The genus Acomys is of growing importance to many research fields. Previous research has shown that individuals differ when exploring new environments and that these behavioural strategies are consistent in time. In this study, we subjected 60 commensal Acomys cahirinus (37 males, 23 females) to a series of seven tests (free exploration, forced exploration under bright illumination, forced exploration under low illumination, hole board test, vertical activity test, elevated plus maze, and voluntary wheel running) to acquire independent behavioural traits and investigate whether and how personality develops in spiny mice. The full series of experiments was performed twice during ontogeny: once in the sub -adult stage (tested at 62-72 days of age) and once in the adult stage (102-112 days of age). We found that behaviour of the animals was repeatable both within (range of R values from 0.155 to 0.726) and across the two life -stages (0.238 to 0.563). While the structure of behaviour in adults was rather clear, it had not been fully crystalized in sub -adults, suggesting personality changes during maturation, even though some individual traits might be repeatable across ontogeny. Notably, the most consistent behavioural traits across the different tests were jumping and rearing, which are not commonly reported.

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.

Frentizole is immunosuppressive drug with low acute toxicity and lifespan-prolonging effect. Recently, frentizole ' s potential to disrupt toxic amyloid fi (Afi) Afi-binding alcohol dehydrogenase (ABAD) interaction in mitochondria in Alzheimer ' s brains has been revealed. Another broadly studied drug with anti-aging and immunosuppressive properties is an mTOR inhibitor - rapamycin. Since we do not yet precisely know what is behind the lifespan-prolonging effect of rapamycin and frentizole, whether it is the ability to inhibit the mTOR signaling pathway, reduction in mitochondrial toxicity, immunosuppressive effect, or a combination of all of them, we have decided within our previous work to dock the entire in-house library of almost 240 Afi-ABAD modulators into the FKBP-rapamycin-binding (FRB) domain of mTOR in order to interlink mTOR-centric and mitochondrial free radical-centric theories of aging and thus to increase the chances of success. Based on the results of the docking study, molecular dynamic simulation and MM-PBSA calculations, we have selected nine frentizole-like compounds (1 - 9). Subsequently, we have determined their real physical-chemical properties (logP, logD, pKa and solubility in water and buffer), cytotoxic/cytostatic, mTOR inhibitory, and in vitro anti senescence (senolytic and senomorphic) effects. Finally, the three best candidates (4, 8, and 9) have been forwarded for in vivo safety studies to assess their acute toxicity and pharmacokinetic properties. Based on obtained results, only compound 4 demonstrated the best results within in vitro testing, the ability to cross the blood-brain barrier and the lowest acute toxicity (LD50 in male mice 559 mg/kg; LD50 in female mice 575 mg/kg).

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.

N-methyl-D-aspartaterecepro receptor (NMDARs) are a subclass of glutamate receptors, which play an essential role in excitatory neurotransmission, but their excessive overactivation by glutamate leads to excitotoxicity. NMDARs are hence a valid pharmacological target for the treatment of neurodegenerative disorders; however, novel drugs targeting NMDARs are often associated with specific psychotic side effects and abuse potential. Motivated by currently available treatment against neurodegenerative diseases involving the inhibitors of acetylcholinesterase (AChE) and NMDARs, administered also in combination, we developed a dually-acting compound 7-phenoxytacrine (7-PhO-THA) and evaluated its neuropsychopharmacological and drug-like properties for potential therapeutic use. Indeed, we have confirmed the dual potency of 7-PhO-THA, i.e. potent and balanced inhibition of both AChE and NMDARs. We discovered that it selectively inhibits the GluN1/GluN2B subtype of NMDARs via an ifenprodil-binding site, in addition to its voltage-dependent inhibitory effect at both GluN1/GluN2A and GluN1/GluN2B subtypes of NMDARs. Furthermore, whereas NMDA-induced lesion of the dorsal hippocampus confirmed potent anti-excitotoxic and neuroprotective efficacy, behavioral observations showed also a cholinergic component manifesting mainly in decreased hyperlocomotion. From the point of view of behavioral side effects, 7-PhO-THA managed to avoid these, notably those analogous to symptoms of schizophrenia. Thus, CNS availability and the overall behavioral profile are promising for subsequent investigation of therapeutic use.

Evidence from clinical and preclinical studies implicates dysfunction of N-methyl-D-aspartate receptors (NMDARs) in schizophrenia progression and symptoms. We investigated the antipsychotic effect of two neuroactive steroids in an animal model of schizophrenia induced by systemic application of MK-801. The neuroactive steroids differ in their mechanism of action at NMDARs. MS-249 is positive, while PA-Glu is a negative allosteric NMDAR modulator. We hypothesized that the positive NMDA receptor modulator would attenuate deficits caused by MK-801 co-application more effectively than PA-Glu. The rats were tested in a battery of tests assessing spontaneous locomotion, anxiety and cognition. Contrary to our expectations, PA-Glu exhibited a superior antipsychotic effect to MS-249. The performance of MS-249-treated rats in cognitive tests differed depending on the level of stress the rats were exposed to during test sessions. In particular, with the increasing severity of stress exposure, the performance of animals worsened. Our results demonstrate that enhancement of NMDAR function may result in unspecific behavioral responses. Positive NMDAR modulation can influence other neurobiological processes besides memory formation, such as anxiety and response to stress.

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.

One of the major neuropeptide groups in insects is adipokinetic hormone/red pigment-concentrating hormone (AKH/RPCH) family of peptides. AKH had improving effects on depression and anxiety in animal models and it may be a new treatment choice in these disorders. Aim of this study was to investigate effects of Anax imperator AKH (Ani-AKH), Libellula auripennis AKH (Lia-AKH) and Phormia-Terra hypertrehalosemic hormone (Pht-HrTH) on animal behavior in olfactory bulbectomy (OBX) model and in posttraumatic stress disorder (PTSD) model of Wistar-albino rats. Lia-AKH and Pht-HrTH significantly increased time spent in escape platform’s quadrant compared to sham control while Lia-AKH significantly increased time spent in escape platform’s quadrant compared to OBX controls in probe trial of Morris water maze (MWM). Ani-AKH, Lia-AKH and Pht-HrTH significantly decreased immobility time compared to OBX controls in forced swimming test (FST). Pht-HrTH significantly increased %open arm time compared to OBX controls in elevated plus maze (EPM) test. Ani-AKH significantly increased %open arm entry compared to sham control while Ani-AKH and Pht-HrTH significantly increased %open arm entry compared to OBX controls in EPM. In PTSD study Ani-AKH and Lia-AKH significantly decreased immobility time compared to traumatized controls in FST. In acoustic startle reflex test, Ani-AKH, Lia-AKH and Pht-HrTH significantly decreased average startle amplitude compared to non-traumatized controls in PTSD study. Metabolomic studies showed that AKH may affect glutamatergic and dopaminergic system and neurochemistry. In conclusion, AKH peptides had wide ranging effects on behavior and improved performance in OBX and PTSD models in rats.

Human settlements represent a specific environment where commensal animals are exposed to different selective pressures than their wild-living conspecifics. Despite the importance of commensal rodents for human health and economy, little is known about how a transition to a commensal way of life changes the behaviour of the animals. We tested twelve populations of spiny mice (Acomys spp.) in two open field-type tests - a vertical test and a hole board test. In the vertical test, a wire mesh for climbing was offered to spiny mice. We used a multipopulation approach using two commensal and ten non-commensal spiny mouse populations to account for inter-population variability. We aimed to investigate whether there are differences in behaviour of commensal and non-commensal populations with special regard to their exploratory activity both on the ground and on the wire mesh. We found that all non-commensal populations behaved similarly despite their long separate evolutionary histories. Contrary, the commensal populations were less exploratory on the ground in both tests. We concluded that this change was associated with their transition to commensalism. This shows that selective pressures of the commensal environment are able to induce noticeable changes in behaviour after a very short evolutionary time.

Objective: Adipokinetic hormone (AKH) plays a role in sugar and lipid metabolism in insects. Previous studies of AKH showed memory improvements in a schizophrenia rat model that displayed memory impairment and reduced depression in a rat olfactory bulbectomy model. In this study, we investigated the effects of the adipokinetic hormone/red pigment-concentrating hormone (AKH/RPCH) family of peptides on brain neurotransmitter levels and brain neurochemistry in a schizophrenia rat model. Materials and Methods: We administered AKH/RPCH peptides for 4 days sub-chronically, both in naive rats and also in the MK-801-induced schizophrenia rat model. Liquid chromatography-mass spectrometry apparatus was used for targeted and untargeted analysis of rat neurochemistry. Results: Increased brain glutamate levels characteristic of MK-801 peptide-treated rats were significantly reduced by AKH. Furthermore, AKH also increased brain dopamine levels in both naive and MK-801 rats. Metabolomic studies have shown that AKH affects lipid and glutamate metabolism, while hypertrehalosaemic hormone plays a role in sugar metabolism and inflammation. Conclusion: According to our results, AKH might affect dopaminergic and glutamatergic systems and reverse the effects of MK-801, possibly affecting NMDA receptors.

Background: Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is characterized as a multi-factorial disorder with a prevalent genetic component. Due to the unknown etiology, current treatment based on acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate receptors (NMDAR) antagonist is effective only temporary. It seems that curative treatment will necessarily be complex due to the multifactorial nature of the disease. In this context, the so-called "multi-targeting" approach has been established. Objectives: The aim of this study was to develop a multi-target-directed ligand (MTDL) combining the support for the cholinergic system by inhibition of AChE and at the same time ameliorating the burden caused by glutamate excitotoxicity mediated by the NMDAR receptors. Methods: We have applied common approaches of organic chemistry to prepare a hybrid of 6-chlorotacrine and memantine. Then, we investigated its blocking ability towards AChE and NMDRS in vitro, as well as its neuroprotective efficacy in vivo in the model of NMDA-induced lessions. We also studied cytotoxic potential of the compound and predicted the ability to cross the blood-brain barrier. Results: A novel molecule formed by combination of 6-chlorotacrine and memantine proved to be a promising multipotent hybrid capable of blocking the action of AChE as well as NMDARs. The presented hybrid surpassed the AChE inhibitory activity of the parent compound 6-Cl-THA twofold. According to results it has been revealed that our novel hybrid blocks NMDARs in the same manner as memantine, potently inhibits AChE and is predicted to cross the blood-brain barrier via passive diffusion. Finally, the MTDL design strategy was indicated by in vivo results which showed that the novel 6-Cl-THA-memantine hybrid displayed a quantitatively better neuroprotective effect than the parent compound memantine. Conclusion: We conclude that the combination of two pharmacophores with a synergistic mechanism of action into a single molecule offers great potential for the treatment of CNS disorders associated with cognitive decline and/or excitotoxicity mediated by NMDARs.

Introduction: Chemotherapy-induced cognitive impairment is defined as clinically and statistically important decrease of cognitive functions often related to chemotherapy. The study focused on neurobiological substrate of chemobrain adapted to an animal model. Methods: Chemotherapeutics have been used according human lymphoma therapies in all phases comprising combinations of drugs: adriamycin, bleomycin, cyclophosphamide, dacarbazine, etoposide, vincristine and prednisone. Weight loss up to 4% was a limiting factor of drug dose used in Wistar rats. Rats were subjected to behavioral testing prior, immediately after, and in 3 months delay to administration of the chemotherapy. At these intervals, blood, and nerve tissue were collected and then immune-histological and neuro-chemical analysis was performed. The battery of behavioral tests comprised of: open field, elevated plus maze, social behavior test, and cognitive tests of the Y-maze. Results: Our behavioral outcomes indicated for a combination of motivation deficit and cognitive impairment after chemotherapy. It should not be neglected that rats generally have lower locomotor activity after post-treatment. This finding could also suggest a "sickness behavior" effect which is less pronounced with much time span after treatment. Lack of habituation indicates for learning and memory problems. We have also measured transient changes in blood cells counts, namely white blood cells (WBC), after ABVD, CHOP chemotherapy. Similarly in both regimes, drugs administration dropped number of WBC up to 30%, which did not fully return to the number before treatment. BEACOPP therapies decreased counts of lymphocytes, which have returned to beginning levels after delay. Immuno-histological analysis pointed at a clear decrease in the number of newly emerging neurons in the dentate gyrus. In addition to changes in the number of neurons, there were also differences in morphology of neurons. Following chemotherapy a relatively high percentage of cells exhibited abnormal orientation and poor or totally absent arborization. Conclusions: Overall, we have introduced the novel animal model of neurobiological substrate of chemobrain induced by the application of selected chemotherapeutic regimens. This model can be useful to study neuroprotective and precognitive drugs. Acknowledgements: The work was supported from projects number ERDF PharmaBrain CZ.02.1.01/0.0/0.0/16_025/0007444, AZV 16-29857A and NPUI LO1611. Keywords: chemotherapy; Hodgkin lymphoma (HL); non-Hodgkin lymphoma (NHL).

Several olfactory receptors (ORs) have been characterized outside the olfactory neuroepithelium in neuronal and non-neuronal tissues, where they were implicated in the recognition of diverse chemical signals. ORs have been found to regulate melanogenesis in skin melanocytes, and OR expression has been found in the human brain nigrostriatal dopaminergic neurons, where production of melanin occurs as neuromelanin and can change with age; OR expression is downregulated in Parkinson’s disease. Therefore, we propose several odorants as new functional ligands to ORs expressed in non-olfactory pigmented cells as dopaminergic neurons and melanocytes, where, by acting on cAMP-induced melanin production, they could help to counteract melanogenic and neurodegenerative dysfunctions, including melanoma and Parkinson’s disease.

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate excitatory neuro-transmission in the mammalian central nervous system (CNS), and their dysregulation results in the aetiology of many CNS syndromes. Several NMDAR modulators have been used successfully in clinical trials (including memantine) and NMDARs remain a promising pharmacological target for the treatment of CNS syndromes. 1,2,3,4-Tetrahydro-9-aminoacridine (tacrine; THA) was the first approved drug for Alzheimer's disease (AD) treatment. 7-methoxyderivative of THA (7-MEOTA) is less toxic and showed promising results in patients with tardive dyskinesia. We employed electrophysiological recordings in HEK293 cells and rat neurones to examine the mechanism of action of THA and 7-MEOTA at the NMDAR. We showed that both THA and 7-MEOTA are "foot-in-the-door" open-channel blockers of GluNl/GluN2 receptors and that 7-MEOTA is a more potent but slower blocker than THA. We found that the IC50 values for THA and 7-MEOTA exhibited the GluN1/GIuN2A < GluNl/G1uN2B < GluN1/GluN2C = GluN1/GluN2D relationship and that 7-MEOTA effectively inhibits human GluNl/GluN2A-M817V receptors that carry a pathogenic mutation. We also showed that 7-MEOTA is a "foot-in-the-door" open-channel blocker of GluNl/GluN3 receptors, although these receptors were not inhibited by memantine. In addition, the inhibitory potency of 7-MEOTA at synaptic and extrasynaptic hippocampal NMDAR5 was similar, and 7-MEOTA exhibited better neuroprotective activity when compared with THA and memantine in rats with NMDA-induced lesions of the hippocampus. Finally, intraperitoneal administration of 7-MEOTA attenuated MK-801-induced hyperlocomotion and pre-pulse inhibition deficit in rats. We conclude that 7-MEOTA may be considered for the treatment of diseases associated with the dysfunction of NMDARs.

The mechanism of tacrine as a precognitive drug has been considered to be complex and not fully understood. It has been reported to involve a wide spectrum of targets involving cholinergic, gabaergic, nitrinergic and glutamatergic pathways. Here, we review the effect of tacrine and its derivatives on the NMDA receptors (NMDAR) with a focus on the mechanism of action and biological consequences related to the Alzheimer's disease treatment. Our findings indicate that effect of tacrine on glutamatergic neurons is both direct and indirect. Direct NMDAR antagonistic effect is often reported by in vitro studies; however, it is achieved by high tacrine concentrations which are not likely to occur under clinical conditions. The impact on memory and behavioral testing can be ascribed to indirect effects of tacrine caused by influencing the NMDAR-mediated currents via M1 receptor activation, which leads to inhibition of Ca2+-activated potassium channels. Such inhibition prevents membrane repolarization leading to prolonged NMDAR activation and subsequently to long term potentiation. Considering these findings, we can conclude that tacrine-derivatives with dual cholinesterase and NMDARs modulating activity may represent a promising approach in the drug development for diseases associated with cognitive dysfunction, such as the Alzheimer disease.

Herein, we report a new class of amide-based inhibitors (1-4) of N-methyl-d-aspartate receptors (NMDARs) that were prepared as analogues of pregnanolone sulfate (PAS) and pregnanolone glutamate (PAG) - the steroidal neuroprotective NMDAR inhibitors. A series of experiments were conducted to evaluate their physicochemical and biological properties: (i) the inhibitory effect of compounds 3 and 4 on NMDARs was significantly improved (IC50=1.0 and 1.4μM, respectively) as compared with endogenous inhibitor - pregnanolone sulfate (IC50=24.6μM) and pregnanolone glutamate (IC50=51.7μM); (ii) physicochemical properties (logP and logD) were calculated; (iii) Caco-2 assay revealed that the permeability properties of compounds 2 and 4 are comparable with pregnanolone glutamate; (iv) compounds 1-4 have minimal or no adverse hepatic effect; (v) compounds 1-4 cross blood-brain-barrier.

Objective The aim of our study was to test whether ketamine produces an antidepressant effect in animal model of olfactory bulbectomy and assess the role of mammalian target of rapamycin (mTOR) pathway in ketamine’s antidepressant effect. Methods Bulbectomized (OBX) rats and sham controls were assigned to four subgroups according to the treatment they received (ketamine, saline, ketamine + rapamycin, and saline + rapamycin). The animals were subjected to open field (OF), elevated plus maze (EPM), passive avoidance (PA), Morris water maze (MWM), and Carousel maze (CM) tests. Blood samples were collected before and after drug administration for analysis of phosphorylated mTOR level. After behavioral testing, brains were removed for evaluation of brain-derived neurotrophic factor (BDNF) in prefrontal cortex (PFC) and hippocampus. Results Ketamine normalized hyperactivity of OBX animals in EPM and increased the time spent in open arms. Rapamycin pretreatment resulted in elimination of ketamine effect in EPM test. In CM test, ketamine + rapamycin administration led to cognitive impairment not observed in saline-, ketamine-, or saline + rapamycin-treated OBX rats. Prefrontal BDNF content was significantly decreased, and level of mTOR was significantly elevated in OBX groups. Conclusions OBX animals significantly differed from sham controls in most of the tests used. Treatment had more profound effect on OBX phenotype than controls. Pretreatment with rapamycin eliminated the anxiolytic and antidepressant effects of ketamine in task-dependent manner. The results indicate that ketamine + rapamycin application resulted in impaired stress responses manifested by cognitive deficits in active place avoidance (CM) test. Intensity of stressor (mild vs. severe) used in the behavioral tests had opposite effect on controls and on OBX animals.

Chronický stres vyvolaný socialni izolaci u mysi vede k signifikantnimu sniženi hladin neurosteroidů v mozku ve srovnani s kontrolami žijicimi ve skupině. Snižene hladiny GABAergnich neurosteroidů v plazmě a v mozkomisnim moku byly zaznamenane i u pacientů trpicich depresemi. Dlouhodobe vystaveni stresu může vest ke sniženi ACTH sekrece, ktera ma za nasledek zvýsenou aktivitu HPA osy a nepřiměřene reakce na nove stimuly.