Polyphenols in Inner Ear Neurobiology, Health and Disease: From Bench to Clinics

Abstract

There is substantial experimental and clinical interest in providing effective ways to both prevent and slow the onset of hearing loss. Auditory hair cells, which occur along the basilar membrane of the cochlea, often lose functionality due to age-related biological alterations, as well as from exposure to high decibel sounds affecting a diminished/damaged auditory sensitivity. Hearing loss is also seen to take place due to neuronal degeneration before or following hair cell destruction/loss. A strategy is necessary to protect hair cells and XIII cranial/auditory nerve cells prior to injury and throughout aging. Within this context, it was proposed that cochlea neural stem cells may be protected from such aging and environmental/noise insults via the ingestion of protective dietary supplements. Of particular importance is that these studies typically display a hormetic-like biphasic dose-response pattern that prevents the occurrence of auditory cell damage induced by various model chemical toxins, such as cisplatin. Likewise, the hormetic dose-response also enhances the occurrence of cochlear neural cell viability, proliferation, and differentiation. These findings are particularly important since they confirmed a strong dose dependency of the significant beneficial effects (which is biphasic), whilst having a low-dose beneficial response, whereas extensive exposures may become ineffective and/or potentially harmful. According to hormesis, phytochemicals including polyphenols exhibit biphasic dose-response effects activating low-dose antioxidant signaling pathways, resulting in the upregulation of vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Modulation of the vitagene network through polyphenols increases cellular resilience mechanisms, thus impacting neurological disorder pathophysiology. Here, we aimed to explore polyphenols targeting the NF-E2-related factor 2 (Nrf2) pathway to neuroprotective and therapeutic strategies that can potentially reduce oxidative stress and inflammation, thus preventing auditory hair cell and XIII cranial/auditory nerve cell degeneration. Furthermore, we explored techniques to enhance their bioavailability and efficacy.

Keywords: HSPs neuroprotection; Nrf2; hormesis; polyphenols; vitagenes.

Figure 1

Canonical and non-canonical activation of Nrf2. Nrf2 is localized in the cytosol and interacts with KEAP1 for ubiquitination and proteasomal degradation, under basal conditions. Oxidative stress causes conformational changes of KEAP1-C151, leading to Nrf2 dissociation. Free Nrf2 enters into the nucleus where it forms dimers with MAF proteins and binds to the antioxidant response element (ARE) regulatory sequences of target genes, inducing their expression. In the non-canonical Nrf2 activation, polyphenol-dependent inhibition of autophagy results in increased p62, which competitively binds with KEAP1 and thus contributes to Nrf2 activation in a KEAP1-C151-independent manner. The relationship with hormesis is inferred.

Figure 2

Schematic representation of hormetic neuroprotection. Polyphenols modulate Nrf2-related vitagenes in the low range of hormetic dose–response. On the other hand, at higher stimulation, detrimental effects are observed and neurodegeneration occurs.

Figure 3

Chemical structure of major polyphenolic compounds: (A) epigallocatechin gallate, (B) resveratrol, (C) hydroxytyrosol, (D) curcumin, (E) gallic acid, (F) phloroglucinol, (G) rosmarinic acid, (H) caffeic acid, (I) ferulic acid.