Chemobrain in blood cancers: How chemotherapeutics interfere with the brain's structure and functionality, immune system, and metabolic functions.

Cancer treatment brings about a phenomenon not fully clarified yet, termed chemobrain. Its strong negative impact on patients' well-being makes it a trending topic in current research, interconnecting many disciplines from clinical oncology to neuroscience. Clinical and animal studies have often reported elevated concentrations of proinflammatory cytokines in various types of blood cancers. This inflammatory burst could be the background for chemotherapy-induced cognitive deficit in patients with blood cancers. Cancer environment is a dynamic interacting system. The review puts into close relationship the inflammatory dysbalance and oxidative/nitrosative stress with disruption of the blood-brain barrier (BBB). The BBB breakdown leads to neuroinflammation, followed by neurotoxicity and neurodegeneration. High levels of intracellular reactive oxygen species (ROS) induce the progression of cancer resulting in increased mutagenesis, conversion of protooncogenes to oncogenes, and inactivation of tumor suppression genes to trigger cancer cell growth. These cell alterations may change brain functionality, as well as morphology. Multidrug chemotherapy is not without consequences to healthy tissue and could even be toxic. Specific treatment impacts brain function and morphology, functions of the immune system, and metabolism in a unique mixture. In general, a chemo-drug's effects on cognition in cancer are not direct and/or in-direct, usually a combination of effects is more probable. Last but not least, chemotherapy strongly impacts the immune system and could contribute to BBB disruption. This review points out inflammation as a possible mechanism of brain damage during blood cancers and discusses chemotherapy-induced cognitive impairment.

Minireview: Animal model of schizophrenia from the perspective of behavioral pharmacology: Effect of treatment on cognitive functions.

Schizophrenia is a debilitating mental disorder characterized by positive, negative and cognitive symptoms. Whereas positive symptoms are satisfactorily addressed by current antipsychotic treatment, negative and cognitive symptomatic treatment remains largely ineffective. This review investigates the treatment efficacy regarding cognitive symptoms and evaluates the contribution of different monoamine receptor systems involved in schizophrenia pathophysiology to cognition. In the review, we included preclinical studies assessing the effect of different treatments on cognition in pre-pulse inhibition and two spatial cognitive tests. While pre-pulse inhibition investigates pre-attentive processes operating outside of conscious awareness, the spatial tasks require continuous attention and active engagement in task solving for a successful outcome. The schizophrenia-like phenotype was attained by acute or subchronic administration of non-competitive NMDA receptor antagonist MK-801.

The effect of hypertension on adult hippocampal neurogenesis in young adult spontaneously hypertensive rats and Dahl rats.

The dentate gyrus of the hippocampus is one of the few places in the brain where neurogenesis occurs in adulthood. Nowadays, an increasing number of children and young adults are affected by hypertension, one of the factors in the development of cerebrovascular diseases and age-related cognitive deficits. Since these cognitive deficits are often hippocampus-dependent, it is possible that hypertension exerts this effect via decreasing adult neurogenesis which has been shown to be essential for a range of cognitive tasks. We used spontaneously hypertensive rats, which develop hypertension in the first weeks of life. Half of them were treated with the antihypertensive drug captopril. We found that the drug-induced lowering of blood pressure in this period did not affect the rate of adult neurogenesis. In a second experiment, we used another animal model of hypertension - salt-sensitive and salt-resistant strains of Dahl rats. A high-salt diet induces hypertension in the salt-sensitive strain, but not in the salt-resistant strain. The high-salt diet led to salt-induced hypertension, but did not affect the level of adult neurogenesis in the dentate gyrus of the hippocampus. We conclude that hypertension does not significantly affect the rate of hippocampal neurogenesis in young adult rats.

Statin-induced changes in mitochondrial respiration in blood platelets in rats and human with dyslipidemia.

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used drugs for lowering blood lipid levels and preventing cardiovascular diseases. However, statins can have serious adverse effects, which may be related to development of mitochondrial dysfunctions. The aim of study was to demonstrate the in vivo effect of high and therapeutic doses of statins on mitochondrial respiration in blood platelets. Model approach was used in the study. Simvastatin was administered to rats at a high dose for 4 weeks. Humans were treated with therapeutic doses of rosuvastatin or atorvastatin for 6 weeks. Platelet mitochondrial respiration was measured using high-resolution respirometry. In rats, a significantly lower physiological respiratory rate was found in intact platelets of simvastatin-treated rats compared to controls. In humans, no significant changes in mitochondrial respiration were detected in intact platelets; however, decreased complex I-linked respiration was observed after statin treatment in permeabilized platelets. We propose that the small in vivo effect of statins on platelet energy metabolism can be attributed to drug effects on complex I of the electron transport system. Both intact and permeabilized platelets can be used as a readily available biological model to study changes in cellular energy metabolism in patients treated with statins.

Higher doses of (+)MK-801 (dizocilpine) induced mortality and procedural but not cognitive deficits in delayed testing in the active place avoidance with reversal on the Carousel.

Schizophrenia is a devastating disorder affecting 1 % of the world's population. An important role in the study of this disease is played by animal models. Since there is evidence that acute psychotic episodes can have consequences on later cognitive functioning, the present study has investigated the effects of a single systemic application of higher doses of (+)MK-801 (3 mg/kg and 5 mg/kg) to adult male Long-Evans rats from the Institute's breeding colony on delayed testing in the active place avoidance task with reversal on the Carousel (a rotating arena). Besides significant mortality due to the injections, a disruption of procedural functions in active place avoidance, after the dose 5 mg/kg was observed. It was concluded that Long-Evans rats from our breeding colony do not represent a suitable biomodel for studying the effects of single high-dose NMDA antagonists.

Spatial navigation: implications for animal models, drug development and human studies.

Spatial navigation and memory is considered to be a part of the declarative memory system and it is widely used as an animal model of human declarative memory. However, spatial tests typically involve only static settings, despite the dynamic nature of the real world. Animals, as well as people constantly need to interact with moving objects, other subjects or even with entire moving environments (flowing water, running stairway). Therefore, we design novel spatial tests in dynamic environments to study brain mechanisms of spatial processing in more natural settings with an interdisciplinary approach including neuropharmacology. We also translate data from neuropharmacological studies and animal models into development of novel therapeutic approaches to neuropsychiatric disorders and more sensitive screening tests for impairments of memory, thought, and behavior.

Place avoidance tasks as tools in the behavioral neuroscience of learning and memory.

Spatial navigation comprises a widely-studied complex of animal behaviors. Its study offers many methodological advantages over other approaches, enabling assessment of a variety of experimental questions and the possibility to compare the results across different species. Spatial navigation in laboratory animals is often considered a model of higher human cognitive functions including declarative memory. Almost fifteen years ago, a novel dry-arena task for rodents was designed in our laboratory, originally named the place avoidance task, and later a modification of this approach was established and called active place avoidance task. It employs a continuously rotating arena, upon which animals are trained to avoid a stable sector defined according to room-frame coordinates. This review describes the development of the place avoidance tasks, evaluates the cognitive processes associated with performance and explores the application of place avoidance in the testing of spatial learning after neuropharmacological, lesion and other experimental manipulations.

Delayed effects of elevated corticosterone level on volume of hippocampal formation in laboratory rat.

We studied delayed effects of elevated plasma levels of corticosterone (Cort) on volumetry, neuronal quantity, and gross marks of neurodegeneration in the hippocampal formation of Long-Evans rats. Animals were exposed to increased CORT levels for three weeks via implanted subcutaneous pellets. Volumetry, neuronal quantification and gross marks of degeneration were measured seven weeks after the termination of CORT treatment. We observed significant differences in volumes and especially in laterality of hippocampal subfields between control and CORT-treated animals. We found that the left hippocampus was substantially larger than the right hippocampus in the corticosterone-treated group, but not in the control group. In the control group, on the other hand, right hippocampal volume was markedly higher than all other measured volumes (hippocampal left control, hippocampal left CORT-treated and hippocampal right CORT-treated). Left hippocampal volume did not differ between the groups.

Effect of alpha(1)-adrenergic antagonist prazosin on behavioral alterations induced by MK-801 in a spatial memory task in Long-Evans rats.

Animal models of neuropsychiatric disorders are current topics in behavioral neuroscience. Application of non-competitive antagonists of NMDA receptors (such as MK-801) was proposed as a model of schizophrenia, as it leads to specific behavioral alterations, which are partly analogous to human psychotic symptoms. This study examined an animal model of schizophrenia induced by a systemic application of MK-801 (0.15 and 0.20 mg/kg) into rats tested in the active allothetic place avoidance (AAPA) task. Previous studies suggested that MK-801 may interact in vivo with other neurotransmitter systems, including noradrenergic system. Our experiments therefore evaluated the hypothesis that both locomotor stimulation and deficit in avoidance behavior in AAPA task induced by this drug would be reversible by application of alpha(1)-adrenergic antagonist prazosin (1 and 2 mg/kg). The results showed that both doses of prazosin partially reversed hyperlocomotion induced by higher doses of MK-801 and an avoidance deficit measured as number of entrances into the shock sector. Interestingly, no effect of prazosin on the MK-801-induced decrease of maximum time between two entrances (another measure of cognitive performance) was observed. These results support previous data showing that prazosin can compensate for the hyperlocomotion induced by MK-801 and newly show that this partial reduction sustains even in the forced locomotor conditions, which are involved in the AAPA task. The study also shows that certain parameters of avoidance efficiency may be closely related to locomotor activity, whereas other measures of cognition may more selectively reflect cognitive changes.

Ryanodine receptors, voltage-gated calcium channels and their relationship with protein kinase A in the myocardium.

We present a review about the relationship between ryanodine receptors and voltage-gated calcium channels in myocardium, and also how both of them are related to protein kinase A. Ryanodine receptors, which have three subtypes (RyR1-3), are located on the membrane of sarcoplasmic reticulum. Different subtypes of voltage-gated calcium channels interact with ryanodine receptors in skeletal and cardiac muscle tissue. The mechanism of excitation-contraction coupling is therefore different in the skeletal and cardiac muscle. However, in both tissues ryanodine receptors and voltage-gated calcium channels seem to be physically connected. FK-506 binding proteins (FKBPs) are bound to ryanodine receptors, thus allowing their concerted activity, called coupled gating. The activity of both ryanodine receptors and voltage-gated calcium channels is positively regulated by protein kinase A. These effects are, therefore, components of the mechanism of sympathetic stimulation of myocytes. The specificity of this enzyme's targeting is achieved by using different A kinase adapting proteins. Different diseases are related to inborn or acquired changes in ryanodine receptor activity in cardiac myocytes. Mutations in the cardiac ryanodine receptor gene can cause catecholamine-provoked ventricular tachycardia. Changes in phosphorylation state of ryanodine receptors can provide a credible explanation for the development of heart failure. The restoration of their normal level of phosphorylation could explain the positive effect of beta-blockers in the treatment of this disease. In conclusion, molecular interactions of ryanodine receptors and voltage-gated calcium channels with PKA have a significant physiological role. However, their defects and alterations can result in serious disturbances.

Regulation of selectivity and translocation of aquaporins: an update.

All living beings need to solve the problem of controlled transport of water. To this purpose, a special group of integral membrane proteins called aquaporins has evolved. There are 13 known members of this family that act as channels for water and small solutes, such as glycerol and urea. Although they allow large flux of water, they successfully prevent passage of protons. Here, we present the review of the data from the literature on the selectivity mechanism of aquaporins. The regulation of aquaporin activity occurs through regulation of expression of their genes, changing the localization of the already existing proteins in the cells and direct regulation of the activity in situ. We present the review of new data on the mechanisms of direct regulation. Special emphasis is on the advances in comprehension of aquaporin-2 translocation in collecting tubule cells of the kidney. Four elements of this process are described: 1) the role of protein kinase A and phosphorylation of serine 256 on aquaporin-2, 2) the transport of vesicles along the microtubules toward the apical membrane, 3), the removal of cytoskeletal subapical obstruction and the role of Rho GTPase and ezrin-radixin-moesin proteins in this, and 4) elevation of the cytosolic Ca2+ concentration, the fusion of the vesicle with the apical membrane and the role of SNARE proteins in exocytosis.