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Aging is closely related to the main aspects of multiple sclerosis (MS). The average age of the MS population is increasing and the number of elderly MS patients is expected to increase. In addition to neurons, N-methyl-D-aspartate receptors (NMDARs) are also expressed on non-neuronal cells, such as immune cells. The aim of this study was to investigate the role of NMDARs in experimental autoimmune encephalomyelitis (EAE) in young and aged rats. Memantine, a non-competitive NMDAR antagonist, was administered to young and aged Dark Agouti rats from day 7 after immunization. Antagonizing NMDARs had a more favourable effect on clinical disease, reactivation, and apoptosis of CD4+ T cells in the target organ of aged EAE rats. The expression of the fractalkine receptor CX3CR1 was increased in memantine-treated rats, but to a greater extent in aged rats. Additionally, memantine increased Nrf2 and Nrf2-regulated enzymes’ mRNA expression in brain tissue. The concentrations of superoxide anion radicals, malondialdehyde, and advanced oxidation protein products in brain tissue were consistent with previous results. Overall, our results suggest that NMDARs play a more important role in the pathogenesis of EAE in aged than in young rats.

Aging is closely related to the main aspects of multiple sclerosis (MS). The average age ofthe MS population is increasing and the number of elderly MS patients is expected to increase. Inaddition to neurons,N-methyl-D-aspartate receptors (NMDARs) are also expressed on non-neuronalcells, such as immune cells. The aim of this study was to investigate the role of NMDARs inexperimental autoimmune encephalomyelitis (EAE) in young and aged rats. Memantine, a non-competitive NMDAR antagonist, was administered to young and agedDark Agoutirats from day7 after immunization. Antagonizing NMDARs had a more favourable effect on clinical disease,reactivation, and apoptosis of CD4+T cells in the target organ of aged EAE rats. The expression ofthe fractalkine receptor CX3CR1 was increased in memantine-treated rats, but to a greater extent inaged rats. Additionally, memantine increased Nrf2 and Nrf2-regulated enzymes’ mRNA expressionin brain tissue. The concentrations of superoxide anion radicals, malondialdehyde, and advancedoxidation protein products in brain tissue were consistent with previous results. Overall, our resultssuggest that NMDARs play a more important role in the pathogenesis of EAE in aged than in young rats.

Uvod: Rukopis je složena veština koja može biti narušena u mnogim neurološkim i psihijatrijskim oboljenjima. Kinematička analiza rukopisa i motorna pravila su objektivan metod u proceni rukopisa. Cilj: Cilj ovog istraživanja bila je analiza rukopisa u deficitu pažnje sa hiperaktivnošću (ADHD), multiploj sklerozi kod dece i adolescenata (PedMS), depresiji major kod dece i adolescenata (PedMDD) i poređenje sa zdravim kontrolama u cilju procene narušenja fine motorike i uticaja farmakoterapije. Procenjivan je i uticaj dominantne ruke na rukopis kod zdravih. Metode istraživanja: Korišćena je digitalna tabla za pisanje koja registruje kinematičke parametre rukopisa i analizirane su i upoređivane eksperimentalne grupe ispitanika sa ADHD, PedMS i PedMDD sa zdravim kontrolama. Takođe su upoređivani levoruki i desnoruki zdravi ispitanici. Rezultati: Pokazano je kinematičko narušenje rukopisa u eksperimentalnim grupama koje je posledica: narušenja fine motorike, pažnje i anticipacije greške u ADHD, subkliničkog neurološkog i kognitivnog oštećenja u PedMS, psihomotornog usporenja u PedMDD. Farmakoterapija ima uticaja na kinematiku rukopisa u navedenim grupama. Dominantna ruka utiče zanemarljivo na kinematiku rukopisa i to pre svega usled biomehaničkih razlika. Nije pokazano odstupanje od motornih pravila u ispitivanim grupama. Zaključak: Kinematička analiza rukopisa može biti objektivan i senzitivan metod u kliničkim studijama u dečjoj populaciji. Ovom metodom moguće je detektovati subkliničke neurološke i kognitivne poteškoće u ADHD, PedMS i PedMDD kao i uticaj farmakoterapije na iste. Ruka kojom se piše nije od velikog uticaja na kinematiku rukopisa., psychiatric disorders. Kinematic analysis of handwriting and motor rules are an objective method in the evaluation of handwriting. Aim: The aim of this study was to analyze handwriting in attention deficit/hyperactivity disorder (ADHD), multiple sclerosis in childhood and adolescence (PedMS), major depression in childhood and adolescence (PedMDD) and to compare it with healthy controls to assess fine motor impairment and the effects of pharmacotherapy. The influence of the dominant hand on the handwriting in healthy people was also assessed. Method: A digital writing board which register kinematic parameters of handwriting was used and experimental groups of subjects with ADHD, PedMS and PedMDD with healthy controls were analyzed and compared. Left-handed and right-handed healthy subjects were also compared. Results: Kinematic impairment of handwriting in experimental groups has been shown as a consequence of: impaired fine motor skills, attention and anticipation of error in ADHD, subclinical neurological and cognitive impairment in PedMS, psychomotor retardation in PedMDD. Pharmacotherapy has an impact on the kinematics of handwriting in these groups. The dominant hand has a negligible effect on the kinematics of the handwriting, primarily due to biomechanical differences. No deviation from motor rules was shown in the examined groups. Conclusion: Kinematic analysis of handwriting could be an objective and sensitive method in clinical studies in the pediatric population. With this method, it is possible to detect subclinical neurological and cognitive difficulties in ADHD, PedMS and PedMDD, as well as the influence of pharmacotherapy on them. The dominant hand has a minor influence on the kinematics of the handwriting.

Ibogain, primenjen u jediničnoj oralnoj dozi (1-25 mg/kg telesne mase (t.m)) se koristi kao agens u sprečavanju različitih oblika zavisnosti kod ljudi. Njegovi efekti traju i do 72 h. Ex vivo rezultati pokazuju da ibogain izaziva potrošnju energije u ćelijama i njenu restituciju, što je praćeno povećanjem stvaranja reaktivnih vrsta kiseonika i aktivnosti antioksidativne odbrane. Stoga je cilj ovog rada bio da istraži efekte jedinične oralne doze ibogaina (1 ili 20 mg/kg t.m.) na antioksidativnu odbranu u različitim tkivima pacova. Posle 6 i 24 h nakon ingestije ibogaina, histološka ispitivanja su pokazala pojačanu glikogenolitičku aktivnost hepatocita, koja je bila najviša posle 24 h kod životinja koje su primile 20 mg/kg ibogaina. Nije bilo promena u aktivnosti antioksidativnih enzimani u jetri ni u eritrocitima u tim periodima što ukazuje na izostanak sistemskog efekta na nivou oksidativnog pritiska. U jetri se povećala aktivnost ksantin oksidaze kod pacova koji su primili ibogain u dozi od 20 mg/kg u poređenju sa kontrolama što ukazuje na brži obrt adenozina. Nivo TBARS u jetri je povišen kod grupe tretirane sa 1 mg/kg posle 24 h u poređenju sa kontrolama što sugeriše postojanje umerenog oksidativnog stresa. U srcu je utvrđeno da ibogain nakon 6 h smanjuje količinu proteinskih -SH grupa što ukazuje na unutar-proteinsku oksidaciju, koja zajedno sa narušenom energetskom homeostazom može dovesti do promena u srčanom radu i nastanka diskretnih oštećenja. Ibogain inhibira ex vivo kontraktilnost ileuma u nivou doza ispod mM, pri čemu je efekat kod električne stimulacije, u odnosu na toničnu, značajno veći. Rezultati pretretmana na ileumu ex vivo ukazuju da ibogain svoje dejstvo ostvaruje delimično preko KATP kanala. Ibogain izaziva u ileumu ex vivo povećanje aktivnosti superoksid dismutaze (SOD) i katalaze (KAT), ali se ti efekti gube dodavanjem glibenklamida..., Ibogaine, administered as a single oral dose (1-25 mg/kg body weight, (b.w.)), has been used as an addiction-interrupting agent. Its effects persist for up to 72 h. Ex vivo results showed that ibogaine induced cellular energy consumption and restitution, followed by increased reactive oxygen species production and antioxidant activity. Therefore, the aim of this work was to explore the effect of a single oral dose of ibogaine (1 or 20 mg/kg b.w.) on antioxidative defenses in different rat tissues. Six and 24 h after ibogaine administration, histological examination showed glycogenolytic activity in hepatocytes, which was highest after 24 h in animals that received 20 mg/kg ibogaine. There were no changes in the activities of antioxidant enzymes in the liver and erythrocytes after ibogaine treatment, regardless of the dose. These results suggest there were no systemic ibogaine effects regarding antioxidant defense. Hepatic xanthine oxidase activity was elevated in rats that received 20 mg/kg compared to the controls, suggesting faster adenosine turnover. TBARS concentration was elevated in the group treated with 1 mg/kg after 24 h compared to the controls, suggesting mild oxidative stress. It was shown that ibogaine in heart after 6 h diminished the amount of protein -SH groups suggesting intra-protein oxidation, which along disturbed energetic homeostasis could lead to discrete cellular oxidative damages and possible heart failure. Ibogaine inhibited ex vivo ileum contractile activity with doses below mM. The effect was stronger in electrically stimulated contractions than tonic. Pretreatment with different potassium channel related agents showed that ibogaine obtained its inhibitory activity partially through KATP channels...

It has been shown in electrophysiological studies that the ligand L-655,708 possesses a binding selectivity and a moderate inverse agonist functional selectivity for α5-containing GABA-A receptors. The present study is aimed to investigate the antidepressant effects of the ligand L-655,708 in the forced swim test (FST) and its impact on locomotor activity in rats. The behavior of the animals was recorded with a digital camera, and the data were analyzed by one-way ANOVA, followed by Dunnett’s test. In FST, L-655,708 significantly decreased immobility time at a dose of 3 mg/kg after a single and repeated administration (p<0.05), exerting acute and chronic antidepressant effects. However, it did not induce significant differences in the time of struggling behavior during FST. Furthermore, L-655,708 did not show a significant effect on locomotor activity (p>0.05). These data suggest that negative modulation at GABA-A receptors containing the α5 subunit may produce antidepressant effects in rats. These effects were not confounded by locomotor influences., U elektrofi ziološkim ispitivanjima pokazano je da ligand L-655,708 poseduje selektivnost u vezivanju i umerenu inverznu agonističku aktivnost za GABA-A receptore koji sadrže α5 podjedinicu. Ova studija ima za cilj ispitivanje antidepresivnih efekata liganda L-655,708 u testu forsiranog plivanja (FST) i njegov uticaj na lokomotornu aktivnost kod pacova. Ponašanje životinja je praćeno pomoću digitalne kamere, a podaci su analizirani primenom jednostepene analize varijanse (ANOVA) i Dunett-ovim testom. U testu forsiranog plivanja L-655,708 statistički značajno smanjuje vreme imobilnosti pri dozi od 3 mg/kg, nakon jednokratne i ponavljane primene (p0,05). Ovi podaci ukazuju da negativna modulacija GABA-A receptora koji sadrže α5 podjedinicu može ispoljiti antidepresivne efekte kod pacova. Ovi efekti su bez izraženih lokomotornih uticaja.

GABA (γ-aminobuterna kiselina) predstavlja glavni inhibitorni neurotransmiter centralnog nervnog sistema i većinu svojih inhibitornih efekata ostvaruje putem jonotropnih GABA-A receptora. Receptori koji sadrže α1, α2, α3, ili α5 subjedinicu, u kombinaciji sa γ2 i nekom od β subjedinica, predstavljaju dominantnu frakciju GABA-A receptora S obzirom na svoju kompleksnu strukturu, GABA-A receptori su označeni u ovom radu kao GABAA-BDZ-Cl receptorski kompleks. GABA-ergička sinapsa je mesto delovanja nekoliko različitih klasa lekova koji moduliraju inhibitornu neurotransmisiju i koriste se u farmakoterapiji anksioznih poremećaja, poremećaja sna, epilepsije, obustave alkohola, kao i za uvođenje i održavanje anestezije. Nedavno je utvrđeno da lekovi sa antidepresivnim efektima i stabilizatori raspoloženja u značajnoj meri utiču i na GABA-ergičku transmisiju, a da promene u inhibitornoj neurotransmisiji mogu imati ključnu ulogu u patofiziologiji depresije. Ova hipoteza je potkrepljena i klinčkim nalazima u kojima je utvrđen redukovan nivo GABA-e u korteksu pacijenata koji boluju od depresije, a koji se normalizuje nakon terapije antidepresivima. Benzodiazepini (BDZ), kao najčešće propisivani psihofarmaci, deluju kao pozitivni modulatori GABA-ergičke neurotransmisije i agonisti specifičnih BDZ receptora. Međutim, istraživanja lokalizacije i funkcionisanja BDZ receptora su pokazala postojanje nove, drugačije klase supstanci koje deluju na nivou ovih receptora ali kao negativni modulatori, odnosno inverzni agonisti. Naime, pokazano je postojanje supstanci, najčešće iz klase β-karbolina, koji stimulišu BDZ receptor, ali u suprotnom smislu od BDZ. Dok BDZ pokazuju anksiolitičke i amnezijske efekte, od inverznih agonista se očekuje da pokažu drugačije bihejvioralne efekte, anksiogene i potencijalno promnestičke efekte, odnosno uticaj na kogniciju i motivaciju. S jedne strane, genetska istraživanja, uz korišćenje modifikovanih linija životinja, ukazuju na korelaciju između poremeća, GABA (γ - aminobutyric acid) is the major inhibitory neurotransmitter of central nervous system and mo st of its inhibitory effects achieve through ionotorpic GABA - A receptors. Receptors containing α1, α2, α3, or α5 subunit, in combination with γ2 and one of the β subunits, represent the dominant fraction of GABA - A receptors Due to its complex structure, GA BA - A receptors have been identifi ed in this paper as a GABA A - BDZ - Cl receptor complex. GABA - ergic synapse is the site of action of several different classes of drugs that modulate inhibitory neurotransmission and are used in the pharmacotherapy of anxiety d isorders, sleep disorders, epilepsy, alcohol cessation, and for the introduction and maintenance of anesthesia. It is increasingly recognized that drugs with antidepressant/mood - stabilizing effects profoundly alter GABAergic transmission, and that changes in inhbititory neurotransmission may play a key role in the pathophysiology of depression. This hypothesis is supported by clinical findings demonstrating reductions in cortical GABA levels in patients suffering with depression, which are restored to norma l levels with antidepressant treatment. Benzodiazepines (BDZ), as the most c ommonly prescribed p sycho tropic drugs , act as positive modulators of GABA - ergic neurotransmission and specific BDZ receptor agonists. However, studies of localization and function ing of BDZ receptor have shown the existence of a new, different classes of substances that act at the level of the receptor but as negative modulators, or inverse agonists. Namely, it has been shown the existence of substances, mos tly from the class β - car bolins, that stimulate BDZ receptor, but in the opposite sense of BDZ. While BDZ show anxiolytic and amnesic effects, inverse agonists are expected to show different behavio u ral effects, and potentially anxiogenic and promnesic effects, i.e. effects on cog nition and motivation. On the one hand, genetic research, using modified

Benzodiazepine (BZ) site ligands affect vigilance, anxiety, memory processes, muscle tone and epileptogenic propensity through modulation of neurotransmission at GABA(A) receptors containing alpha 1, alpha 2, alpha 3 or alpha 5 subunits, and may have numerous experimental and clinical applications. The ability of non-selective BZ site inverse agonists to enhance cognition, documented in animal models and human studies, is clinically not feasible due to potentially unacceptable psychomotor effects. Most investigations to date have proposed the alpha 1 and/or alpha 5 subunit-containing GABA(A) receptors as comprising the memory-modulating population of these receptors. The novel ligand PWZ-029, which we synthesized and characterized electrophysiologically, possesses in vitro binding selectivity and moderate inverse agonist functional selectivity at alpha 5-containing GABA(A) receptors. This ligand has also been examined in rats in the passive and active avoidance, spontaneous locomotor activity, elevated plus maze and grip strength tests, primarily predictive of the effects on the memory acquisition, basal locomotor activity, anxiety level and muscle tone, respectively. The improvement of task learning was detected at the dose of 5 mg/kg in the passive, but not active avoidance test. The inverse agonist PWZ-029 had no effect on anxiety or muscle tone, whereas at higher doses (10 and 20 mg/kg) it decreased locomotor activity. This effect was antagonized by flumazenil. and also by the lower (but not the higher) dose of an agonist (SH-053-R-CH3-2'F) selective for GABA(A) receptors containing the alpha 5 subunit. The hypolocomotor effect of PWZ-029 was not antagonized by the antagonist beta-CCt exhibiting a preferential affinity for alpha 1-subunit-containing receptors. These data suggest that moderate negative modulation at GABA(A) receptors containing the alpha 5 subunit is a sufficient condition for eliciting enhanced encoding/consolidation of declarative memory, while