Role of Melatonin in Potential Treatment of Vertigo: Study
The acute phase of vertigo appears in several vestibular syndromes with different pathophysiology, such as Meniere's disease (MD), vestibular neuritis (VN), vestibular migraine (VM), and benign paroxysmal positional vertigo (BPPV). Due to the involvement of the inner ear, the symptoms may include not only recurrent attacks of vertigo but also fluctuating hearing loss or tinnitus. In addition, multiple central nervous system conditions associated with migraine or cerebrovascular and neurodegenerative disorders have been described, which can manifest vertiginous attacks.
Vestibular syndromes imply that metabolic factors may act in their development, such as (1) multiple neurotransmitters with different effects: excitatory (glutamate, dopamine, and serotonin), modulating (histamine and enkephalins), or inhibitory (GABA and glycine); (2) inflammatory cytokines (TNF and IL3); (3) reactive oxygen species (ROS); and (4) other factors.
Although the different types of vertigo imply a different pathophysiology, the treatment of the acute crisis is usually symptomatic, which implies a similar pharmacological management, which generally acts by exerting a sedative effect. For this reason, among others, antihistamines, anticholinergics, benzodiazepines, or antidopaminergic drugs are used. However, considering that the incidence of vertiginous syndrome is particularly higher in the elderly population, in this and other risk groups, the use of a lower dose of the aforementioned drugs or the use of other treatments with fewer side effects could be useful.
In this study, the authors Joaquin Guerra and Jesus Devesa analyzed the possible role that melatonin, a harmless hormone, could play in regulating the acute phase of vertigo.
Melatonin and the Vestibular Pathway
Melatonin performs extensive functions not only in the inner ear but also in the vestibular pathway, regulating its function. With respect to the central vestibular structures, MT1 and MT2 receptors are also found in the vestibular nuclei, the thalamic vestibular pathway, and the cerebral and cerebellar cortex.
Clinically, melatonin receptors found in the area postrema, a structure in the medulla oblongata of the brainstem, can modulate vomiting and other sympathetic responses that characterize the attack of vertigo.
The paraventricular nuclei and the reuniens connect with the limbic system, and this may be the reason for their regulation in mood and sedation, relevant elements for the control of vertigo.
Furthermore, melatonin has been proposed as a prophylactic agent in the prevention of migraine attacks, a condition that can be associated with vertigo. In addition, in patients with bilateral vestibular loss, there is a lack of synchronization between temperature and the rest-activity cycle, which affects the physiology of melatonin regulation. Although the effect of melatonin can be exerted by direct action, it is true that it has the potential to modulate other compounds, enhancing or inhibiting them, and thus their actions.
Role of Melatonin as an Anti-Inflammatory and Antioxidant Vestibular Agent
Vertigo patients show higher levels of reactive oxygen species (ROS) and superoxide metabolites than healthy subjects. Oxidative stress may be due to the physiological stress that vertigo induces. The antioxidant effect of melatonin is well known, since it acts as a direct scavenger of free radicals with the ability to detoxify both reactive oxygen and reactive nitrogen species.
Gentamicin induces an increase in the levels of ROS and proapoptotic Bcl-2-associated protein X (Bax) in utricular hair cells, in turn inhibiting the expression of B-cell lymphoma 2 (Bcl-2). Melatonin reverses this event by inhibiting the expression of caspase-3. This protein is essential in the activation of programmed cell death.
Interestingly, in patients with chronic subjective dizziness, an inflammatory response with elevated serum levels of tumor necrosis factor α (TNF) and interferon c (IFNc) has been reported. Vestibular syndromes exhibit inflammatory reactions during acute attacks and subjects with chronic vertigo have higher basal levels of inflammatory mediators, so that melatonin theoretically would be able to regulate not only attacks but also recurrences, given its regulation of the release of various cytokines.
Melatonin may exert beneficial effects by blocking the activity of vestibular oxidative and inflammatory stress through several pathways.
Melatonin as a Modulator in the Vestibular Neurotransmission
Gamma-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the vestibular pathway. Of the three GABA receptors described, GABA-A and GABA-B are involved in vestibular neurotransmission. GABA plays a plausible role in inner ear afferent transmission, but its role as the primary transmitter at this level is unclear.
The central vestibular nuclei receive inhibitory inputs that are mediated by GABA-A and GABA neurons and controls vomit. Although there is no report directly involving melatonin in this effect in vestibular structures, it has been demonstrated that this hormone modulates dopamine and can inhibit its release in specific areas in the CNS of mammals, such as the hypothalamus, hippocampus, striatum, medulla-pons, and retina.
Other compounds involved in vestibular neurochemistry, such as substance P or calcitonin gene-related peptide (CGRP), both implicated in migraine, and thus potentially vestibular migraine (VM), are also inhibited by melatonin.
Regulation of Melatonin in the Vestibular Sympathetic Activity
Melatonin release is controlled by the sympathetic innervation of the pineal gland, which mediates the inhibitory effect of light on pineal melatonin secretion. This pathway begins in the retina, influencing the biological clock of the suprachiasmatic nucleus and then inhibits the paraventricular nucleus and interrupts the stimulation of the intermediolateral nucleus, inducing melatonin synthesis.
The effects of melatonin on the autonomic system cause a reduction in the adrenergic flow and induce relaxation of the smooth muscle of the arterial wall by increasing the availability of nitric oxide. Furthermore, melatonin is capable of lowering blood pressure, specifically binding to its MT1 and MT2 receptors in blood vessels, thus blocking the catecholaminergic response.
In humans, exogenous use of melatonin has been shown to be effective in reducing circulating catecholamine levels, as well as blood pressure, carotid pulsatility index and sympathetic nerve responses to orthostatic stress.
Based on the data included in this review, it seems that the use of melatonin in the acute phase of vertigo can be highly effective, although more studies and clinical trials are needed. However, despite the fact that the effect in humans may be more limited than in laboratory animals, it is evident that the adjuvant use of melatonin with other drugs could not only improve the vestibular symptoms of acute vertigo crisis but also prevent the increase of doses of commonly used drugs with the consequent increase in pharmacological toxicity. This type of combined treatment would be especially indicated in risk groups, such as the elderly population. Moreover, melatonin is a practically harmless hormone; the lethal dose 50 could not be found yet.
"Although systemic administration is safe and favors effects on different organs of the vestibular pathway, it remains to be seen whether topical (transtympanic) administration could be effective for pathologies of peripheral origin. A route of entry for various metabolites with oxidizing or inflammatory power is the round window. The main advantage of this approach relies on the fact that melatonin would perfuse directly to the inner ear, as it occurs with the intratympanic corticosteroid treatment. Moreover, treating melatonin topically could minimize the effect of mediators that access through this route of entry, implied in the development of vestibular syndromes such as labyrinthitis or endolymphatic hydrops. In conclusion melatonin administration in vertigo could be a new therapeutic effect of melatonin, among the many already described that this hormone exerts in human pathologies."
Source: Joaquin Guerra and Jesus Devesa; Hindawi International Journal of Otolaryngology Volume 2021