Very low doses of muscimol and baclofen ameliorate cognitive deficits and regulate protein expression in the brain of a rat model of streptozocin-ind…

2018

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…

γ1- and γ2-melanocyte stimulating hormones induce central anxiogenic effects and potentiate ethanol withdrawal responses in the elevated plus-maze te…

2008

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 sub…

Neuroprotective action of diazepam at very low and moderate doses in Alzheimer's disease model rats

2018

Abstract 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 moder…

Opposite effects of γ1- and γ2-melanocyte stimulating hormone on regulation of the dopaminergic mesolimbic system in rats

2004

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.

GABA-containing compound gammapyrone protects against brain impairments in Alzheimer's disease model male rats and prevents mitochondrial dysfunction…

2018

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…

Mildronate enhances learning/memory and changes hippocampal protein expression in trained rats.

2013

Previously we demonstrated that mildronate [3-(2,2,2-trimethylhydrazinium) propionate dihydrate], a representative of the aza-butyrobetaine class of compounds, protects mitochondrial metabolism under conditions such as ischemia. Mildronate also acted as a neuroprotective agent in an azidothymidine-induced mouse model of neurotoxicity, as well as in a rat model of Parkinson's disease. These observations suggest that mildronate may stimulate processes involved in cell survival and change expression of proteins involved in neurogenic processes. The present study investigated the influence of mildronate on learning and memory in the passive avoidance response (PAR) test and the active condition…

Synthesis and studies of calcium channel blocking and antioxidant activities of novel 4-pyridinium and/or N-propargyl substituted 1,4-dihydropyridine…

2014

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 act…

A New Tool for the Analysis of the Effect of Intracerebrally Injected Anti-Amyloid-β Compounds

2021

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 wit…

Introductory letter from the Presidents of the Latvian, Estonian and Lithuanian Societies of Pharmacology.

2016

A Novel 1,4-Dihydropyridine Derivative Improves Spatial Learning and Memory and Modifies Brain Protein Expression in Wild Type and Transgenic APPSweD…

2015

Ca2+ blockers, particularly those capable of crossing the blood-brain barrier (BBB), have been suggested as a possible treatment or disease modifying agents for neurodegenerative disorders, e.g., Alzheimer's disease. The present study investigated the effects of a novel 4-(N-dodecyl) pyridinium group-containing 1,4-dihydropyridine derivative (AP-12) on cognition and synaptic protein expression in the brain. Treatment of AP-12 was investigated in wild type C57BL/6J mice and transgenic Alzheimer's disease model mice (Tg APPSweDI) using behavioral tests and immunohistochemistry, as well as mass spectrometry to assess the blood-brain barrier (BBB) penetration. The data demonstrated the ability …

Mildronate as a Regulator of Protein Expression in a Rat Model of Parkinson’s Disease

2011

Background. Mildronate (3-[2,2,2-trimethylhydrazinium] propionate dihydrate) traditionally is a well-known cardioprotective drug. However, our recent studies convincingly demonstrated its neuroprotective properties. The aim of the present study was to evaluate the influence of mildronate on the expression of proteins that are involved in the differentiation and survival of the nigrostriatal dopaminergic neurons in the rat model of Parkinson’s disease (PD). The following biomarkers were used: heat shock protein 70 (Hsp70, a molecular chaperone), glial cell line-derived nerve growth factor (GDNF, a growth factor promoting neuronal differentiation, regeneration, and survival), and neural cell …

Subchronic administration of auranofin reduced amyloid-β plaque pathology in a transgenic APPNL-G-F/NL-G-F mouse model

2020

Abstract 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 n…

Neuroprotective Properties of Mildronate, a Small Molecule, in a Rat Model of Parkinson’s Disease

2010

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); …

Pharmacology in Estonia, Latvia and Lithuania: From historical roots to nowadays achievements.

2016

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 de…

Neuroinflammation and acetylcholinesterase overexpression as the main targets for low doses of GABA-A receptor agonists in Alzheimer's disease rat mo…

2018

The Fundamental Role of Melanocortins in Brain Processes

2003

The discoveries of the latest ten years have shed new light in understanding the roles of melanocortins and their receptors in brain functions and in the development of different pathologies. Since 1992 when genes encoded melanocortin receptor five subtypes were identified, cloned and characterized, the molecular mechanisms underlying different effects such as skin darkening, behaviour, food intake, anti-inflammatory action, analgesia have been clarified. The contribution of melanocortins and their receptors in the physiological control of organism homeostasis has become as the background for the search of agonists and antagonists of separate receptor subtypes, that can be targeted to the m…

Improved method for cannula fixation for long-term intracerebral brain infusion

2017

Abstract 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 ap…

Identification of Abies sibirica L. Polyprenols and Characterisation of Polyprenol-Containing Liposomes

2020

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&ndash

Pilot study to evaluate the assessment methods of the basic pharmacology course at the Faculty of Medicine of the University of Latvia

2018

Mildronate improves cognition and reduces amyloid-β pathology in transgenic Alzheimer's disease mice

2013

Mildronate, a carnitine congener drug, previously has been shown to provide neuroprotection in an azidothymidine-induced mouse model of neurotoxicity and in a Parkinson's disease rat model. The aim of this study was to investigate the effects of mildronate treatment on cognition and pathology in Alzheimer's disease (AD) model mice (APP(SweDI)). Mildronate was administered i.p. daily at 50 or 100 mg/kg for 28 days. At the end of treatment, the animals were behaviorally and cognitively tested, and brains were assessed for AD-related pathology, inflammation, synaptic markers, and acetylcholinesterase (AChE). The data show that mildronate treatment significantly improved animal performance in w…

Intranasal Administration of Extracellular Vesicles Derived from Human Teeth Stem Cells Improves Motor Symptoms and Normalizes Tyrosine Hydroxylase E…

2018

Abstract 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-…

Pharmacological research on natural substances in Latvia: Focus on lunasin, betulin, polyprenol and phlorizin

2016

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 …

Memory-enhancing and brain protein expression-stimulating effects of novel calcium antagonist in Alzheimer’s disease transgenic female mice

2016

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/mem…

Expression of endogenous mouse APP modulates β-amyloid deposition in hAPP-transgenic mice

2017

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 …

Uzņēmējdarbības vide un Satversmes tiesa:Satversmes tiesas nolēmumu nozīme izcilas uzņēmējdarbības vides veidošanā Latvijā

2016

Maģistra darbā ‘‘Uzņēmējdarbības vide un Satversmes tiesa: Satversmes tiesas nolēmumu nozīme izcilas uzņēmējdarbības vides veidošanā Latvijā’’ sniegta uzņēmējdarbības vidi ietekmējošo faktoru analīze, to atspoguļojums politikas plānošanas dokumentos un normatīvajos aktos. Tāpat maģistra darbā analizēta Satversmes tiesas nozīme uzņēmējdarbības vides veidošanā, īpašu uzmanību pievēršot tās kompetencei un sprieduma nozīmei. Sīkāk maģistra darbā analizēti autores ieskatā nozīmīgākie Satversmes tiesas spriedumi lietās, kas ierosinātas pēc uzņēmēju pieteikumiem, un to ietekme uz uzņēmējdarbības vidi. Maģistra darba mērķis ir noskaidrot Satversmes tiesas spriedumu ietekmi uz uzņēmējdarbības vides …

Makašānu Salenieku kapulauks: apbedījumu veidi un hronoloģija

2018

Bakalaura darba mērķis ir izanalizēt Salenieku Makašānu kapulaukā esošās apbedīšanas tradīcijas, apbedījumus un kapu piedevas, kā arī precizēt kapulauka hronoloģiju. Pamatā darba izstrādē izmantoti pārskati par kapulaukā veiktajiem izrakumiem un to laikā iegūtā senlietu kolekcija. Darbā tiek apskatīti Salenieku Makašānu kapulaukā esošie dažādie apbedīšanas veidi. Pētīta izrakumos iegūtā informācija par uzkalniņos un akmeņu krāvumos atrastajiem kapiem. Lai precizētu kapulauka hronoloģiju tiek meklētas analoģijas Salenieku Makašānu kapulaukā atrastajām kapu piedevām.

"Bāriņtiesa kā bērna vislabāko interešu aizsargātāja"

2014

Bakalaura darbā ‘‘Bāriņtiesa kā bērna vislabāko interešu aizsargātāja’’ sniegta bāriņtiesas vēsturiskā attīstība, tās kompetence un funkcijas bērna tiesību aizsargāšanā, analizēts bāriņtiesas atzinums kā viens no tiesiskajiem instrumentiem, caur ko bāriņtiesa nodrošina bērna vislabākās intereses. Bakalaura darba mērķis ir noskaidrot tiesai sniegtā bāriņtiesas atzinuma ietekmi uz tiesas pieņemtajiem nolēmumiem lietās, kas izriet no aizgādības un saskarsmes tiesībām, un izzināt prakses problēmas, kas rodas no lietā esošā bāriņtiesas atzinuma. Bakalaura darba rezultātā secināts, ka praksē pastāv pretruna ar Civilprocesa likuma 97.pantu un vairumā gadījumu tiesas par galveno pierādījumu lietās,…

Grāmatvedības darba organizācija un analīze SIA "ABC"

2012

Bakalaura darbs “Grāmatvedības darba organizācija un analīze SIA”ABC”” tika izstrādāts, jo Latvijas uzņēmumos nepieciešami labi kvalificēti grāmatveži un grāmatvedības organizācija labākajā līmenī. Bez grāmatvedības organizācijas uzņēmums nespētu darboties un kontrolēt savas izmaksas un ieņēmumus, tāpēc autore izvērtēja grāmatvedības organizācijas politiku un analizēja SIA”ABC” grāmatvedības organizāciju. Bakalaura darba mērķis ir izpētīt informāciju, kas saistīta ar grāmatvedības darbu uzņēmumos, un analizēt konkrētā uzņēmuma (SIA „ABC”) grāmatvedības darbu un grāmatvedības organizāciju. Bakalaura darba uzdevums ir izvērtēt un analizēt grāmatvedības organizāciju saskaņā ar Latvijas Republi…