Access of Corticosteroids to Brain Targets

Multidrug resistance P glycoprotein (Pgp or MDR1) is a cell membrane protein that pumps various substances from the cell to the extracellular environment. Because of its activity, Pgp is a barrier to exogenous substances. Synthetic glucocorticoids such as dexamethasone are recognized by Pgp as substrates and are removed from the cells (de Kloet 1997; Meijer et al. 1998). This has been elegantly demonstrated in vitro. That dexamethasone is a substrate for Pgp can also be demonstrated in vivo using Pgp knockout mice. Upon administration of 3H-labeled dexamethasone or 3H prednisone (Karssen et al. 2002) to these mutants, the radioactive steroids were demonstrated to accumulate in the typical target sites: hippocampus, PVN, and biogenic amine neurons. Surprisingly, the 3H-labeled cortisol that is also not retained in wildtype mice with the proper activity of Pgp pump shows profound retention in the Pgp knockouts (Karssen et al. 2001). Hence, corticosterone seems the only steroids that readily penetrate the mouse brain, since also the penetration of aldosterone is hampered. This remarkable dichotomy between cortisol and corticosterone is maintained in people. While in the blood, the ratio cortisol/corticosterone is 10:1, this ratio is decreased to 10:4 in the cerebrospinal fluid (Karssen et al. 2005).

The access of corticosteroids to its brain receptors is regulated by P-glycoprotein transporters in the blood-brain barrier and by an intracellular oxidoreductase.

There is an additional, intracellular mechanism that determines access of corticosterone, cortisol, and aldosterone to the nucleus and finally to the genome. The enzyme 11-p-hydroxysteroid dehydrogenase type 2 (HSD-2) is an oxidase that specifically inactivates cortisol and corticosterone, but not aldosterone. HSD-2 acts as gatekeeper blocking access of the naturally occurring glucocorticoids but allowing binding of bioactive aldosterone to the mineralocorticoid receptors (MR) and the genome (Edwards et al. 1988; Funder et al. 1988). In adult rodent brain, the expression of HSD-2 is discrete and restricted to some periventricular tissues where aldosterone activates circuits involved in salt appetite. Remarkably, also the solitary nucleus

(NTS) near the area postrema expresses abundantly HSD-2. This group of cells has projections innervating the forebrain and provides the limbic-forebrain circuits with an aldosterone-selective mechanism which have been postulated to underlie salt appetite and preference and harbors vital cognitive functions to store spatial information on salt resources (Geerling and Loewy 2009). The HSD-1 isoform is a reductase widely present in the brain and has the capacity (e.g., in the liver) to regenerate bioactive cortisol and corticosterone. Inhibitors to the HSD-1 isoform were developed as a strategy to limit overexposure to corticosteroids (Chapman et al. 2013).

The Fukushima disaster from 2011 has significantly increased the incidence of tinnitus and Meniere syndrome in the local population.

Both HSD proteins have been found in the inner ear: HSD-2 was found in the endolymphatic sac of the inner ear of rodents (Akiyama et al. 2010), whereas HSD-1 was identified in the stria vascularis and in the outer and inner auditory hair cells (Terakado et al. 2011). Endolymphatic sac is responsible for the resorption, transport, and recirculation of ions in the entire inner ear, i.e., in the cochlea and in the vestibular system. It is believed that individuals diagnosed with the Meniere syndrome have occasionally increased hydraulic pressure within the inner ear endolymphatic system often attributed to the hyperactivity of the endolymphatic sac. This hyperactivity induces a triad of symptoms: vertigo, hearing loss, and tinnitus. Interestingly, patients with Meniere syndrome often report having an attack after being exposed to emotional stress. In the inner ear, upon stress-induced overproduction of cortisol, the decreased activity of HSD-2 or the increased activity of HSD-1 could lead to upregu- lated infiltration of cortisol, decreased accessibility of aldosterone, and dysregulation of ion dynamics that are responsible for the attacks. Unfortunately, no study addressed this issue in people yet, as only a postmortem study could answer open questions. Recently published systematic review revealed two facts: the first one was confirmation of the association between Meniere syndrome and posttraumatic stress disorder and health anxiety, whereas the second was a need for large, properly designed and conducted epidemiological studies (Kirby and Yardley 2008). Recent study investigating the incidence of otological conditions following the disaster in Fukushima (earthquake and subsequent nuclear accident) in the local Fukushima population demonstrated significant increase in the number of new cases of Meniere syndrome and also of tinnitus coinciding with an increased number of comorbid mental stress-related conditions, such as depression or anxiety (Hasegawa et al. 2015).

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