CaMKIIα mediates spermidine-induced memory enhancement in rats: A potential involvement of PKA/CREB pathway.

Memory consolidation is associated with the regulation of protein kinases, which impact synaptic functions and promote synaptogenesis. The administration of spermidine (SPD) has been shown to modulate major protein kinases associated with memory improvement, including the Ca2+-dependent protein kinase (PKC) and cAMP-dependent protein kinase (PKA), key players in the cAMP response element-binding protein (CREB) activation. Nevertheless, the initial mechanism underlying SPD-mediated memory consolidation remains unknown, as we hypothesize a potential involvement of the memory consolidation precursor, Ca2+/calmodulin-dependent protein kinase II-α (CaMKIIα), in this process. Based on this, our study aimed to investigate potential interactions among PKC, PKA, and CREB activation, mediated by CaMKIIα activation, in order to elucidate the SPD memory consolidation pathway. Our findings suggest that the post-training administration of the CaMKII inhibitor, KN-62 (0.25 nmol, intrahippocampal), prevented the memory enhancement induced by SPD (0.2 nmol, intrahippocampal) in the inhibitory avoidance task. Through western immunoblotting, we observed that phosphorylation of CaMKIIα in the hippocampus was facilitated 15 min after intrahippocampal SPD administration, resulting in the activation of PKA and CREB, 180 min after infusion, suggesting a possible sequential mechanism, since SPD with KN-62 infusion leads to a downregulation in CaMKIIα/PKA/CREB pathway. However, KN-62 does not alter the memory-facilitating effect of SPD on PKC, possibly demonstrating a parallel cascade in memory acquisition via PKA, without modulating CAMKIIα. These results suggest that memory enhancement induced by SPD administration involves crosstalk between CaMKIIα and PKA/CREB, with no PKC interaction.

The implications of exercise in Drosophila melanogaster: insights into Akt/p38 MAPK/Nrf2 pathway associated with Hsp70 regulation in redox balance maintenance.

This study investigated the potential effects of exercise on the responses of energy metabolism, redox balance maintenance, and apoptosis regulation in Drosophila melanogaster to shed more light on the mechanisms underlying the increased performance that this emerging exercise model provides. Three groups were evaluated for seven days: the control (no exercise or locomotor limitations), movement-limited flies (MLF) (no exercise, with locomotor limitations), and EXE (with exercise, no locomotor limitations). The EXE flies demonstrated greater endurance-like tolerance in the swimming test, associated with increased citrate synthase activity, lactate dehydrogenase activity and lactate levels, and metabolic markers in exercise. Notably, the EXE protocol regulated the Akt/p38 MAPK/Nrf2 pathway, which was associated with decreased Hsp70 activation, culminating in glutathione turnover regulation. Moreover, reducing the locomotion environment in the MLF group decreased endurance-like tolerance and did not alter citrate synthase activity, lactate dehydrogenase activity, or lactate levels. The MLF treatment promoted a pro-oxidant effect, altering the Akt/p38 MAPK/Nrf2 pathway and increasing Hsp70 levels, leading to a poorly-regulated glutathione system. Lastly, we demonstrated that exercise could modulate major metabolic responses in Drosophila melanogaster aerobic and anaerobic metabolism, associated with apoptosis and cellular redox balance maintenance in an emergent exercise model.

Iron overload during the embryonic period develops hyperactive like behavior and dysregulation of biogenic amines in Drosophila melanogaster.

Iron (Fe) is used in various cellular functions, and a constant balance between its uptake, transport, storage, and use is necessary to maintain its homeostasis in the body. Changes in Fe metabolism with a consequent overload of this metal are related to neurological changes and cover a broad spectrum of diseases, mainly when these changes occur during the embryonic period. This work aimed to evaluate the effect of exposure to Fe overload during the embryonic period of Drosophila melanogaster. Progenitor flies (male and female) were exposed to ferrous sulfate (FeSO4) for ten days in concentrations of 0.5, 1, and 5 â€‹mM. After mating and oviposition, the progenitors were removed and the treatment bottles preserved, and the number of daily hatches and cumulative hatching of the first filial generation (F1) were counted. Subsequently, F1 flies (separated by sex) were subjected to behavioral tests such as negative geotaxis test, open field test, grooming, and aggression test. They have evaluated the levels of dopamine (DA), serotonin (5-HT), octopamine (OA), tryptophan and tyrosine hydroxylase (TH), acetylcholinesterase, reactive species, and the levels of Fe in the progenitor flies and F1. The Fe levels of F1 flies are directly proportional to what is incorporated during the period of embryonic development; we also observed a delay in hatching and a reduction in the number of the hatch of F1 flies exposed during the embryonic period to the 5mM Fe diet, a fact that may be related to the reduction of the cell viability of the ovarian tissue of progenitor flies. The flies exposed to Fe (1 and 5 â€‹mM) showed an increase in locomotor activity (hyperactivity) and a significantly higher number of repetitive movements. In addition to a high number of aggressive encounters when compared to control flies. We can also observe an increase in the levels of biogenic amines DA and 5-HT and an increase in TH activity in flies exposed to Fe (1 and 5 â€‹mM) compared to the control group. We conclude that the hyperactive-like behavior demonstrated in both sexes by F1 flies exposed to Fe may be associated with a dysregulation in the levels of DA and 5-HT since Fe is a cofactor of TH, which had its activity increased in this study. Therefore, more attention is needed during the embryonic development period for exposure to Fe overload.

Modulation of glutamate levels and Na+,K+-ATPase activity contributes to the chrysin memory recovery in hypothyroidism mice.

Abnormalities in the thyroid hormones, like in hypothyroidism, are closely related to dementia and Alzheimer's disease demonstrating the main symptom of these disorders: memory deficit. In this study we evaluated the effect of chrysin on deficit spatial and aversive memories and the contribution of glutamatergic, cholinergic pathways and Na+, K+-ATPase activity on hippocampus and prefrontal cortex in hypothyroid adult female mice C57BL/6. Hypothyroidism was induced by the continuous exposure to 0.1% methimazole (MTZ) in drinking water for 31 days. The exposure to MTZ was associated to low plasma levels of thyroid hormones (TH) compared to the control group on the 32nd. Subsequently, euthyroid and MTZ-induced hypothyroid mice received (intragastrically) either vehicle or chrysin (20 mg/kg) once a day for 28 consecutive days. After treatments mice performed the following behavioral assessments: open-field test (OFT), morris water maze (MWM) and passive avoidance test. Additionally, plasma TH levels were measured again, as well as glutamate levels, Na+,K+-ATPase and acetylcholinesterase (AChE) activities were analyzed in the hippocampus and prefrontal cortex of mice. Mice with hypothyroidism showed a deficit of spatial and aversive memory and chrysin treatment reversed these deficits. It also reduced the levels of glutamate and decreased Na+,K+-ATPase activity in both cerebral structures in the hypothyroid mice compared with the euthyroid ones, with the exception of glutamate in the hippocampus, which was a partial reversal. AChE activity was not altered by treatments. Together, our results demonstrate that chrysin normalized hippocampal glutamate levels and Na+,K+-ATPase activity, which could be involved in the reversal of memory deficit.

Nanoencapsulation of lutein and its effect on mice's declarative memory.

Lutein is a xanthophyll carotenoid widely known by its biological properties and low toxicity. When located in the brain, lutein may inhibit damage mechanisms, acting in neural cells maintenance. However, this carotenoid is very sensitive to external agents such as heat, light, pH and oxidation, besides presenting low absorption in gastrointestinal tract due its low solubility in water. Encapsulation procedures have shown promising results to increase lutein stability and bioavailability. In this work, lutein was encapsulated in polyvinylpyrrolidone (PVP) matrix by the dissolution in common solvent method. Nanoparticles were characterized in respect to morphology, water solubility, and interactions between PVP and lutein. In vivo tests were carried out in order to investigate the influence of lutein encapsulation on mice's declarative memory. Ex vivo tests were also carried out to determine if nanoparticles may cause any inflammatory process per se. Results indicated that lutein was successfully encapsulated in PVP while nanoparticles presented spherical shape and uniform size. Encapsulation was able to increase water solubility of lutein by more than 43 times, which may be attributed to the formation of soluble complexes trough hydrogen bonds between lutein hydroxyl group and PVP carbonyl group. In vivo studies showed that the administration of free lutein at 100mg·kg-1 and lutein-loaded PVP nanoparticles at 10 and 1.5mg·kg-1 significantly increased mice's object recognition index, meaning that significant lower doses of lutein were needed to achieve the same effect when lutein was encapsulated. Ex vivo studies showed that lutein-loaded nanoparticles administration did not alter inflammatory parameters in plasma, liver and brain of mice. In this sense, lutein-loaded PVP nanocapsules showed to be an advantageous alternative to increase water solubility and to improve the memory of mice without causing inflammatory damage per se.

Modulation of learning and memory by natural polyamines.

Spermine and spermidine are natural polyamines that are produced mainly via decarboxylation of l-ornithine and the sequential transfer of aminopropyl groups from S-adenosylmethionine to putrescine by spermidine synthase and spermine synthase. Spermine and spermidine interact with intracellular and extracellular acidic residues of different nature, including nucleic acids, phospholipids, acidic proteins, carboxyl- and sulfate-containing polysaccharides. Therefore, multiple actions have been suggested for these polycations, including modulation of the activity of ionic channels, protein synthesis, protein kinases, and cell proliferation/death, within others. In this review we summarize these neurochemical/neurophysiological/morphological findings, particularly those that have been implicated in the improving and deleterious effects of spermine and spermidine on learning and memory of naïve animals in shock-motivated and nonshock-motivated tasks, from a historical perspective. The interaction with the opioid system, the facilitation and disruption of morphine-induced reward and the effect of polyamines and putative polyamine antagonists on animal models of cognitive diseases, such as Alzheimer's, Huntington, acute neuroinflammation and brain trauma are also reviewed and discussed. The increased production of polyamines in Alzheimer's disease and the biphasic nature of the effects of polyamines on memory and on the NMDA receptor are also considered. In light of the current literature on polyamines, which include the description of an inborn error of the metabolism characterized by mild-to moderate mental retardation and polyamine metabolism alterations in suicide completers, we can anticipate that polyamine targets may be important for the development of novel strategies and approaches for understanding the etiopathogenesis of important central disorders and their pharmacological treatment.

Hippocampal PKA/CREB pathway is involved in the improvement of memory induced by spermidine in rats.

Spermidine (SPD) is an endogenous polyamine that modulates N-methyl-D-aspartate (NMDA) receptor function, and has been reported to facilitate memory formation. In the current study we determined whether or not the PKA/CREB signaling pathway is involved in SPD-induced facilitation of memory of inhibitory avoidance task in adult rats. The post-training administration of the cAMP-dependent protein kinase (PKA) inhibitor, N-[2-bromocinnamylamino)ethyl]-5-isoquinoline sulfonamide [H-89, 0.5 ρmol intrahippocampal (ih)] or the antagonist of the NMDA receptor polyamine-binding site (arcaine, 0.02 nmol ih) with SPD (0.2 nmol ih) prevented memory improvement induced by SPD. Intrahippocampal administration of SPD (0.2 nmol) facilitated PKA and cAMP response element-binding protein (CREB) phosphorylation in the hippocampus 180 min, but not 30 min, after administration, and increased translocation of the catalytic subunit of PKA into the nucleus. Arcaine (0.02 nmol) and H-89 (0.5 ρmol) prevented the stimulatory effect of SPD on PKA and CREB phosphorylation. These results suggest that memory enhancement induced by the ih administration of SPD involves the PKA/CREB pathways in rats.