In vitro screening of major neurotransmitter systems possibly involved in the mechanism of action of antibodies to S100 protein in released-active form

Evgeniy A Gorbunov, Irina A Ertuzun, Evgeniya V Kachaeva, Sergey A Tarasov, Oleg I EpsteinOOO “NPF “MATERIA MEDICA HOLDING”, Moscow, Russian FederationAbstract: Experimentally and clinically, it was shown that released-active form of antibodies to S100 protein (RAF of Abs to S100) exerts a wide range of pharmacological activities: anxiolytic, antiasthenic, antiaggressive, stress-protective, antihypoxic, antiischemic, neuroprotective, and nootropic. The purpose of this study was to determine the influence of RAF of Abs to S100 on major neurotransmitter systems (serotoninergic, GABAergic, dopaminergic, and on sigma receptors as well) which are possibly involved in its mechanism of pharmacological activity. Radioligand binding assays were used for assessment of the drug influence on ligand–receptor interaction. [35S]GTPγS binding assay, cyclic adenosine monophosphate HTRF™, cellular dielectric spectroscopy assays, and assays based on measurement of intracellular concentration of Ca2+ ions were used for assessment of agonist or antagonist properties of the drug toward receptors. RAF of Abs to S100 increased radioligand binding to 5-HT1F, 5-HT2B, 5-HT2Cedited, 5-HT3, and to D3 receptors by 142.0%, 131.9%, 149.3%, 120.7%, and 126.3%, respectively. Also, the drug significantly inhibited specific binding of radioligands to GABAB1A/B2 receptors by 25.8%, and to both native and recombinant human sigma1 receptors by 75.3% and 40.32%, respectively. In the functional assays, it was shown that the drug exerted antagonism at 5-HT1B, D3, and GABAB1A/B2 receptors inhibiting agonist-induced responses by 23.24%, 32.76%, and 30.2%, respectively. On the contrary, the drug exerted an agonist effect at 5-HT1A receptors enhancing receptor functional activity by 28.0%. The pharmacological profiling of RAF of Abs to S100 among 27 receptor provides evidence for drug-related modification of major neurotransmitter systems.Keywords: dopamine agent, released-activity, serotonin agent, sigma1 recepto

The role of IGF-1 signaling in skeletal muscle atrophy

Insulin-like growth factor 1 (IGF-1) is a key anabolic growth factor stimulating phosphatidylinositol 3-kinase (PI3K)/Akt signaling which is well known for regulating muscle hypertrophy. However, the role of IGF-1 in muscle atrophy is less clear. This review provides an overview of the mechanisms via which IGF-1 signaling is implicated in several conditions of muscle atrophy and via which mechanisms protein turnover is altered. IGF-1/PI3K/Akt signaling stimulates the rate of protein synthesis via p70S6Kinase and p90 ribosomal S6 kinase and negatively regulates protein degradation, predominantly by its inhibiting effect on proteasomal and lysosomal protein degradation. Caspase-dependent protein degradation is also attenuated by IGF/PI3K/Akt signaling, whereas evidence for an effect on calpain-dependent protein degradation is inconclusive. IGF-1/PI3K/Akt signaling reduces during denervation-, unloading-, and joint immobilization-induced muscle atrophy, whereas IGF-1/PI3K/Akt signaling seems unaltered during aging-associated muscle atrophy. During denervation and aging, IGF-1 overexpression or injection counteracts denervation- and aging-associated muscle atrophy, despite enhanced anabolic resistance with regard to IGF-1 signaling with aging. It remains unclear whether pharmacological stimulation of IGF-1/PI3K/Akt signaling attenuates immobilization- or unloading-induced muscle atrophy. Exploration of the possibilities to interfere with IGF-1/PI3K/Akt signaling reveals that microRNAs targeting IGF-1 signaling components are promising targets to counterbalance muscle atrophy. Overall, the findings summarized in this review show that in disuse conditions, but not with aging, IGF-1/PI3K/Akt signaling is attenuated and that in some conditions stimulation of this pathway may alleviate skeletal muscle atrophy