Tinnitus: network pathophysiology-network pharmacology

Ana B. Elgoyhen,^1,* Berthold Langguth,² Sven Vanneste,³ and Dirk De Ridder³

Abstract

Tinnitus, the phantom perception of sound, is a prevalent disorder. One in 10 adults has clinically significant subjective tinnitus, and for one in 100, tinnitus severely affects their quality of life. Despite the significant unmet clinical need for a safe and effective drug targeting tinnitus relief, there is currently not a single Food and Drug Administration (FDA)-approved drug on the market. The search for drugs that target tinnitus is hampered by the lack of a deep knowledge of the underlying neural substrates of this pathology. Recent studies are increasingly demonstrating that, as described for other central nervous system (CNS) disorders, tinnitus is a pathology of brain networks. The application of graph theoretical analysis to brain networks has recently provided new information concerning their topology, their robustness and their vulnerability to attacks. Moreover, the philosophy behind drug design and pharmacotherapy in CNS pathologies is changing from that of “magic bullets” that target individual chemoreceptors or “disease-causing genes” into that of “magic shotguns,” “promiscuous” or “dirty drugs” that target “disease-causing networks,” also known as network pharmacology. In the present work we provide some insight into how this knowledge could be applied to tinnitus pathophysiology and pharmacotherapy.

Keywords: graph analysis, brain networks, network pharmacology, phantom percept, tinnitus, small-world, scale-free, magic bullets

Tinnitus pharmacotherapy: where do we stand?

Tinnitus, the phantom perception of sound, represents a highly prevalent and distressing condition. Although most cases of tinnitus derive from deprivation of auditory input, it goes beyond the classical definition of an otologic illness, since it encompasses a range of symptoms that are likely to place a huge burden on patients and significantly impair quality of life (Jastreboff, 1990). This can include irritability, agitation, stress, insomnia, anxiety, and depression. In fact, for one in 100 adults, tinnitus affects their ability to lead a normal day-to-day life (Vio and Holme, 2005). Estimates indicate that 13 million people in Western Europe and the USA currently seek medical advice for their tinnitus (Vio and Holme, 2005).

The quest toward finding a drug that targets tinnitus has not been that fulfilling. Although a wide variety of compounds is used off-label to treat tinnitus patients, there is still no US Food and Drug Administration (FDA) or European Medicines Agency (EMA) approved drug on the market. The list of used compounds includes anticonvulsants, anxiolytic, antidepressants, NMDA antagonists, cholinergic antagonists, antihistamines, vasodilators, antipsychotics, and calcium antagonists, to name a few (Langguth et al., 2009; Elgoyhen and Langguth, 2010). In some cases, the rationale behind the use of them is to treat the co-morbidities that come along with tinnitus, like depression and anxiety (Johnson et al., 1993; Sullivan et al., 1993; Bahmad et al., 2006). In others, it is derived from the use of drugs which are effective in disorders thought to share some commonalities with tinnitus, like anticonvulsants used in epilepsy (Hoekstra et al., 2011) and the calcium antagonist gabapentin used in neuropathic pain (Bauer and Brozoski, 2007). Even further, some drugs are used based on known underlying neuronal changes thought to be a neural correlate of tinnitus. Such is the case of NMDA receptor antagonists (Azevedo and Figueiredo, 2007; Figueiredo et al., 2008; Suckfull et al., 2011) and GABA_A agonists (Johnson et al., 1993; Gananca et al., 2002; Azevedo and Figueiredo, 2007), used with the hope of reversing the increased neuronal excitability observed in several regions of the auditory pathway (Eggermont and Roberts, 2004). Some drugs have been reported to provide moderate relief of symptoms in a subset of patients. However, most drugs have not proven sufficient effectiveness in randomized controlled clinical trials in order to be approved and marketed specifically for tinnitus (Langguth et al., 2009; Elgoyhen and Langguth, 2010; Langguth and Elgoyhen, 2011).

Thus, novel pharmacological approaches for treating tinnitus are required in order to address a widely recognized, yet largely underserved, and unmet, clinical need. Although early on classified as an auditory problem, recent work is indicating that tinnitus is a central nervous system (CNS) disorder, where dynamic multiple parallel overlapping brain networks are involved (Eggermont and Roberts, 2004; Schlee et al., 2009a, b; De Ridder et al., 2011a). Thus, strategies followed in the development of drugs for other CNS pathologies might give some insight into possible avenues in the design of tinnitus pharmacotherapies. In the present work we review some recent trends in the discovery of CNS acting drugs, describe new ways of analyzing brain networks in health and disease and propose how this knowledge could be extrapolated to tinnitus.

Fuente: Front Syst Neurosci. 2012; 6: 1.

Published online 2012 January 25. doi:  10.3389/fnsys.2012.00001

PMCID: PMC3265967

Nota: por razones del diseño del Blog este trabajo se publica dividido en secciones en las proximas entradas con el mismo nombre