Further characterization of agmatine binding to mitochondrial membranes: involvement of imidazoline I2 receptor.

Agmatine, a divalent diamine with two positive charges at physiological pH, is transported into the matrix of liver mitochondria by an energy-dependent mechanism, the driving force of which is the electrical membrane potential. Its binding to mitochondrial membranes is studied by applying a thermodynamic treatment of ligand-receptor interactions on the analyses of Scatchard and Hill. The presence of two mono-coordinated binding sites S(1) and S(2), with a negative influence of S(2) on S(1), has been demonstrated. The calculated binding energy is characteristic for weak interactions. S(1) exhibits a lower binding capacity and higher binding affinity both of about two orders of magnitude than S(2). Experiments with idazoxan, a ligand of the mitochondrial imidazoline receptor I(2), demonstrate that S(1) site is localized on this receptor while S(2) is localized on the transport system. S(1) would act as a sensor of exogenous agmatine concentration, thus modulating the transport of the amine by its binding to S(2)

Clinical Phenotypes and Comorbidity in European Sleep Apnoea Patients

Background Clinical presentation phenotypes of obstructive sleep apnoea (OSA) and their association with comorbidity as well as impact on adherence to continuous positive airway pressure (CPAP) treatment have not been established. Methods A prospective follow-up cohort of adult patients with OSA (apnoea-hypopnoea index (AHI) of 655/h) from 17 European countries and Israel (n = 6,555) was divided into four clinical presentation phenotypes based on daytime symptoms labelled as excessive daytime sleepiness ("EDS") and nocturnal sleep problems other than OSA (labelled as "insomnia"): 1) EDS (daytime+/nighttime-), 2) EDS/insomnia (daytime+/nighttime+), 3) non-EDS/noninsomnia (daytime-/nighttime-), 4) and insomnia (daytime-/nighttime+) phenotype. Results The EDS phenotype comprised 20.7%, the non-EDS/non-insomnia type 25.8%, the EDS/ insomnia type 23.7%, and the insomnia phenotype 29.8% of the entire cohort. Thus, clinical presentation phenotypes with insomnia symptoms were dominant with 53.5%, but only 5.6% had physician diagnosed insomnia. Cardiovascular comorbidity was less prevalent in the EDS and most common in the insomnia phenotype (48.9% vs. 56.8%, p<0.001) despite more severe OSA in the EDS group (AHI 35.0\ub125.5/h vs. 27.9\ub122.5/h, p<0.001, respectively). Psychiatric comorbidity was associated with insomnia like OSA phenotypes independent of age, gender and body mass index (HR 1.5 (1.188-1.905), p<0.001). The EDS phenotype tended to associate with higher CPAP usage (22.7 min/d, p = 0.069) when controlled for age, gender, BMI and sleep apnoea severity. Conclusions Phenotypes with insomnia symptoms comprised more than half of OSA patients and were more frequently linked with comorbidity than those with EDS, despite less severe OSA. CPAP usage was slightly higher in phenotypes with EDS

Pharmacological and Nonpharmacological Interventions to Arrest Neuroprogression in Psychiatric Disorders

The concept of neuroprogression describes the progressive course of the disorder and stresses the progressive, recurrent, and chronic course of the disease entity under consideration. It subsumes clinical manifestations of the disease process and may also entail morphological, biochemical, neurochemical, immunological, physiological, and genetic aspects that contribute to the progressive course of the disease in question. In an attempt to identify the appropriate agent or method that could arrest neuroprogression in psychiatric patients, we conducted an evaluation of the use of anti-inflammatory drugs under the perspective of current pharmacological and neurophysiological data. This evaluation included the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as adjunctive treatment to conventional pharmacotherapy as well as the use of natural products exerting anti-inflammatory properties (i.e., ω-3 fatty acids) given as adjunctive or monotherapeutic treatments in less severe cases. The therapeutic significance of nonpharmacological methods, such as psychotherapy, physical exercise, and body-mind therapies, was also considered and will be discussed in this chapter. In conclusion, the role of psychotropic and select anti-inflammatory drugs in arresting neuroprogression is a very promising new frontier in psychiatric research and clinical practice. Modulators of a specific prostanoid synthase or receptor across the cyclooxygenase (COX)-2 downstream pathway along with new multitarget NSAIDs are expected to be tested by the pharmaceutical industry as potential agents to antagonize neuroprogression. Meanwhile, salicylates and selective COX-2 inhibitors could still be used in carefully selected subgroups of patients. Psychotherapy and nonpharmacological, stress-relieving methods should be considered as adjunctive tools to aid in arresting neuroprogression. © 2017 S. Karger AG, Basel