Pro-cognitive effects of dual tacrine derivatives acting as cholinesterase inhibitors and NMDA receptor antagonists.

Therapeutic options for Alzheimer's disease are limited. Dual compounds targeting two pathways concurrently may enable enhanced effect. The study focuses on tacrine derivatives inhibiting acetylcholinesterase (AChE) and simultaneously N-methyl-D-aspartate (NMDA) receptors. Compounds with balanced inhibitory potencies for the target proteins (K1578 and K1599) or increased potency for AChE (K1592 and K1594) were studied to identify the most promising pro-cognitive compound. Their effects were studied in cholinergic (scopolamine-induced) and glutamatergic (MK-801-induced) rat models of cognitive deficits in the Morris water maze. Moreover, the impacts on locomotion in the open field and AChE activity in relevant brain structures were investigated. The effect of the most promising compound on NMDA receptors was explored by in vitro electrophysiology. The cholinergic antagonist scopolamine induced a deficit in memory acquisition, however, it was unaffected by the compounds, and a deficit in reversal learning that was alleviated by K1578 and K1599. K1578 and K1599 significantly inhibited AChE in the striatum, potentially explaining the behavioral observations. The glutamatergic antagonist dizocilpine (MK-801) induced a deficit in memory acquisition, which was alleviated by K1599. K1599 also mitigated the MK-801-induced hyperlocomotion in the open field. In vitro patch-clamp corroborated the K1599-associated NMDA receptor inhibitory effect. K1599 emerged as the most promising compound, demonstrating pro-cognitive efficacy in both models, consistent with intended dual effect. We conclude that tacrine has the potential for development of derivatives with dual in vivo effects. Our findings contributed to the elucidation of the structural and functional properties of tacrine derivatives associated with optimal in vivo pro-cognitive efficacy.

Mini-review: Brain energy metabolism and its role in animal models of depression, bipolar disorder, schizophrenia and autism.

Mitochondria are cellular organelles essential for energy metabolism and antioxidant defense. Mitochondrial impairment is implicated in many psychiatric disorders, including depression, bipolar disorder, schizophrenia, and autism. To characterize and eventually find effective treatments of bioenergetic impairment in psychiatric disease, researchers find animal models indispensable. The present review focuses on brain energetics in several environmental, genetic, drug-induced, and surgery-induced animal models of depression, bipolar disorder, schizophrenia, and autism. Most reported deficits included decreased activity in the electron transport chain, increased oxidative damage, decreased antioxidant defense, decreased ATP levels, and decreased mitochondrial potential. Models of depression, bipolar disorder, schizophrenia, and autism shared many bioenergetic deficits. This is in concordance with the absence of a disease-specific brain energy phenotype in human patients. Unfortunately, due to the absence of null results in examined literature, indicative of reporting bias, we refrain from making generalized conclusions. Present review can be a valuable tool for comparing current findings, generating more targeted hypotheses, and selecting fitting models for further preclinical research.

Testing an emotion regulation model of physical activity in adolescents with anorexia nervosa: A pilot ecological momentary assessment.

OBJECTIVE: Adolescents with anorexia nervosa (AN) often show increased levels of exercise and physical activity. Psychological models suggest that physical activity in AN might attenuate momentary negative affect. However, this has not been directly tested in adolescents with AN, and it remains unclear whether this is a distinct mechanism of physical activity in AN compared with healthy controls (HCs). METHOD: In a 1-day ecological momentary assessment, 32 adolescent inpatients with AN and 30 HCs responded to hourly questions on momentary affect while wearing an actigraph to objectively assess physical activity. RESULTS: Linear mixed models identified that adolescents with AN experienced more aversive tension, more negative affect, and less positive affect throughout the day than HCs. Preliminary evidence for a momentary association of higher levels of physical activity with positive affect were found for both groups, whereas higher levels of physical activity were associated with less negative affect in adolescents with AN only. When correcting for multiple testing, interactions did not hold statistical significance. DISCUSSION: Our results indicate a down-regulation effect of physical activity on negative affect for AN and a more general up-regulation effect of positive affect. However, our sample size was small, and replication of our findings is needed.

Mitochondrial genome modulates myocardial Akt/Glut/HK salvage pathway in spontaneously hypertensive rats adapted to chronic hypoxia.

Recently we have shown that adaptation to continuous normobaric hypoxia (CNH) decreases myocardial ischemia/reperfusion injury in spontaneously hypertensive rats (SHR) and in a conplastic strain (SHR-mtBN). The protective effect was stronger in the latter group characterized by a selective replacement of the SHR mitochondrial genome with that of a more ischemia-resistant Brown Norway strain. The aim of the present study was to examine the possible involvement of the hypoxia inducible factor (HIF)-dependent pathway of the protein kinase B/glucose transporters/hexokinase (Akt/GLUT/HK) in this mitochondrial genome-related difference of the cardioprotective phenotype. Adult male rats were exposed for 3 wk to CNH ([Formula: see text] 0.1). The expression of dominant isoforms of Akt, GLUT, and HK in left ventricular myocardium was determined by real-time RT-PCR and Western blotting. Subcellular localization of GLUTs was assessed by quantitative immunofluorescence. Whereas adaptation to hypoxia markedly upregulated protein expression of HK2, GLUT1, and GLUT4 in both rat strains, Akt2 protein level was significantly increased in SHR-mtBN only. Interestingly, a higher content of HK2 was revealed in the sarcoplasmic reticulum-enriched fraction in SHR-mtBN after CNH. The increased activity of HK determined in the mitochondrial fraction after CNH in both strains suggested an increase of HK association with mitochondria. Interestingly, HIF1a mRNA increased and HIF2a mRNA decreased after CNH, the former effect being more pronounced in SHR-mtBN than in SHR. Pleiotropic effects of upregulated Akt2 along with HK translocation to mitochondria and mitochondria-associated membranes can potentially contribute to a stronger CNH-afforded cardioprotection in SHR-mtBN compared with progenitor SHR.

Adaptation to chronic continuous hypoxia potentiates Akt/HK2 anti-apoptotic pathway during brief myocardial ischemia/reperfusion insult.

Adaptation to chronic hypoxia represents a potential cardioprotective intervention reducing the extent of acute ischemia/reperfusion (I/R) injury, which is a major cause of death worldwide. The main objective of this study was to investigate the anti-apoptotic Akt/hexokinase 2 (HK2) pathway in hypoxic hearts subjected to I/R insult. Hearts isolated from male Wistar rats exposed either to continuous normobaric hypoxia (CNH; 10% O2) or to room air for 3 weeks were perfused according to Langendorff and subjected to 10 min of no-flow ischemia and 10 min of reperfusion. The hearts were collected either after ischemia or after reperfusion and used for protein analyses and quantitative fluorescence microscopy. The CNH resulted in increased levels of HK1 and HK2 proteins and the total HK activity after ischemia compared to corresponding normoxic group. Similarly, CNH hearts exhibited increased ischemic level of Akt protein phosphorylated on Ser473. The CNH also strengthened the interaction of HK2 with mitochondria and prevented downregulation of mitochondrial creatine kinase after reperfusion. The Bax/Bcl-2 ratio was significantly lower after I/R in CNH hearts than in normoxic ones, suggesting a lower probability of apoptosis. In conclusion, the Akt/HK2 pathway is likely to play a role in the development of a cardioprotective phenotype of CNH by preventing the detachment of HK2 from mitochondria at reperfusion period and decreases the Bax/Bcl-2 ratio during I/R insult, thereby lowering the probability of apoptosis activation in the mitochondrial compartment.