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Polyprenols are natural substances that are known for their role as cell membrane protectors from peroxidation. However, there is a lack of information about their effect on the performance of athletes. Therefore, we studied the effects of polyprenol on athlete performance. A total of 30 male floorball players participated in this study, 16 of whom were taking 30 mg polyprenol liposome caps and 14 of whom were not. All of the participants underwent VO2max exhaustive incremental cycling testing, before and after the use of polyprenols. VO2peak and other cardiorespiratory variables were measured to evaluate cardiorespiratory adaptation. For the polyprenol users (PU) the oxygen pulse (O2/HR) increased by 0.9 ml/beat, while in the control group (C) decreased by 0.4 ml/beat from before to after the use of polyprenols (p < 0.05). The diastolic pressure (Pdia) decreased by 4 mmHg for the PU, while it increased by 10 mmHg in the C (p < 0.05). The stroke volume (SVc) in the PU increased by 2.9 ml, while that in the C decreased by 7.4 ml (p < 0.05). In conclusion, polyprenols improved oxygen consumption efficiency by increasing SVc and O2/HR.

Background: A wide range of techniques has been developed over the past decades to characterize amyloid-β (Aβ) pathology in mice. Until now, no method has been established to quantify spatial changes in Aβ plaque deposition due to targeted delivery of substances using ALZET® pumps. Objective: Development of a methodology to quantify the local distribution of Aβ plaques after intracerebral infusion of compounds. Methods: We have developed a toolbox to quantify Aβ plaques in relation to intracerebral injection channels using Zeiss AxioVision® and Microsoft Excel® software. For the proof of concept, intracerebral stereotactic surgery was performed in 50-day-old APP-transgenic mice injected with PBS. At the age of 100 days, brains were collected for immunhistological analysis. Results: The toolbox can be used to analyze and evaluate Aβ plaques (number, size, and coverage) in specific brain areas based on their location relative to the point of the injection or the injection channel. The tool provides classification of Aβ plaques in pre-defined distance groups using two different approaches. Conclusion: This new analytic toolbox facilitates the analysis of long-term continuous intracerebral experimental compound infusions using ALZET® pumps. This method generates reliable data for Aβ deposition characterization in relation to the distribution of experimental compounds.

One of the long-term goals of the certification systems (FSC (Forest Stewardship Council) and PEFC (Program for the Endorsement of Forest Certification)) of sustainably managed forests that provide both social, environmental, and economic benefits is to completely phase out the use of chemical pesticides to protect planting material. It is in the interest of both nurseries and forest owners to find successful alternative, environmentally friendly solutions to safeguard pine saplings against Curculionidae. The studied two-year-old pine stands are located in the Hylocomiosa forest type with a total area of 4.27 ha. In 2016 clear-cutting was carried out, and in the spring of 2018, containerized seedlings were planted in areas with partial soil scarification in three repetitions in each area. Six plots with three variants in each of the repetitions were prepared. The work aims to evaluate the effectiveness of the use of P.sylvestris protection against damage Curculionidae while comparing untreated (control) lots with the ones treated with the systemic insecticide Actara or wax based on the number of damages and growth of seedlings. The intensity of tree damage and the incidence of damage over two years, depending on the type of seedling treatment, was assessed, and the average tree heights were measured and compared. With an increase in the incidence of weevil damage, the intensity of damage is also observed. At the same time, a significant (p>0.05) difference in lesions between the types of treatment of seedlings has not been established. Within two years, the death of trees due to weevil damage is insignificant - 2 % of all seedlings treated with the systemic insecticide Actara, 5 % of seedlings treated with wax Kvaae, and 6 % of untreated seedlings or control. The treatment of seedlings significantly affected their growth in the first and second years after planting (p less than 0.05). The use of wax Kvaae resulted in higher costs and similar protection effectiveness as the use of chemical means.

Callosotomy is an invasive method that is used preclinically to study the role of interhemispheric functional connectivity in the brain. In small animals, it is technically challenging to perform. To date, there exists two main approaches for transecting the corpus callosum in rodents: trephine hole(s) or unilateral craniotomy. Both of these approaches will cause damage to other brain structures, mainly the cerebral cortex, or injury of large vessels, such as the superior sinus, that may lead to intracranial hemorrhage and animal death. In this study, we present a novel approach for complete corpus callosotomy in adult mice using an interhemispheric approach combined with bilateral and extended craniotomy across the midline. This study demonstrated that bilateral and extended craniotomy provided the visual space required for hemisphere and sinus retraction, thus keeping large blood vessels and surrounding brain structures intact during transection of the corpus callosum under surgical microscope using fine, standardized surgical instruments. We also emphasized the importance of good post-operative care leading to optimal recovery, increasing overall animal survival, and reducing the number of animals used in the experiments, which are crucial in conducting long-term studies. Taken together, this approach can provide higher reproducibility and smaller variability of study results among animals, including long-term behavioral studies in mice. This novel interhemispheric approach to complete callosotomy will facilitate further studies, helping to extend knowledge of the corpus callosum in interhemispheric transfer and its role in various neurological and psychiatric pathologies.

The annual shoot elongation could be described by a non-linear growth model to characterize differences in its dynamics among spruce genotypes, the effect of each shoot elongation phase on the total shoot length, and the genetic differences for a particular growth phase. The terminal shoot length was measured in two open-pollinated progeny trials of Norway spruce on average once per week during the ninth growing season. For the analysis, 10% of families with the longest annual increment (shoot) and 10% with the shortest were selected for each trial. The Gompertz model was fitted to individual tree data, and the mean values of its coefficients for each group of families were obtained. Family significantly (p &lt, 0.001) affected total shoot length and all growth rhythm parameters, with similar trends reported in both studied sites. Heritability of Gompertz model coefficients in most cases exceeded that of the tree height. The superior10% of families started shoot elongation slightly but non-significantly earlier (all p &gt, 0.05) than the other groups of families and had more intense shoot elongation (mm per day) during the entire growing season. A strong negative relation was found between the slope coefficient of the cumulative shoot elongation lines and the total height increment. The group of families with the longest increment had flatter relative shoot elongation lines, indicating relatively more evenly distributed growth within the growing season. In contrast, families with the shortest increment tended to accumulate a higher proportion of height increment during the active growth phase and reduced relative growth intensity more rapidly. The 10% of families with the largest annual increment showed superior characteristics in all shoot elongation phases, resulting in 30&ndash, 40% longer shoots compared to the 10% of families with the smallest annual increment. The significant differences in Gompertz model coefficients indicate that genotypes with favorable growth patterns might be selected.

Drainage ensures flow of water and access of oxygen to the roots of the trees. Therefore, melioration systems have been established in a third of the forest area of Latvia, and for the most part highly productive stands can be observed in these areas. Water flow in these systems is often stopped by beaver dams. The aim of our case study was to assess the impact of ditch reconstruction on the increment of the coniferous trees. Increment cores were collected from 169 trees at a distance up to 45 m from the ditch in the drainage system that was reconstructed 8 years prior. Drainage system reconstruction reversed the trend of declining radial increment for both Scots pine and Norway spruce; however, the influence of this measure over an 8 year period was statistically significant, notable (55%) and positive only for Norway spruce, growing closest to the edge of the ditch. Other growth limiting factors need to be considered and tackled to ensure the highest effect of the investment in drainage system reconstruction, including choice of the tree species, stand density, age, availability of nutrients.

Alzheimer's disease (AD) is the most common cause of dementia. Neuropathological processes, including the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles, and neuroinflammation, lead to cognitive impairment at middle and eventually later stages of AD progression. Over the last decade, focused efforts have explored repurposed drug approaches for AD pathophysiological mechanisms. Recently, auranofin, an anti-inflammatory drug, was shown to have therapeutic potential in a number of diseases in addition to rheumatoid arthritis. Surprisingly, no data regarding the effects of auranofin on cognitive deficits in AD mice or the influence of auranofin on Aβ pathology and neuroinflammatory processes are available. In the present study, we used 14-month-old transgenic male APP

Early manifestations of Alzheimer's disease (AD) include neuroinflammation, disrupted neurotransmission and cognitive deficits. Impairment of the GABAergic system is essentially involved in the pathogenesis of AD. Traditionally, agonists of GABAA receptors at doses above 1 mg/kg are known to possess memory impairing effects. However, we have previously found that GABAA receptor GABA site ligand muscimol at very low doses acted contrary – enhanced spatial learning/memory, as well as prevented neuroinflammation and augmented neurotransmission in AD model rats. Therefore, in the present study we focused on the assessment of the effects of non-sedative – very low (0.05 mg/kg) and moderate (1 mg/kg) – doses of diazepam, a positive allosteric modulator of benzodiazepine site of GABAA receptors. Its effects on spatial learning/memory and brain proteins related to neuroinflammation (GFAP and Iba-1), synaptic plasticity (SYP1), as well as acetylcholine breakdown and GABA biosynthesis were studied. Non-transgenic AD model rats (intracerebroventricular streptozocin injection) were used with the aim to mimic the pre-dementia stage of AD in humans. The obtained data showed that diazepam at both doses protected against streptozocin induced detrimental effects by enhancing spatial learning/memory, preventing neuroinflammation, preserving synaptic plasticity, as well as normalizing the hippocampal and cortical protein expression related to acetylcholine breakdown and GABA biosynthesis. One may suggest that at low and moderate doses diazepam is targeting non-specific, probably allosteric GABAA receptor sites, thus leading to stimulatory effects that can be beneficial for diazepam use in early pre-dementia stages of AD.

Background Implanted osmotic minipumps are commonly used for long-term, brain-targeted delivery of a wide range of experimental agents by being connected to a catheter and a cannula. During the stereotactical surgery procedure, the cannula has to be placed correctly in the x-y directions and also with respect to the injection point in the z-direction (deepness). However, the flat fixation base of available cannula holders doesn’t allow an easy, secure fixation onto the curve-shaped skull. New method We have developed a modified method for a better fixation of the cannula holder by using an easy-to-produce, skull-shaped silicone spacer as fixation adapter. Results We describe the application and its fast and reliable production in the lab. Comparison with existing method(s) Superglue or cement is currently being used as the method of choice. However, the curve-shaped skull surface does not fit well with the flat and rigid cannula adapter which leads to fixation problems over time causing wide infusion channels and often also to leakage problems from intracerebrally applied agents towards the surface meninges. As another consequence of the inappropriate fixation, the cannula may loosen from the skull before the end of the experiment or it causes damage to the brain tissue, harming the animals with leading to a failure of the whole experiment. Conclusions The easy-to-produce spacer facilitates the crucial step of long-term, stereotactic brain infusion experiments with intracerebral catheters in a highly secure and reproducible way.

The needles of conifer trees are one of the richest sources of natural polyprenols. Polyprenol homologs from Abies sibirica L. lipophilic 80% purified extract were analyzed and quantified. In total, 10 peaks (Prenol-11 to Prenol-20) were observed in the ultra-high-performance liquid chromatography–diode array detector (UHPLC-DAD) chromatogram of Siberian fir with the most abundant compound being Prenol-15 (relative amount 37.23 + 0.56% of the total polyprenol yield). Abies sibirica L. polyprenol solubility and incorporation efficiency into liposomes were studied in various commercially available lecithin mixtures (Phosal IP40, Phosal 75SA, and Lipoid P45). The resulting multilamellar polyprenol liposomes were morphologically characterized by Light and Transmission Electron Microscopy, and the liposome size was discovered to be polymodal with the main peak at 1360 nm (90% of the volume). As polyprenols are fully soluble only in lipids, a liposomal formulation based upon co-solubilization and a modified ethanol injection method of polyprenols into the ethanol-phospholipid system was developed for the entrapment and delivery of polyprenols for potential commercial applications in food supplement and cosmetic industries.

Climate change is linked to increase in frequency and/or severity of different damages in forest stands. Birch (Betula spp.) stands can be significantly affected by wind and snow (freezing rain). Aim of our study was to assess, if admixture of other tree species reduces the proportion of damaged trees in birch stands. Data from total of 836 sample plots (size 500m2) in birch stands at the age of up to 81 year were analysed. Among the mixed sands (MS) and pure stands (PS >80% of single tree species), the mean proportion (± confidence interval) of damage was assessed from the total number (TN) and basal area (BA) of overstory (first layer) trees. MS were further assessed in two groups – one or more species in admixture (MS+1 and MS+2). The proportion of mixed birch stands was increasing with age: from average of 21% at the age of up to 20 years to 64% at the age of 61-70 years, most likely do to difference in historical management. In period between the 1950th and 1990th, birch was considered as undesirable species and the older stands formed mainly due to low survival of coniferous trees and natural ingrowth of birch, whereas starting from the 1990th birch was more widely recognized and used as target species. Proportion of undamaged birch trees (both, when assessed as TN or BA) was not significantly different between MS and PS. Also presence of second layer trees did not affect the proportion of damaged overstory trees significantly. There were significant differences among the groups of mixed stands: more wind or snow damaged trees were found in certain age groups in stands with more than one admixture species present. Creating a mixed birch stands in comparison to pure stands of the same tree species may not result in lower frequency of damaged trees, thus this approach cannot be automatically recommended as a tool for adaptation to climate change

In this concise review the current research in plant bioactive compound studies in Latvia is described. The paper summarizes recent studies on substances from edible plants (e.g., cereals and apples) or their synthetic analogues, such as peptide lunasin, as well as substances isolated from inedible plants (e.g., birch and conifer), such as pentacyclic triterpenes (e.g., betulin, betulinic acid, and lupeol) and polyprenols. Latvian researchers have been first to demonstrate the presence of lunasin in triticale and oats. Additionally, the impact of genotype on the levels of lunasin in cereals was shown. Pharmacological studies have revealed effects of lunasin and synthetic triterpenes on the central nervous system in rodents. We were first to show that synthetic lunasin causes a marked neuroleptic/cataleptic effect and that betulin antagonizes bicuculline-induced seizures (a GABA A receptor antagonist). Studies on the mechanisms of action showed that lunasin binds to dopamine D1 receptors and betulin binds to melanocortin and gamma-aminobutyric acid A receptors therefore we suggest that these receptors play an essential role in lunasin's and betulin's central effects. Recent studies on conifer polyprenols demonstrated the ability of polyprenols to prevent statin-induced muscle weakness in a rat model. Another study on plant compounds has demonstrated the anti-hyperglycemic activity of phlorizin-containing unripe apple pomace in healthy volunteers. In summary, research into plant-derived compounds in Latvia has been focused on fractionating, isolating and characterizing of lunasin, triterpenes, polyprenols and phlorizin using in vitro, and in vivo assays, and human observational studies.

The prevalence of Alzheimer's disease (AD) is higher in females than in males, and causes more severe cognitive, memory and behavioral impairments. Previously, in male transgenic (Tg) APPSweDI mice, we reported that the novel lipophilic 1,4-dihydropyridine (DHP) derivative AP-12 crossed the blood-brain barrier, blocked neuronal and vascular calcium channels, changed brain protein expression and improved behavior. In this study, we used female Tg APPSweDI mice to assess the effects of AP-12 on behavior, and brain protein expression, with a particular focus on those of the GABAergic system. The results showed that in female Tg mice, similar to male Tg mice, AP-12 improved spatial learning/memory performance in the water maze test and demonstrated anxiolytic effect in the elevated zero maze (after single administration of AP-12) and elevated plus maze (after chronic injections of AP-12). In addition, we demonstrated upregulated expression of glutamate decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) in the cingulate cortex and hippocampus, pointing to the role of the GABAergic system as one of the neural networks dysregulated in AD. In both female and male mice, AP-12 did not change the expression of hippocampal Homer-1, a protein which is involved in synaptic plasticity. However, in cingulate cortex, the staining density of Homer-1 was significantly increased in female mice. Further, female mice (similar to male mice) did not show changes in brain AChE expression and in the amyloid beta load in the hippocampus and cingulate cortex. In conclusion, the memory enhancing, anxiolytic and protein expression effects of AP-12 did not show sex specificity in APPSweDI mice. Considering the ability of AP-12 to block brain calcium channels and improve memory by enhancing the GABAergic and synaptic plasticity processes, AP-12 is a promising compound which merits further pre-clinical studies to investigate its usefulness in the treatment of AD.

Alzheimer’s disease (AD) is the most common cause of dementia. Neuropathological processes, including the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles, and neuroinflammation, lead to cognitive impairment at middle and eventually later stages of AD progression. Over the last decade, focused efforts have explored repurposed drug approaches for AD pathophysiological mechanisms. Recently, auranofin, an anti-inflammatory drug, was shown to have therapeutic potential in a number of diseases in addition to rheumatoid arthritis. Surprisingly, no data regarding the effects of auranofin on cognitive deficits in AD mice or the influence of auranofin on Aβ pathology and neuroinflammatory processes are available. In the present study, we used 14-month-old transgenic male APPNL-G-F/NL-G-F mice to assess the effects of subchronic administration of auranofin at low doses (1 and 5 mg/kg, intraperitoneal) on spatial memory, Aβ pathology and the expression of cortical and hippocampal proteins (glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule-1 (Iba-1)) and proteins related to synaptic plasticity (glutamic acid decarboxylase 67 (GAD67), homer proteins homologue-1 (Homer-1)). The data demonstrated that auranofin significantly decreased Aβ deposition in the hippocampus and the number of Aβ plaques in the cingulate cortex, but it did not have memory-enhancing effects or induce changes in the expression of the studied proteins. Our current results highlight the importance of considering further pre-clinical research to investigate the possible beneficial effects of auranofin on the other pathological aspects of AD.

Neuroinflammation, oxidative stress, decreased glucose/energy metabolism, and disrupted neurotransmission are changes that occur early in sporadic Alzheimer's disease (AD), manifesting as mild cognitive impairment. Recently, the imbalanced function of the gamma-aminobutyric acid (GABA) system was identified as a critical factor in AD progression. Thus, maintaining balance among neurotransmitter systems, particularly the GABA system, can be considered a beneficial strategy to slow AD progression. The present study investigated the effects of the compound gammapyrone, a molecule containing three GABA moieties: "free" moiety attached to the position 4 of the 1,4-dihydropyridine (DHP) ring, and two "crypto" moieties as part of the DHP scaffold. The "free" and "crypto" GABA moieties are linked by a peptide bond (-CONH-), resulting in a peptide-mimicking structure. In a nontransgenic male rat AD model generated by intracerebroventricular (icv) streptozocin (STZ) administration, gammapyrone (0.1 and 0.5 mg/kg ip) mitigated the impairment of spatial learning and memory, prevented astroglial and microglial neuroinflammation, and normalized acetylcholine breakdown and GABA biosynthesis. In PC12 cells, gammapyrone protected against oxidative stress, mitochondrial dysfunction and apoptosis caused by the mitochondrial toxin di-2-ethylhexyl phthalate (DEHP). Gammapyrone did not bind to GABA-A and GABA-B receptors in vitro; therefore, we cannot attribute its neuroprotective action to a specific interaction with GABA receptors. Nevertheless, we suggest that the peptide-like regulatory mechanisms of gammapyrone or its allosteric modulatory properties are essential for the observed effects. Since, the icv STZ model resembles the early stages of AD, gammapyrone, and/or its congeners could be useful in the design of anti-dementia drugs.

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting millions of people worldwide. At present, there is no effective cure for PD; treatments are symptomatic and do not halt progression of neurodegeneration. Extracellular vesicles (EVs) can cross the blood–brain barrier and represent promising alternative to the classical treatment strategies. In the present study, we examined therapeutic effects of intranasal administration of EVs derived from human exfoliated deciduous teeth stem cells (SHEDs) on unilateral 6-hydroxydopamine (6-OHDA) medial forebrain bundle (MFB) rat model of PD. CatWalk gait tests revealed that EVs effectively suppressed 6-OHDA-induced gait impairments. All tested gait parameters (stand, stride length, step cycle, and duty cycle) were significantly improved in EV-treated animals when compared with 6-OHDA-lesion group rats. Furthermore, EVs slowed down numbers of 6-OHDA-induced contralateral rotations in apomorphine test. Improvements in motor function correlated with normalization of tyrosine hydroxylase expression in the striatum and substantia nigra. In conclusion, we demonstrated, for the first time, the therapeutic efficacy of intranasal administration of EVs derived from SHEDs in a rat model of PD induced by 6-OHDA intra-MFB lesion. Our findings could be potentially exploited for the development of new treatment strategies against PD.

Polyprenols (PPs) have been identified in almost all living organisms. The richest source of PPs is the needles of conifer trees. Endogenously, PPs, similarly to cholesterol, are synthesised in human and animal cells via the mevalonate pathway. Previous studies have demonstrated the anti-oxidant properties of PPs. To our knowledge, no studies have been published on the influence of PPs on muscle strength. We hypothesised that administration of PPs could prevent changes in muscle functioning caused by statins (weakness, etc.). In the present study, atorvastatin (80 mg/kg) was used as a model compound. PPs at doses 1, 10 and 20 mg/kg were administered. Both drugs were given per os for 16 days. The influence of atorvastatin, PPs and their combination on behaviour, muscle strength, plasma cholesterol and creatine kinase activity was assessed in female Wistar rats. Our data demonstrated that atorvastatin considerably impaired muscle strength, whereas PPs protected that effect. Neither PPs, nor atorvastatin influenced plasma cholesterol levels, whereas PPs at dose 20 mg/kg elevated creatine kinase activity by about 25%. PPs at the tested doses did not alter behaviour, indicating safety of central nervous system functions. The obtained data suggest usefulness of PPs as a complement in statin therapy to reduce muscle-related side effects.

Recent studies devoted to neuroprotection have focused on the role of the gamma-aminobutyric acid (GABA) system in regulating neuroinflammatory processes which play a key role in the neurodegenerative processes observed in Alzheimer's disease (AD) by inducing glial cell overactivation and impairing neurotransmission. Data on the efficacy of classical GABA-A and GABA-B receptor agonists (muscimol and baclofen, respectively) in animal models of AD are not available. Moreover, no published studies have examined the ability of optimal doses of these compounds to prevent neuroinflammation, the alterations in neurotransmission and cognitive deficits. In the present study, we used a non-transgenic rat model of AD obtained by intracerebroventricular streptozocin (STZ) injection and assessed the effects of muscimol and baclofen at very low doses (0.01-0.05mg/kg) on spatial memory and the expression of cortical and hippocampal proteins related to neuroinflammation, namely proteins involved in astroglial functions (glial fibrillary acidic protein, GFAP), GABA synthesis (GABA synthesizing enzyme, glutamic acid decarboxylase 67, GAD67) and acetylcholine degradation (acetylcholine esterase). The presented study demonstrated that in a rat model of STZ-induced AD both muscimol and baclofen at the tested doses exerted memory-enhancing and anti-inflammatory effects, as well as normalization of acetylcholine esterase and GABA expression. We suggested that the function of very low doses of GABA receptor agonists differs from typical GABA-related inhibition and may be mediated by the allosteric sites of GABA receptors or other non-specific cell regulatory pathways.

The novel 1,4-dihydropyridine derivatives containing the cationic pyridine moiety at the position 4, and the N-propargyl group as a substituent at position 1 of the 1,4-DHP cycle were designed, synthesised, and assessed in biological tests. Among all the novel compounds, the 4-(N-dodecyl) pyridinium group-containing compounds 11 (without the N-propargyl group) and 12 (with the N-propargyl group) demonstrated the highest calcium antagonistic properties against neuroblastoma SH-SY5Y (IC50 about 5–14 mM) and the vascular smooth muscle A7r5 cell (IC50 – 0.6–0.7 mM) lines, indicating that they predominantly target the L-type calcium channels. These compounds showed a slight total antioxidant activity. At concentrations close to those of L-type calcium channel blocking ones, compound 12 did not affect mitochondrial functioning; also, no toxicity was obtained in vivo. The N-propargyl group as a substituent at position 1 of the 1,4-DHP cycle did not essentially influence the compounds’ activity. The 4-(N-dodecyl) pyridinium moiety-containing compounds can be considered as prototype molecules for further chemical modifications and studies as cardioprotective/neuroprotective agents. This study was supported by ESF project No. 2009/ 0217/1DP/1.1.1.2.0/09/APIA/VIAA/031; the EuroNanoMed project ‘‘CheTherDel’’; Portuguese Research Council (FCT), Faculty of Medicine, Centre for Neuroscience and Cell Biology (CNC) and Marine and Environmental Research Centre (IMAR–CMA) of the University of Coimbra, Portugal.

Amyloid-β (Aβ) deposition is one of the hallmarks of the amyloid hypothesis in Alzheimer’s disease (AD). Mouse models using APP-transgene overexpression to generate amyloid plaques have shown to model only certain parts of the disease. The extent to which the data from mice can be transferred to man remains controversial. Several studies have shown convincing treatment results in reducing Aβ and enhancing cognition in mice but failed totally in human. One model-dependent factor has so far been almost completely neglected: the endogenous expression of mouse APP and its effects on the transgenic models and the readout for therapeutic approaches. Here, we report that hAPP-transgenic models of amyloidosis devoid of endogenous mouse APP expression (mAPP-knockout / mAPPko) show increased amounts and higher speed of Aβ deposition than controls with mAPP. The number of senile plaques and the level of aggregated hAβ were elevated in mAPPko mice, while the deposition in cortical blood vessels was delayed, indicating an alteration in the general aggregation propensity of hAβ together with endogenous mAβ. Furthermore, the cellular response to Aβ deposition was modulated: mAPPko mice developed a pronounced and age-dependent astrogliosis, while microglial association to amyloid plaques was diminished. The expression of human and murine aggregation-prone proteins with differing amino acid sequences within the same mouse model might not only alter the extent of deposition but also modulate the route of pathogenesis, and thus, decisively influence the study outcome, especially in translational research.

This Info article offers an overview on the main historical facts and the current perspectives of the scientific and educational competence in field of pharmacology in three European countries on Baltic sea East coast: Estonia, Latvia and Lithuania. The research areas have changed constantly due to economical and political reasons during the last 200 years and today do cover quite different pharmacological areas in each of Baltic countries and are recognized internationally. Today the main topics of studies in Estonia are the pharmacology of neurodegenerative diseases, mood disorders and brain plasticity; the role of mitochondria in neurodegenerative diseases, and the epigenetics of drug dependence. In Latvia, the primary research areas include molecular, neuropharmacology, particularly search for novel medicines capable to halt neurodegenerative diseases as well as cardiovascular pharmacology. In Lithuania the main focus is on clinical pharmacology, rational use of drugs, pharmacoepidemiology and pharmacoeconomy, in experimental pharmacology on regenerative medicine and nephropharmacology. All three countries have their own active Societies of Pharmacology.

Previously, we have found that mildronate [3-(2,2,2-trimethylhydrazinium) propionate dihydrate], a small molecule with charged nitrogen and oxygen atoms, protects mitochondrial metabolism that is altered by inhibitors of complex I and has neuroprotective effects in an azidothymidine-neurotoxicity mouse model. In the present study, we investigated the effects of mildronate in a rat model of Parkinson’s disease (PD) that was generated via a unilateral intrastriatal injection of the neurotoxin 6-hydroxydopamine (6‑OHDA). We assessed the expression of cell biomarkers that are involved in signaling cascades and provide neural and glial integration: the neuronal marker TH (tyrosine hydroxylase); ubiquitin (a regulatory peptide involved in the ubiquitin-proteasome degradation system); Notch-3 (a marker of progenitor cells); IBA-1 (a marker of microglial cells); glial fibrillary acidic protein, GFAP (a marker of astrocytes); and inducible nitric oxide synthase, iNOS (a marker of inflammation). The data show that in the 6-OHDA-lesioned striatum, mildronate completely prevented the loss of TH, stimulated Notch-3 expression and decreased the expression of ubiquitin, GFAP and iNOS. These results provide evidence for the ability of mildronate to control the expression of an array of cellular proteins and, thus, impart multi-faceted homeostatic mechanisms in neurons and glial cells in a rat model of PD. We suggest that the use of mildronate provides a protective effect during the early stages of PD that can delay or halt the progression of this neurodegenerative disease.

Little is known about the endogenous functions of gamma1- and gamma2-melanocyte stimulating hormones (gamma1- and gamma2-MSH). Although gamma-MSHs bind to melanocortin receptor subtypes 3 and 4, we have previously shown that these peptides also influence non-melanocortinergic processes, such as dopaminergic and GABAergic. The aim of this study was to determine the effects of gamma1- and gamma2-MSH (at doses 0.3, 1 and 2 nmol/mouse/5 microl) on the anxiety levels in mice in elevated plus maze. Three experimental paradigms were performed to assess the effects of peptides on: a) ethanol withdrawal; b) acute ethanol-induced anxiolytic action; c) peptides per se. We used ethanol as the model substance, since its action involves either dopaminergic/GABAergic or melanocortinergic processes. gamma-MSHs were administered intracisternally in mice and behavioural responses were assessed in the elevated plus maze test. This study provides the first demonstration of an anxiogenic effect of gamma1- and gamma2-MSH, their synergistic/additive effect on ethanol withdrawal-induced anxiety behaviour, and an antagonism of peptides involved in the anxiolytic action of ethanol. Furthermore, results suggest that gamma-MSHs belong to an anxiogenic peptide family that may play an important role in anxiety disorders as well as in the development of alcohol dependence and/or alcohol withdrawal-induced behaviours.

By use of the brain microdialysis technique we show that administration of gamma(1)-melanocyte stimulating hormone (gamma(1)-MSH) into the ventral tegmental area of anaesthetized rats causes an increase in the release of extracellular dopamine and its metabolite 3,4-dihydroxyphenylacetic acid in the nucleus accumbens, while gamma(2)-MSH causes the opposite effect. Moreover, gamma(2)-MSH pre-treatment considerably reduced the gamma(1)-MSH-induced effects. Our findings suggest an opposing action of two gamma-MSH-activated pathways on the mesolimbic dopaminergic system, which could be important in the maintenance of a balanced psychoactivation state.