zhang, 2014). This
molecule, acting through the melatonin receptor, seems to affect sleep, mood,
sexual maturation and reproduction, immune function, aging and the
antioxidative defense system. Clinical research has explored several influences
that melatonin could exert on a wide range of disorders, symptoms and
pathologies (Altun et al., 2007, Lanfumey et al., 2013). A clinical study
conducted on healthy volunteers revealed that low plasma melatonin
concentrations may significantly correlate with the development of subjective
idiopathic tinnitus (Lasisi et al., 2012). Melatonin is thought to produce
therapeutic effects through different mechanisms such as antioxidant and free
radical scavenger activities. Furthermore, melatonin appears to interfere with the
peripheral and central autonomic systems, with a subsequent decrease in tone of
the adrenergic system and increase in cholinergic activity (Simko et al., 2010).
Melatonin exerts advantageous vascular changes that improve labyrinth
perfusion, thus protecting the inner ear from hypoxia. Melatonin can reduce
muscular tone, and it may relieve tensor tympani muscle spasms, thus improving
symptoms. In addition to relieving tinnitus, melatonin improves sleep quality
(Hurtuk et at., 2011; Miroddi et al., 2015; Pinpdda et al., 2010).
Melatonin, dubbed the hormone of darkness, is known to regulate a wide variety
of physiological processes in mammals. Dubocovich and Markowska (2005)
describes well-defined functional responses mediated through activation of high-
affinity MT1 and MT2 protein coupled receptors viewed as potential targets for
drug discovery. MT1 melatonin receptors modulate neuronal firing, arterial
vasoconstriction, cell proliferation in cancer cells, and reproductive and
metabolic functions. Activation of MT2 melatonin receptors phase shift circadian
rhythms of neuronal firing in the suprachiasmatic nucleus (SCN), inhibit
dopamine release in retina, induce vasodilation and inhibition of leukocyte
rolling in arterial beds, and enhance immune responses. The melatonin-mediated
responses elicited by activation of MT1 and MT2 native melatonin receptors are
dependent on circadian time, duration and mode of exposure to endogenous or
exogenous melatonin, and functional receptor sensitivity. Together, these studies
underscore the importance of carefully linking each melatonin receptor type to
specific functional responses in target tissues to facilitate the design and
development of novel therapeutic agent (Dubocovich and Markowska, 2005).
In humans, expression of the MT1-receptor subtype in the SCN was first shown
by Weaver and Reppert 1996. Transcripts for the MT2-receptor were not detected
in humans but in mice (Dubocovich et al., 1998). The role of melatonin in the
SCN has been described in several rodent studies and may be also valid for
humans. The general opinion is that melatonin is an endogenous synchronizer
(Cajochen et al., 2003). It provides the SCN with the information about the night
and timed secretion of melatonin adjusts to the light/dark cycle. In rats it is able
to stabilize circadian rhythms, reinforce them and maintain their mutual phase
relationship. Furthermore, melatonin entrains free running activities in rodents
(Korf et al., 2003). The mechanisms behind these effects are an inhibiting of
neuronal firing, which might be important for defining SCN sensitivity to
entraining stimuli. In humans this might contribute to the regulation of sleep.
Ekmekcioglu et al. (2003) identified MT1 and MT2 receptors in human coronary
arteries from pathological samples and also from healthy controls. Furthermore,
Ekmekcioglu et al. (2001a) presented preliminary evidence for a circadian
variation of the MT1-receptor in coronary arteries. The role of melatonin in
human coronary arteries needs to be evaluated. Ekmekcioglu et al. (2003) and
Ekmekcioglu et al. (2001b) showed that both types of MT-receptors are present
in the human aorta. Monroe and Watts, (1998) assume that melatonin has
vasodilatory effects, since studies in aortic rings from rat and rabbits showed that
melatonin induces vasodilatation.
Melatonin, the main hormone produced by the pineal gland, displays a circadian
rhythm peaking at night (Arendt, 1995). Pinealocytes uses tryptophan as
substrate for melatonin synthesis, and melatonin levels change as a function of
tryptophan availability (Yaga et al., 1993). Pyridoxine is converted to its active
coenzyme form, pyridoxal phosphate (PLP). More than 60 PLP-dependent
enzymes are known, including enzymes that participate in decarboxylation
reactions such as the decarboxylation of DOPA to dopamine and 5-
hydroxytryptophan to serotonin (Abou-Saif and Lipman, 2001, Salzmann et
al., 2000). The activity of pyridoxine as a coenzyme in the tryptophan
metabolism was described in the kinurenine and methoxyindole pathways.
Pyridoxine acts as a coenzyme of 5-hydroxytryptophan decarboxylase. The
enzyme carboxylates 5-hydroxytryptophan to serotonin, the immediate precursor
of melatonin. The effect of pyridoxine on aromatic amino acid decarboxylase
activity supports a regulatory role of pyridoxine on the synthesis of
neurotransmitters (Dolina et al.,1993, Geng et al., 1995). Melatonin was shown
to increase brain pyridoxal phosphokinase activity, inhibition of glutaminergic
neurotransmission, resulting in inhibitory effects on central nervous system
activity (Acuna-Castroviejo et al., 1986 Luboshitzky et al., 2002).
In study Lasisi et al. (2012), the main finding is that low plasma melatonin and
vitamin B12 have significant correlation with the development of tinnitus among
the elderly. Melatonin is a neurohormone produced centrally by the pineal gland;
it regulates the sleep-wake cycle by inducing sleepiness and reducing body
temperature through its effects on the circadian clock (Megwalu et al., 2006;
Saunders, 2007). Several researchers have reported that melatonin is useful in
the treatment of tinnitus, even in cases associated with sleep disturbance
(Megwalu et al., 2006; Simko and Paulis, 2007).
Ginkgo biloba L.
Ginkgo biloba L., also popularly known as living fossil, possesses a variety of
biological and pharmacological activities (Singh et al., 2008). The 2 main
pharmacologically active groups of compounds present in the Ginkgo leaf extract
are the flavonoids and the terpenoids (Smith and Luo, 2004). Flavonoids, also
called phenylbenzopyrones or phenylchromones, are a group of low molecular
weight substances that are widely spread in the plant kingdom. Flavonoids
present in the Ginkgo leaf extract are flavones, flavonols, tannins, biflavones
(amentoflavone, bilobetol, 5-methoxybilobetol, ginkgetin, isoginkgetin and
sciadopitysin), and associated glycosides of quercitin and kaempferol attached to
3-rhamnosides, 3-rutinosides, or p-coumaric esters (McKenna et al., 2000).
These compounds are known to act mainly as antioxidants/free radical
scavengers, enzyme inhibitors, and cation chelators (DeFeudis and Drieu,
2000). Two types of terpenoids are present in Ginkgo as lactones
(nonsaponifiable lipids present as cyclic esters): ginkgolides and the bilobalide
(Mahadevan and Park, 2008; Smith and Luo, 2004).
The extracts of the leaves of Ginkgo biloba have been found to possess
cardioprotective, antiasthmatic, antidiabetic, hepatoprotective and potent CNS
activities (Liebgott et al., 2000; Naik and Panda, 2007).
The constituents of G. biloba are potent scavengers of free radicals (Naik et al.,
2006; Pietri et al., 1997). By scavenging free radicals and ROS, G. biloba
inhibits lipid peroxidation and augments levels of endogenous antioxidants.
Literature reports extensive work on the cardioprotective activity of Ginkgo
biloba extracts (EGb). Most studies have shown EGb to improve the recovery of
post ischemic cardiac function (coronary flow, aortic flow, LVdP and its first
derivative) in the ischemic reperfused myocardium (Bao et al., 2008; Clostre,
2001).
It has been demonstrated that EGb protects the heart by its antioxidant properties
and its ability to adjust fibrinolytic activity (Panda and Naik, 2014) In study
Haramaki et al. (1994). EGb diminished the decrease of myocardial ascorbate
content after 40 minutes of ischemia and 20 minutes of reperfusion and also
suppressed the increase of dehydroascorbat.
Clinically, it has been prescribed to treat CNS disorders such as Alzheimer's
disease and cognitive deficits. It exerts allergy and changes in bleeding time.
While its mutagenicity or carcinogenic activity has not been reported, its
components, quercetin, kaempferol and rutin have been shown to be genotoxic.
There are no standards or guidelines regulating the constituent components of
Ginkgo biloba leave extract nor are exposure limits imposed (Chan et al., 2007).
The standardized Ginkgo biloba extract (EGb 761) is recommended for the
treatment of geriatric memory disorders including vascular and
neurodegenerative dementia. Its use is steadily increasing around the world
(Alber Kader et al., 2007). Clinical efficacy in cognitive decline and dementia
has been confirmed by a series of randomized, double-blind, placebo-controlled
clinical trials (Beck et al., 2016; Gauthier and Schlaefke, 2014; Janssen et al.,
2010; Weinmann et al., 2010; Tan et al., 2015). Improved microcirculation,
enhanced neuroplasticity and support of mitochondrial energy production have
been discussed as underlying mechanisms of action (Spieß et al., 2014).
However, these suggested modes of action are mainly based on animal and in-
vitro-data and have not been verified in human (Beck et al., 2016).
Hesperidin
Fortunately, organisms are endowed with a series of agents that can either
directly detoxify radicals or their associated reactants (free radical scavengers) or

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they metabolize them to innocuous molecules (antioxidative enzymes) (Kozina
et al., 2007; Tengattini et al., 2008).
Hesperidin is a naturally occurring flavonoide that exists in citrus and other
plants and can be isolated in large amounts from the peels of Citrus aurantium
(bitter orange), Citrus sinensis (sweet orange), and Citrus unshiu (satsuma
mandarin) (Crozier et al., 2009). Hesperidin is reported to exert a wide range of
pharmacological effects such as antioxidant, anti-inflammatory, anti
hypercholesterolemic and anticarcinogenic properties (Chen et al., 2010). It has
also been demonstrated that hesperidin can protect neurons against various types
of insults associated with many neurodegenerative diseases (Cho, 2006). In study
Tamilselvam et al. (2013) investigated the neuroprotective effect of hesperidin
on rotenone-induced cellular model for Parkinson disease by analysing its effect
on rotenonemediated oxidative stress generation, mitochondrial dysfunction and
apoptosis in human neuroblastoma SK-N-SH cells. Their data suggests that
hesperidin exerts neuroprotective effect against rotenone due to its antioxidant
effect, maintenance of mitochondrial function, and antiapoptotic properties in a
neuroblastoma cell line.
Phytochemicals, particularly antioxidants from natural sources such as fruits,
vegetables and herbs have gained popularity due to their protective properties
against several chronic diseases such as cancer and cardiovascular diseases
(Temple, 2000). Among the natural compounds extracted from plants,
polyphenols have received much attention due to their powerful
antioxidant,antimicrobial and antiviral activities as well as their capacity to
inhibit the proliferation of cancer cells, protect neuron against oxidative stress,
stimulate vasodilation, reduce vascularization and improve insulin secretion (Del
Rio et al., 2010). Polyphenols are adiverse class of chemical compounds that
share the ability to act as chain breaking antioxidants, which are proposed to
protect against the damage caused by free radicals to DNA cell membrane and
cell components (Dziri et al., 2012). Moreover, they exhibit antibacterial,
antiinflammatory, antiallergenic, antiarthrogenic and antithrombotic effects
(Ajila et al., 2010). Recent research on the nutritional aspects have shown that
polyphenols are able to modulate nutrient availability through the inhibition of
digestive enzymes involved in lipid and starch break down, which could lead to
beneficial effects on calorie intake, obesity, and bloodglucose (McDougall et al.,
2009, Nagella et al., 2014).
Hesperidin exerts protective action in cardiac tissue by its antihypertensive and
antioxidant properties (Wilmsen et al., 2005). Some reports evidenced that
hesperidin targets peroxisome proliferator-activated receptor-gamma (PPAR-γ) to
exert biological actions (Salam et al., 2008). PPAR-γ being a member of the
ligand-dependent nuclear receptor category regulates glucose, lipid and energy
homeostasis (Hihi et al., 2002; VandenHeuvel, 1999). In addition, PPAR-γ
regulates cellular proliferation and differentiation inducing apoptosis in a wide
spectrum of human tumor cell lines (Ondrey, 2009; VandenHeuvel, 1999).
Flavonoids like hesperidin are reported to possess satisfactory capability to
neutralize free radicals. This antioxidant property may be related to their
pharmacological actions and they may be used as protective agents in a number
of cardiac diseases (Agrawal et al., 2014).
Diosmin
The second natural bioflavonoids is diosmin (3′,5,7-trihydroxy-4′-
methoxyflavone) which is is the aglycone of the flavonoid glycoside diosmin
(3′,5,7-trihydroxy-4′-methoxyflavone-7-ramnoglucoside). Diosmin is hydrolyzed
by enzymes of intestinal microflora before absorption of its aglycone diosmetin.
Diosmin is abundant in the pericarp of various citrus (Campanero et al., 2010;
Del Bano et al., 2004; Nogata et al., 2006) and is considered a vascular-
protecting agent in the treatment of hemorrhoids, lymphedema, varicose veins
and different types of cancer (Camarda et al., 2007; Cesarone et al., 2006; Le
Marchand et al., 2000). As a flavonoid, it also possesses a multitude of
biological activities including anti-inflammatory and antioxidant properties (Jean
and Bodinier, 1994; Guillot et al., 1998). However, its anti-inflammatory and
protective mechanisms on PC12 cells, a model of phenotypic neuronal cells, have
not been studied to date (Milano et al., 2014).
Diosmin is a natural flavone glycoside which can be obtained by
dehydrogenation of the corresponding flavanone glycoside, hesperidin that is
abundant in the pericarp of various citrus fruits (Campanero et al., 2010).
Diosmin treatment of streptozotocin-nicotinamide induced diabetic rats,
ameliorated oxidative stress in plasma and tissues as evidenced by improved
glycemic and antioxidant status along with decreased lipid peroxidation
(Srinivasan and Pari, 2012). Experimental evidence showed the potential of
rutin, a flavonol to delay glomerulosclerosis of diabetic nephropathy (DN) due to
its ability to inhibit cell hypertrophy and the accumulation of ECM mediated by
TGF- β1/Smads and ROS signals in mesangial cells cultured by high glucose
(Tang et al., 2011).
Ruscus aculeatus L.
Ruscus aculeatus L. (butcher’s broom), belonging to the family of Liliaceae,
appears in a great number of dietary supplement patents (Engl, 2006; Rizza et
al., 2011) present in literature, referring R. aculeatus rhizomes extract as an
active ingredient to enhance microcirculation. Indeed, R. aculeatus preparations
are widely distributed in Europe, and have been hardly used for more than 40
years to treat chronic venous insufficiency and vasculitis (Bouskela et al., 1994;
Capra, 1972; Huang et al., 2008). Therefore, oral supplementation with R.
aculeatus extracts may prevent time-consuming, painful, and expensive
complications of varicose veins and other venous insufficiency, representing an
alternative to traditional treatments which require a high degree of patient
compliance to be effective (MacKay, 2001). While anthocyanins are the main
compounds of R. aculeatus skin berries (Longo and Vasapollo, 2005), steroidal
saponins represent the main class of chemical compounds isolated from rhizomes
and roots of R. aculeatus and are considered to be the active compounds of R.
aculeatus commercial products (de Combarieu et al., 2002; Mimaki et al.,
1998a). R. aculeatus saponins are characterized by spirostanol or furostanol
aglycones, bearing a sugar chain at C-1 or at C-3 (de Combarieu et al., 2002;
Kite et al., 2007; Mimaki et al., 1999). In particular, a mixture of two spirostane
aglycons, neoruscogenin and its (25R)-Δ25,27 dihydro derivate ruscogenin, is
considered the active ingredient of some R. aculeatus commercial drugs (de
Combarieu et al., 2002).
L- ascorbic acid - Vitamin C
Vitamin C or ascorbic acid is a water-soluble vitamin, critical for collagen and L-
carnitine biosynthesis, for the conversion of dopamine to norepinephrine; it also
improves iron absorption. Under physiological conditions,this vitamin also acts
as a potent antioxidant (Li and Schellhorn, 2007). Papaverine hydrochloride is a
synthetic alkaloid that exerts a tissue protective effect correlated to antioxidants,
because this substance promotes non-specific smooth muscle relaxation,leading
to vasodilation (Mathis et al., 1997). Antioxidants act synergistically with other
agents or in isolation, functioning in different ways, protecting cell membranes
and also eliminating oxygen free radicals (Polanski et al., 2015; Seidman,
2000).
The beneficial effects of vitamin C supplementation in humans are controversial.
A study reported that vitamin C may improve glycemic control, lowering both
fasting blood glucose and glycated haemoglobin (HbA1c) (Eriksson and
Kohvakk, 1995). Chronic oral administration of vitamin C to patients with type 2
diabetes causes a decline in plasma free radicals that is associated with improved
whole body glucose disposal (Mullan et a., 2002; Paolisso et al., 1995) and
improved endothelial function (Regensteiner et al., 2003). Recently, another
study reported a reduction in the malondialdehyde (MDA) level, a major product
of oxidative damage in both fasting and postprandial states of type 2 diabetic
patients after vitamin C (1000 mg day-1) supplementation for 6 weeks although
no effect was observed on lipid profiles (Mazloom et al., 2011). Some studies
have indicated that the intra-arterial infusion of vitamin C restores endothelium-
dependent vasodilation in patients with type 1 or type 2 diabetes (Timimi et al.,
1998; Ting et al., 1996) suggesting that hyperglycemia-induced oxidative stress
mediates endothelial dysfunction in diabetic patients (Ayepola et al., 2014).
B Vitamins
Except the typical antioxidants for the proper functioning of the nervous and
vascular system in the body are also important B-group vitamins. Maintaining the
proper functioning of the nervous system is very important because it affects the
function of other systems. The nervous system, is responsible for sensing the
internal and external environmental stimulus and as well as coordinating muscles
and organs activities. Thiamine (Vitamin B1) is a coenzyme in the pentose
phosphate pathway, which is a necessary step in the synthesis of fatty acids,
steroids, nucleic acids and the aromatic amino acid precursors to a range of
neurotransmitters and other bioactive compounds essential for brain function
(Kerns et al., 2015). Thiamine playsa neuromodulatory role in the acetylcholine
neurotransmitter system, distinct from its actions as a cofactor during metabolic
processes (Hirsch and Parrott, 2012) and contributes to the structure and
function of cellular membranes, including neurons and neuroglia (Ba, 2008).
The two flavoprotein coenzymes derived from riboflavin, FMN and FAD are
crucial rate limiting factors in most cellular enzymatic processes. As an example,
they are crucial for the synthesis, conversion and recycling of niacin, folate and
vitamin B6, and for the synthesis of all hemo proteins, including hemeglobin,
nitric oxide synthases, P450 enzymes, and proteins involved in electron transfer
and oxygen transport and storage (Rivlin, 2007). The flavoproteins are also co-
factors in the metabolism of essential fatty acids in brain lipids (Sinigaglia-
Coimbra, 2011) the absorption and utilisation of iron (Mushtaq, 2011) and the
regulation of thyroid hormones (Rivlin, 2007). Dysregulation of any of these
processes by riboflavin deficiency would be associated with its own broad
negative consequences for brain function. Riboflavin derivatives also have direct
antioxidant properties and increase endogenous antioxidant status as essential
cofactors in the glutathione redox cycle (Ashoori and Saedisomeolia, 2014).
Vitamin B6 sufficiency is required for optimal health. This is due to the
participation in many different biochemical reactions. Vitamin B6 and its
derivatives are needed, especially for coenzyme functions in main metabolic
pathways in the human body. For that reason, it is clear that a vitamin B6
deficiency, even in mild forms, has effects on the human metabolism. Several

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diseases and impairments of health are connected to the wide variety of B6
functions in suboptimal status. This can also be worsened through ageing
(Spinneker et al., 2007).Vitamin B6 has an important role in the process of
melatonin biosynthesis. Journal of Gergion Med News reported the study on the
30 laboratory white rats which were divided into two groups - experimental and
control groups. The animals in the first group were treated with vitamin B6
injection. Every other day at 22 00, melatonin concentration was defined by
means of ELISA. The experiment has lasted for two months. At the end of the
experiment, the plasma level of melatonin increased by 35,95% in the first group
of animals in comparison with the second control group. It is found that, B6
vitamin injections strengthens melatonin biosynthesis; consequently
strengthening of melatonin biosynthesis influences positive therapeutic effects.
One of the reasons for pathological processes, developed in organism on the
background of B6 vitamin deficiency, is reduction of endogen melatonin
production (No authors listed, 2007).
Vitamin B12 is a largest known biomolecule and the only nutrient with a stable
carbon-metal bond. One molecule of cobalt lies at the centre of each B12
molecule. Isolated B12 is a crystalline compound with a bright red colour, due to
the presence of cobalt. Vitamin B12 works with folic acid in many body
processes including synthesis of DNA, red blood cells and the insulation sheath
(myelin sheath) that surrounds nerve cells and facilitates the conduction of
signals in the nervous system. Severe depletion manifests as pernicious anaemia
which was invariably fatal until the discovery of B12 in liver. But long before
anaemia sets in, other conditions may manifest, most often neurological problems
(numbness, pins and needles sensations a burning feeling in the feet, sharing
muscle fatigue, sleep disorders, memory loss, irrational anger, impaired mental
function and Alzheimers or psychological conditions (dementia, depression,
psychosis and obsessive-compulsive behaviour) (Fallon, 1987; Singh and
Sachan, 2011). There are many reasons for reviewing the neurology of vitamin-
B12 and folic-acid deficiencies together, including the intimate relation between
the metabolism of these two vitamins, their morphologically indistinguishable
megaloblastic anaemias, and their overlapping neuropsychiatric syndromes and
neuropathology, including their related inborn errors of metabolism. Folates and
vitamin B12 have fundamental roles in CNS function at all ages, especially the
methionine-synthase mediated conversion of homocysteine to methionine, which
is essential for nucleotide synthesis and genomic and non-genomic methylation.
Folic acid and vitamin B12 may have roles in the prevention of disorders of CNS
development, mood disorders, and dementias, including Alzheimer's disease and
vascular dementia in elderly people. Vitamin-B12 and folic-acid deficiency and
related inborn errors of metabolism may result in similar megaloblastic anaemias
and overlapping neuropsychiatric complications. In the early stages there is often
dissociation between the neuropsychiatric and haematological manifestations, as
occurs in other general metabolic disorders that affect the CNS. The occurrence
of CNS complications is influenced by the duration as well as the severity of
either deficiency, by predisposing genetic factors, including polymorphisms of
folate or vitamin-B12 dependent enzymes, and by any associated metabolic
disorders. The administration of folic acid in the presence of vitamin-B12
deficiency may be harmful to the nervous system, after brief temporary
improvement, and ultimately harmful to the blood, after more striking but
suboptimal temporary improvement. In the CNS, as in the blood, failure or
blocking of the supply of methyl folate will result in impaired purine, thymidine,
nucleotide, and DNA synthesis, as well as disruption of DNA transcription,
methylation, gene expression, and other epigenetic mechanisms affecting tissue
growth, differentiation, and repair. There is now substantial interest in the role of
folic acid, vitamin B12, and related pathways in nervous-system function and
disease at all ages and the potential use of the vitamins, especially folic acid, in
the prophylaxis of disorders of CNS development, mood, and cognitive decline,
including some dementias (Reynolds, 2006).
Concerning vitamin B12, finding Lasisi et al. (2012) is supported by the report of
Shemesh et al. (1996). They reported that the incidence of vitamin B12
deficiency is significantly higher among patients with tinnitus and noise-induced
hearing loss (47 %) compared with those with noise induced hearing loss alone
and normal subjects who exhibited vitamin B12 deficiency in 27 % and 19 %,
respectively. In addition they reported some improvement in tinnitus and
associated complaints in 12 patients following vitamin B12 replacement therapy.
These suggest a relationship between vitamin B12 deficiency and dysfunction of
the auditory pathway; hence authors recommended that routine vitamin B12
serum levels be determined when evaluating patients for chronic tinnitus.
The presence of tinnitus as the only features in these subjects with low plasma
vitamin B12 suggest that perhaps tinnitus may be one of the early features of the
various neurological abnormalities associated with B12 deficiencies (Lasisi et
al., 2012).
The B vitamins folate, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin) are
important regulators of homocysteine metabolism in the body, and randomized
controlled trials have demonstrated that supplementation with folate (natural
dietary folate or the synthetic folic acid) alone or in combination with vitamins B6
and B12 significantly reduces blood homocysteine concentrations (Bønaa et al.,
2006, Lonn et al., 2006). Although increased intakes of these B vitamins could
plausibly reduce the risk of stroke, findings from observational studies on folate
(Van Guelpen et al., 2005), vitamin B6 (He et al., 2004), and vitamin B12
(Virtanen et al., 2005) in relation to stroke risk have been inconsistent. Likewise,
randomized clinical trials examining the effects of supplemental folic acid and
other B vitamins on stroke incidence among individuals with preexisting
cardiovascular or renal disease have produced conflicting results (Bazzano et al.,
2006, Wang et al., 2007, Larsson et al., 2008).
Globally 24 million people have some form of dementia, with 4.6 million new
cases diagnosed each year. It is estimated that the number of people affected will
double every 20 years and reach 81 million by 2040. Pharmacotherapy of
Alzheimer disease and other dementias can provide only modest cognitive or
disease-modifying benefits. However, even modest benefits may have significant
effects on quality of life, caregiver burden, and societal economic costs.
Increased homocysteine levels in conjunction with low levels of folate, vitamin
B6, and vitamin B12, which interact to control homocysteine, have been reported
to correlate with decreased performance on cognitive tests. For these reasons, B
vitamin supplementation has been proposed to prevent or reverse cognitive
decline. Several studies examined whether supplementation with pyridoxine
hydrochloride (hereinafter “vitamin B6”), cyanocobalamin or hydroxycobalamin
(hereinafter “vitamin B12”), and folic acid can prevent, decrease the progression
rate of, or reverse the neurologic changes associated with age-related
neurodegenerative retinal blood flow via the diacylglycerol-protein kinase C
pathway (Agarwal, 2011).
CONCLUSION
Due to multifactorial mechanisms behind formation of tinnitus it is difficult to
determine the most appropriate treatment. Pharmacological treatments is one of
several potential method of therapy. This review described positive effects of
natural substances on various types of underlying condition that cause tinnitus or
can alleviating symptoms. It was determined that low plasma melatonin and
vitamin B12 have significant correlation with the development of tinnitus among
the elderly. Melatonin exerts advantageous vascular changes that improve
labyrinth perfusion, thus protecting the inner ear from hypoxia. Melatonin can
reduce muscular tone, and it may relieve tensor tympani muscle spasms, thus
improving symptoms. In addition to relieving tinnitus, melatonin improves sleep
quality. The large group of substances with potential positive effect on tinnitus or
for alleviating the symptoms are substances with antioxidant action. Hesperidin
exerts protective action in cardiac tissue by its antihypertensive and antioxidant
properties. The compounds of Ginkgo Biloba L. are known to act mainly as
antioxidants/free radical scavengers, enzyme inhibitors, and cation chelators.
Diosmin as a flavonoid, also possesses a multitude of biological activities
including anti-inflammatory and antioxidant properties. In the pharmacologic
therapy is important not only directly effect of some substances but also their
synergistic action. Synergistic effect can bring different results. Therefore is
necessary evaluating their effect with the combinations with another substances.
Acknowledgments
This work was supported by the Slovak University of Agriculture in Nitra
(KEGA 006/SPU-4/2015, APVV-15-0543,APVV-15-0544, VEGA 1/0857/14)
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