Disease-modifying therapies are needed for Fragile X Syndrome (FXS), as at present there are no effective treatments or cures. Herein, we report on a tetrahydroquinoline-based selective histone deacetylase 6 (HDAC6) inhibitor SW-100, its pharmacological and ADMET properties, and its ability to improve upon memory performance in a mouse model of FXS, Fmr1-/- mice. This small molecule demonstrates good brain penetrance, low-nanomolar potency for the inhibition of HDAC6 (IC50 = 2.3 nM), with at least a thousand-fold selectivity over all other class I, II, and IV HDAC isoforms. Moreover, through its inhibition of the α-tubulin deacetylase domain of HDAC6 (CD2), in cells SW-100 upregulates α-tubulin acetylation with no effect on histone acetylation and selectively restores the impaired acetylated α-tubulin levels in the hippocampus of Fmr1-/- mice. Lastly, SW-100 ameliorates several memory and learning impairments in Fmr1-/- mice, thus modeling the intellectual deficiencies associated with FXS, and hence providing a strong rationale for pursuing HDAC6-based therapies for the treatment of this rare disease.

• MeSH
• benzamidy farmakologie   MeSH
• chinoliny farmakologie   MeSH
• hipokampus účinky léků   metabolismus   MeSH
• histondeacetylasa 6 antagonisté a inhibitory   MeSH
• inhibitory histondeacetylas farmakologie   MeSH
• kognice účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• paměť účinky léků   MeSH
• posttranslační úpravy proteinů účinky léků   MeSH
• syndrom fragilního X enzymologie   patofyziologie   MeSH
• učení účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Acute methanol poisoning leads to optic neuropathy and necrotic lesions of basal ganglia (BG) and subcortical white matter. Survivors of methanol poisoning exhibit long-term executive and memory deficits. Associations between brain volumetry parameters and cognitive sequelae of methanol poisoning are not known. The aim of our study was to identify long-term associations between the cognitive performance of survivors of methanol poisoning and the volume of the brain structures that are selectively vulnerable to methanol. METHODS: We conducted a cross-sectional follow-up study on a sample of patients (n = 33, age 50 ± 14 years, 82% males) who survived acute methanol poisoning during methanol mass poisoning outbreak from September 2012 till January 2013 in the Czech Republic. A battery of neuropsychological tests and brain magnetic resonance imaging were included in the clinical examination protocol. Specific brain structures (putamen, globus pallidus, nucleus caudatus, and frontal white matter) were selected as regions of interest, and their volumes were estimated using the MorphoBox prototype software. RESULTS: In robust multiple regression models, sustained visual attention performance (as assessed by Trail Making Test and Prague Stroop Test) was positively associated with BG structures and frontal white matter volumes (Wald = 9.03 to 85.50, p < 0.01), sensitivity to interference (as assessed by Frontal Battery Assessment) was negatively associated with frontal white matter volume (Wald = 35.44 to 42.25, p < 0.001), and motor performance (as assessed by Finger Tapping Test) was positively associated with globus pallidus and frontal white matter volumes (Wald = 9.66 to 13.29, p < 0.01). CONCLUSIONS: Our results demonstrate that smaller volumes of elements of BG-thalamocortical circuitry, namely the BG and frontal white matter, relate to attention and motor performance in methanol poisoning from a long-term perspective. Disruption of those functional circuits may underlie specific cognitive deficits observed in methanol poisoning.

• MeSH
• bazální ganglia diagnostické zobrazování   MeSH
• bílá hmota diagnostické zobrazování   MeSH
• dospělí MeSH
• exekutivní funkce účinky léků   MeSH
• kognice účinky léků   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• methanol otrava   MeSH
• mozek diagnostické zobrazování   MeSH
• následné studie MeSH
• nervová síť diagnostické zobrazování   MeSH
• neuropsychologické testy MeSH
• paměť účinky léků   MeSH
• pozornost účinky léků   MeSH
• přežívající MeSH
• průřezové studie MeSH
• psychomotorický výkon účinky léků   MeSH
• senioři MeSH
• učení účinky léků   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

RATIONALE: Chronic quinpirole (QNP) sensitization is an established animal model relevant to obsessive-compulsive disorder (OCD) that has been previously shown to induce several OCD-like behavioral patterns, such as compulsive-like checking and increased locomotion. OBJECTIVES: In current study we explored the effect of antiglutamatergic drugs, memantine and riluzole, on cognitive and behavioral performance of QNP sensitized rats. METHODS: During habituation phase, the rats (N = 56) were injected with QNP (0.25 mg/kg) or saline solution (every other day up to 10 injections) and placed into rotating arena without foot shocks for 50-min exploration. Active place avoidance task in rotating arena with unmarked to-be-avoided shock sector was used during acquisition phase. Rats were injected with memantine (1 mg/kg or 5 mg/kg), riluzole (1 mg/kg or 5 mg/kg) or saline solution 30 min before the trial and with QNP (0.25 mg/kg) or saline right before they were placed inside the rotating arena with 60° unmarked shock sector. Locomotion and number of entrances into the shock sector were recorded. RESULTS: QNP sensitization led to a robust deficit in place learning. However, neither memantine nor riluzole did reverse or alleviate the deficit induced by QNP. Contrarily, memantine significantly aggravated QNP induced deficit. CONCLUSIONS: The exacerbation of cognitive deficit following antiglutamatergic agents could be mediated by decreased glutamate concentration in nucleus accumbens and decreased hippocampal activation in the QNP sensitization model.

• MeSH
• agonisté dopaminu farmakologie   MeSH
• antagonisté excitačních aminokyselin farmakologie   MeSH
• chinpyrol farmakologie   MeSH
• chování zvířat účinky léků   MeSH
• kognice účinky léků   MeSH
• krysa rodu rattus MeSH
• memantin farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• obsedantně kompulzivní porucha * MeSH
• pohybová aktivita účinky léků   MeSH
• potkani Long-Evans MeSH
• riluzol farmakologie   MeSH
• učení účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Oxidative stress is a phenomenon associated with imbalance between production of free radicals and reactive metabolites (e.g. superoxide and hydrogen peroxide) and the antioxidant defences. Oxidative stress in individuals with Down syndrome (DS) has been associated with trisomy of the 21st chromosome resulting in DS phenotype as well as with various morphological abnormalities, immune disorders, intellectual disability, premature aging and other biochemical abnormalities. Trisomy 21 in patients with DS results in increased activity of an important antioxidant enzyme Cu/Zn superoxide dismutase (SOD) which gene is located on the 21st chromosome along with other proteins such as transcription factor Ets-2, stress inducing factors (DSCR1) and precursor of beta-amyloid protein responsible for the formation of amyloid plaques in Alzheimer disease. Mentioned proteins are involved in the management of mitochondrial function, thereby promoting mitochondrial theory of aging also in people with DS. In defence against toxic effects of free radicals and their metabolites organism has built antioxidant defence systems. Their lack and reduced function increases oxidative stress resulting in disruption of the structure of important biomolecules, such as proteins, lipids and nucleic acids. This leads to their dysfunctions affecting pathophysiology of organs and the whole organism. This paper examines the impact of antioxidant interventions as well as positive effect of physical exercise on cognitive and learning disabilities of individuals with DS. Potential therapeutic targets on the molecular level (oxidative stress markers, gene for DYRK1A, neutrophic factor BDNF) after intervention of natural polyphenols are also discussed.

• MeSH
• antioxidancia terapeutické užití   MeSH
• cvičení MeSH
• Downův syndrom farmakoterapie   genetika   metabolismus   patofyziologie   psychologie   MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• kognice účinky léků   MeSH
• lidé MeSH
• mozek účinky léků   metabolismus   patofyziologie   MeSH
• oxidační stres účinky léků   MeSH
• učení účinky léků   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

DMSO has been many times described as harmless substance, beneficial in various diseases or pathological states, including brain injury or ischemia. Using Lurcher mutant mice suffering from genetically determined olivocerebellar degeneration and normal wild type mice, we examined the effect of DMSO on spontaneous motor activity and spatial learning and orientation ability. The acute effect of DMSO was studied in mice aged 3, 6, 9 and 22 weeks. DMSO treatment decreased spontaneous activity in the open field and swimming speed in the Morris water maze in both Lurcher mutant and wild type mice. While saline-treated Lurcher mice showed age-related decline of spatial memory in the Morris water maze in DMSO-treated ones such decline did not occur. The mechanism of the effect of DMSO remains unclear. A possible explanation could be modulation of the brain perfusion and metabolism in the aging brain. The improvement of learning ability could be also mediated by a tranquilizing effect of DMSO reducing stress-induced behavioral disinhibition which is supposed to interfere with learning process in Lurcher mutants. Future studies which would investigate DMSO effects in other models of neurodegenerative diseases are necessary to verify its potential therapeutic impact.

• MeSH
• bludiště - učení účinky léků   MeSH
• dimethylsulfoxid farmakologie   MeSH
• mozeček patologie   MeSH
• mutantní kmeny myší MeSH
• myši MeSH
• orientace účinky léků   MeSH
• pohybová aktivita účinky léků   MeSH
• rozpouštědla MeSH
• sexuální faktory MeSH
• učení účinky léků   MeSH
• věkové faktory MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

O systéme odmeny sa hovorí už od roku 1954. Jeho základom je dopamínergická projekcia ventrálnej tegmentálnej oblasti do ventrálneho striata, špecificky do nucleus accumbens. Po desaťročiach výskumu sa však prišlo na to, že dopamín nie je ani tak mediator slasti. ako neurotransmiter motivačnej relevancie. Nové alebo pre organizmus významné environmentálne podnety sú spojené s fázickým dopamínovým uvoľnením, ktoré je signálom pre ich ďalšie učenie. Ide o predikčně učenie, ktorého účelom je anticipovať výskyt environmentálneho podnetu spojeného s odmenou. Poruchy tohto predikčného a s odmenou súvisiaceho učenia možno sledovať v rôznych neuropsychiatrických stavoch. V rámci deficitu dopamínu v nigrostriatálnej dráhe pri Parkinsonovej chorobe je narušené najmä učenie sa z pozitívnej spätnej väzby, kým pri patologickom hráčstve je narušené učenie sa z negatívnej spätnej väzby. Patologické hráčstvo ako komplikácia dopamínergickej liečby Parkinsonovej choroby je špecifická situácia, v ktorej sa objavujú poruchy spätno-väzobného učenia.

The reward system is known since 1954. Its basis is the dopaminergic projection from the ventral tegmental area to the ventral striatum, specifically to the nucleus accumbens. After decades of research we can say, that dopamine is not so much a mediator of pl easure, but the neurotransmitter of motivational relevance. New or salient environmental stimuli are associated with phasic dopamine re lease, which is the signal for their further learning. This is a predictive learning, whose goal is to anticipate the occurrence of an environmen- tal stimulus associated with reward. Disorders of predictive and reward-related learning can be observed in a variety of neurop sychiatric conditions. In the relative absence of dopamine in the nigrostriatal pathway in Parkinson ́s disease, the learning from posi tive feedback is particularly impaired, while in pathological gambling, the learning from negative feedback is impaired. Pathological ga mbling as a complication of dopaminergic treatment of Parkinson ́s disease is a specific situation, in which errors in feedback learnin g occur.

• Klíčová slova
• systém odmeny, predikčné učenie, patologické hráčstvo,
• MeSH
• dopamin * aplikace a dávkování   nedostatek   sekrece   terapeutické užití   MeSH
• dopaminergní neurony MeSH
• hráčství chemicky indukované   patologie   MeSH
• klinické zkoušky jako téma MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• motivace fyziologie   účinky léků   MeSH
• nucleus accumbens fyziologie   MeSH
• odměna MeSH
• Parkinsonova nemoc * farmakoterapie   komplikace   patologie   terapie   MeSH
• učení fyziologie   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH

High doses of mGluR5 antagonists have anticonvulsant effects in multiple seizure models in both adult and immature animals. Data on potential behavioral effects in immature animals are very scarce. The present study investigated whether an antagonist of mGluR5 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) in doses proven to be anticonvulsant affects behavior in immature rats. Animals aged 12, 18 and 25 days received MTEP in doses of 20 and 40 mg/kg i. p. The sensorimotor performance was tested at 15 and 60 min after dosing. Locomotor-exploratory behavior was tested at 20 and 65 min after dosing. An elevated plus maze was used to examine an adaptive form of learning and anxiety-like behavior in 18- and 25-day-old rats at 15, 60 min and 24h. MTEP slightly affected sensorimotor performance, regardless of age. In the open field test, MTEP decreased transiently locomotor-exploratory behavior but did not affect the habituation - a simple form of nonassociative learning. In the elevated plus maze, the drug did not impair transfer latency, an indicator of an adaptive form of learning and memory. An anxiolytic-like effect was observed at 60 min after drug administration. In conclusion, no severe impairment was observed after high anticonvulsant doses of mGlu5 antagonist MTEP in immature animals.

• MeSH
• chování zvířat účinky léků   MeSH
• krysa rodu rattus MeSH
• motorické dovednosti účinky léků   MeSH
• paměť účinky léků   MeSH
• pátrací chování účinky léků   MeSH
• péče o zevnějšek u zvířat účinky léků   MeSH
• potkani Wistar MeSH
• psychomotorický výkon účinky léků   MeSH
• pyridiny farmakologie   MeSH
• receptory metabotropního glutamátu antagonisté a inhibitory   MeSH
• reflex účinky léků   MeSH
• stárnutí psychologie   MeSH
• thiazoly farmakologie   MeSH
• učení účinky léků   MeSH
• úzkost psychologie   MeSH
• vnímání prostoru účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Antagonists of group I metabotropic receptors exhibit anxiolytic action in adult rats. In immature animals we demonstrated anticonvulsant action of MPEP and AIDA, antagonists of group 5 and group 1, respectively. However, there are no developmental data on anxiolytic-like and learning actions of both compounds. This study investigated whether the anticonvulsant dose range of MPEP and AIDA affects anxiety-like behavior and learning ability in immature rats. Animals at 12, 18 and 25 postnatal (P) days received MPEP in doses of 10, 20 or 40 mg/kg i.p., AIDA in doses of 10 or 20 mg/kg i.p. In P18 and P25 rats anxiety-like behavior and locomotor activity were tested in the light-dark box and open-field test at 15 (1st session) and 60 (2nd session) minutes after drug administration. Learning ability of P12, P18, and P25 animals was examined in the homing response test 15 min after drug administration. Both antagonists exhibited anxiolytic-like action in the 1st session, effects in the 2nd session were less marked. In the open-field test both antagonists increased locomotion only in P18 animals. Age-dependent changes were found in the homing response test, the return latency being longer only in P12 animals. While MPEP in doses of 20- and 40-mg/kg in P12 and 40-mg/kg in P18 rats prolonged the homing response, AIDA did not affect the homing behavior. Both MPEP and AIDA exert anxiolytic-like effect also in immature rats. Except for the youngest animals no changes in learning ability in the homing response test were found.

• MeSH
• antagonisté excitačních aminokyselin aplikace a dávkování   farmakologie   MeSH
• anxiolytika aplikace a dávkování   farmakologie   MeSH
• časové faktory MeSH
• indany aplikace a dávkování   farmakologie   MeSH
• krysa rodu rattus MeSH
• náhodné rozdělení MeSH
• neuropsychologické testy MeSH
• pohybová aktivita účinky léků   MeSH
• potkani Wistar MeSH
• pyridiny aplikace a dávkování   farmakologie   MeSH
• receptory metabotropního glutamátu antagonisté a inhibitory   MeSH
• stárnutí MeSH
• učení účinky léků   MeSH
• úzkost farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

Černý trh s léky, jejichž užívání zlepšení funkce mozku, kvete na internetu. Mezi americkými studenty patří k hitům například Ritalin a Adderall. V některých kampusech se s jejich pomocí snažil domoci lepších studijních výsledků každý čtvrtý student.

• MeSH
• farmakologické účinky MeSH
• farmakoterapie MeSH
• fyziologické účinky léků MeSH
• lidé MeSH
• mozek - chemie účinky záření   MeSH
• učení účinky léků   MeSH
• výkonnost MeSH
• Check Tag
• lidé MeSH

Typical N-methyl-D-aspartate (NMDA) receptor antagonists exhibit anticonvulsant action and unwanted effects, even in developing rats. Therefore, we studied the actions of the low-affinity, noncompetitive antagonist memantine and the NR2B-specific antagonist ifenprodil. Seizures (minimal clonic and generalized tonic-clonic) were elicited with pentylenetetrazol (100mg/kg subcutaneously) in rats 7, 12, 18, and 25 days old pretreated with memantine (2.5-40 mg/kg intraperitoneally) or ifenprodil (10-60 mg/kg intraperitoneally). The effects of both drugs were studied in open field and motor performance tests in 12-, 18-, and 25-day-old rats. Memantine suppressed generalized tonic-clonic seizures in all age groups; minimal seizures were potentiated. Ifenprodil abolished the tonic phase of generalized tonic-clonic seizures in 7-, 12-, and 18-day-old rats only; minimal seizures remained untouched. Memantine induced locomotor hyperactivity and compromised motor performance in all age groups. Ifenprodil exerted these effects only in 12-day-old rats; older animals were less active in open field tests. Memantine exhibits both anti- and pro-convulsant and behavioral effects typical of NMDA antagonists. Ifenprodil exerted the same effects in 12-day-old rats, but its anticonvulsant action in 18-day-old rats was accompanied by a decrease in locomotion.

• MeSH
• antagonisté excitačních aminokyselin farmakologie   MeSH
• antikonvulziva farmakologie   MeSH
• chování zvířat účinky léků   MeSH
• epilepsie generalizovaná psychologie   MeSH
• financování organizované MeSH
• konvulziva antagonisté a inhibitory   farmakologie   MeSH
• krysa rodu rattus MeSH
• memantin farmakologie   MeSH
• orientace účinky léků   MeSH
• pentylentetrazol analogy a deriváty   farmakologie   MeSH
• piperidiny farmakologie   MeSH
• pohybová aktivita účinky léků   MeSH
• posturální rovnováha účinky léků   MeSH
• potkani Wistar MeSH
• psychomotorický výkon účinky léků   MeSH
• receptory N-methyl-D-aspartátu antagonisté a inhibitory   MeSH
• síla ruky fyziologie   MeSH
• učení účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• záchvaty farmakoterapie   psychologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH