Interactions between sleep disorders and oral diseases

Dental sleep medicine is a rapidly growing field that is in close and direct interaction with sleep medicine and comprises many aspects of human health. As a result, dentists who encounter sleep health and sleep disorders may work with clinicians from many other disciplines and specialties. The main sleep and oral health issues that are covered in this review are obstructive sleep apnea, chronic mouth breathing, sleep‐related gastroesophageal reflux, and sleep bruxism. In addition, edentulism and its impact on sleep disorders are discussed. Improving sleep quality and sleep characteristics, oral health, and oral function involves both pathophysiology and disease management. The multiple interactions between oral health and sleep underscore the need for an interdisciplinary clinical team to manage oral health‐related sleep disorders that are commonly seen in dental practice.     

pH dependence of the peptide thiol-disulfide oxidase activity of six members of the human protein disulfide isomerase family

Protein folding in the endoplasmic reticulum is often associated with the formation of native disulfide bonds, a process which in vivo is one of the rate limiting steps of protein folding and which is facilitated by the enzyme protein disulfide isomerase (PDI). Higher eukaryotes have multiple members of the PDI family, for example, seventeen human PDIs have been reported to date. With multiple members of the same family being present, even within the same cell, the question arises as to what differential functions are they performing? To date there has been no systematic evaluation of the enzymological properties of the different members of the PDI-family. To address the question of whether different PDI family members have differing thioldisulfide chemistry, we have recombinantly expressed and purified six members of the family, PDI, PDIp, ERp57, ERp72, P5, and PDIr from a single organism, human. An examination of the pH-dependence and nature of the rate limiting step for the peptide thiol-disulfide oxidase activity of these enzymes reveals that, with the exception of PDIr, they are all remarkably similar. In the light of this data potential differential functions for these enzymes are discussed.     

Preclinical characterization of WAY-211612: a dual 5-HT uptake inhibitor and 5-HT1A receptor antagonist and potential novel antidepressant

Background and purpose

As a combination of 5-HT selective reuptake inhibitor (SSRI) with 5-HT_1A receptor antagonism may yield a rapidly acting antidepressant, WAY-211612, a compound with both SSRI and 5-HT_1A receptor antagonist activities, was evaluated in preclinical models.

Experimental approach

Occupancy studies confirmed the mechanism of action of WAY-211612, while its in vivo profile was characterized in microdialysis and behavioural models.

Key results

WAY-211612 inhibited 5-HT reuptake (K_i = 1.5 nmol·L⁻¹; K_B = 17.7 nmol·L⁻¹) and exhibited full 5-HT_1A receptor antagonist activity (K_i = 1.2 nmol·L⁻¹; K_B = 6.3 nmol·L⁻¹; I_max 100% in adenyl cyclase assays; K_B = 19.8 nmol·L⁻¹; I_max 100% in GTPγS). WAY-211612 (3 and 30 mg·kg⁻¹, po) occupied 5-HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5-HT_1A receptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY-211612 (3–30 mg·kg⁻¹, po) raised levels of cortical 5-HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg·kg⁻¹, s.c.) and a 5-HT_1A antagonist (WAY-100635; 0.3 mg·kg⁻¹, s.c). WAY-211612 (3.3–30 mg·kg⁻¹, s.c.) decreased aggressive behaviour in the resident-intruder model, while increasing the number of punished crossings (3–30 mg·kg⁻¹, i.p. and 10–56 mg·kg⁻¹, po) in the mouse four-plate model and decreased adjunctive drinking behaviour (56 mg·kg⁻¹, i.p.) in the rat scheduled-induced polydipsia model.

Conclusions and implications

These findings suggest that WAY-211612 may represent a novel antidepressant.