Background: Accumulated evidence suggests that insulin resistance and impairments in cerebral insulin receptor signaling may contribute to age-related cognitive deficits and Alzheimer's disease. The enhancement of insulin receptor signaling is, therefore, a promising strategy for the treatment of age-related cognitive disorders. The mitochondrial respiratory chain, being involved in insulinstimulated H 2 O 2 production, has been identified recently as a potential target for the enhancement of insulin signaling. The aim of the present study is to examine: (1) whether a specific respiratory substrate, dicholine salt of succinic acid (CS), can enhance insulin-stimulated insulin receptor autophosphorylation in neurons, and (2) whether CS can ameliorate cognitive deficits of various origins in animal models.

The purpose of this research was a comparative analysis of cholinergic synaptic organization following learning and memory in normal and chronic cerebral ischaemic rats in the Morris water maze model. Choline acetyltransferase and protein content were determined in subpopulations of presynapses of “light” and “heavy” synaptosomal fractions of the cortex and the hippocampus, and the cholinergic projective and intrinsic systems of the brain structures were taken into consideration. We found a strong involvement of cholinergic systems, both projective and intrinsic, in all forms of cognition. Each form of cognition had an individual cholinergic molecular profile and the cholinergic synaptic compositions in the ischaemic rat brains differed significantly from normal ones. Our data demonstrated that under ischaemic conditions, instead of damaged connections new key synaptic relationships, which were stable against pathological influences and able to restore damaged cognitive functions, arose. The plasticity of neurochemical links in the individual organization of certain types of cognition gave a new input into brain pathology and can be used in the future for alternative corrections of vascular and other degenerative dementias.

(1) Background. A one-time moderate hypobaric hypoxia (HBH) has a preconditioning effect whose neuronal mechanisms are not studied well. Previously, we found a stable correlation between the HBH efficiency and acoustic startle prepulse inhibition (PPI). This makes it possible to predict the individual efficiency of HBH in animals and to study its potential adaptive mechanisms. We revealed a bi-directional action of nicotinic α7 receptor agonist PNU-282987 and its solvent dimethyl sulfoxide on HBH efficiency with the level of PPI > or < 40%. (2) The aim of the present study was to estimate cholinergic mechanisms of HBH effects in different brain regions. (3) Methods: in rats pretested for PPI, we evaluated the activity of synaptic membrane-bound and water-soluble choline acetyltransferase (ChAT) in the sub-fractions of ‘light’ and ‘heavy’ synaptosomes of the neocortex, hippocampus and caudal brainstem in the intact brain and after HBH. We tested the dose-dependent influence of PNU-282987 on the HBH efficiency. (4) Results: PPI level and ChAT activity correlated negatively in all brain structures of the intact animals, so that the values of the latter were higher in rats with PPI < 40% compared to those with PPI > 40%. After HBH, this ChAT activity difference was leveled in the neocortex and caudal brainstem, while for membrane-bound ChAT in the ‘light’ synaptosomal fraction of hippocampus, it was reversed to the opposite. In addition, a pharmacological study revealed that PNU-282987 in all used doses and its solvent displayed corresponding opposite effects on HBH efficiency in rats with different levels of PPI. (5) Conclusion: We substantiate that in rats with low and high PPI two opposite hippocampal cholinergic mechanisms are involved in hypoxic preconditioning, and both are implemented by forebrain projections via nicotinic α7 receptors. Possible causes of association between general protective adaptation, HBH, PPI, forebrain cholinergic system and hippocampus are discussed.

Most antimicrobial peptides (AMPs) and anticancer peptides (ACPs) fold into membrane disruptive cationic amphiphilic αhelices, many of which are however also unpredictably hemolytic and toxic. Here we exploited the ability of recurrent neural networks (RNN) to distinguish active from inactive and non-hemolytic from hemolytic AMPs and ACPs to discover new non-hemolytic ACPs. Our discovery pipeline involved: 1) sequence generation using either a generative RNN or a genetic algorithm, 2) RNN classification for activity and hemolysis, 3) selection for sequence novelty, helicity and amphiphilicity, and 4) synthesis and testing. Experimental evaluation of thirty-three peptides resulted in eleven active ACPs, four of which were non-hemolytic, with properties resembling those of the natural ACP lasioglossin III. These experiments show the first example of direct machine learning guided discovery of non-hemolytic ACPs.

Moderate one-off hypobaric hypoxia (HBH) provokes preconditioning and prolongs the resistance (T, the time before apnoea) to severe hypobaric hypoxia (SHBH). Hypoxic preconditioning has therapeutic potential; however, the efficiency of hypoxic preconditioning varies greatly and the methods for its preliminary evaluation are absent in both animals and humans. This rodent study evaluates the dependence of SHBH resistance, initiated by HBH, on the rate of sensorimotor gating estimated in the model of the acoustic startle prepulse inhibition (PPI). A stable negative correlation was found between PPI and T. Low doses of the α7 nicotinic receptor agonist, PNU-282987 (PNU), and more pronouncedly dimethyl sulfoxide (DMSO) (a PNU solvent), inverted the correlation between PPI and T from negative to positive. The DMSO and PNU effects were reversed at PPIs of 0.36 -0.40 (36% -40%). DMSO increased T values by 52.2% ± 9.7% in the region of lower HBH efficiency (PPI ≥ 0.40) and reduced it by 35.2% ± 9.3% in the region of higher HBH efficiency (PPI < 0.40). PNU reduced both DMSO effects. The involvement of the central cholinergic mechanisms was substantiated in both DMSO and PNU influences on HBH. In conclusion, 1) PPI can be used to predict the efficiency of hypoxic preconditioning and to study its mechanisms, 2) two opposite cholinergic PPI-related mechanisms participate in the preconditioning effects of HBH, 3) the sensitivity of rats to DMSO and PNU diverges when the PPI is 0.36 -0.40,