RESUMO
Induction of neuroprotective heat-shock proteins via pharmacological Hsp90 inhibitors is currently being investigated as a potential treatment for neurodegenerative diseases. Two major hurdles for therapeutic use of Hsp90 inhibitors are systemic toxicity and limited central nervous system permeability. We demonstrate here that chronic treatment with a proprietary Hsp90 inhibitor compound (OS47720) not only elicits a heat-shock-like response but also offers synaptic protection in symptomatic Tg2576 mice, a model of Alzheimer's disease, without noticeable systemic toxicity. Despite a short half-life of OS47720 in mouse brain, a single intraperitoneal injection induces rapid and long-lasting (>3 days) nuclear activation of the heat-shock factor, HSF1. Mechanistic study indicates that the remedial effects of OS47720 depend upon HSF1 activation and the subsequent HSF1-mediated transcriptional events on synaptic genes. Taken together, this work reveals a novel role of HSF1 in synaptic function and memory, which likely occurs through modulation of the synaptic transcriptome.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Doença de Alzheimer/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Proteínas de Choque Térmico HSP90/metabolismo , Fatores de Transcrição de Choque Térmico , Humanos , Memória/fisiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/terapia , Camundongos , Camundongos Transgênicos , Fatores de Transcrição/genéticaRESUMO
The GM2 gangliosidoses, Tay-Sachs and Sandhoff diseases, are caused by mutations in the HEXA (alpha-subunit) and HEXB (beta-subunit) genes, respectively. Each gene encodes a subunit for the heterodimeric lysosomal enzyme, beta-hexosaminidase A (alpha beta), as well as for the homodimers beta-hexosaminidase B (beta beta) and S (alpha alpha). In this study, we have produced mice that have both Hexa and Hexb genes disrupted through interbreeding Tay-Sachs (Hexa-/-) and Sandhoff (Hexb-/-) disease model mice. Lacking both the alpha and beta-subunits these 'double knockout' mice displayed a total deficiency of all forms of lysosomal beta-hexosaminidase including the small amount of beta-hexosaminidase S present in the Sandhoff disease model mice. More surprisingly, these mice showed the phenotypic, pathologic and biochemical features of the mucopolysaccharidoses, lysosomal storage diseases caused by the accumulation of glycosaminoglycans. The mucopolysaccharidosis phenotype is not seen in the Tay-Sachs or Sandhoff disease model mice or in the corresponding human patients. This result demonstrates that glycosaminoglycans are crucial substrates for beta-hexosaminidase and that their lack of storage in Tay-Sachs and Sandhoff diseases is due to functional redundancy in the beta-hexosaminidase enzyme system.
Assuntos
Gangliosidoses/genética , Lisossomos/enzimologia , Camundongos Knockout , Mucopolissacaridoses/genética , beta-N-Acetil-Hexosaminidases/genética , Animais , Comportamento Animal , Encéfalo/patologia , Cromatografia em Camada Fina , Modelos Animais de Doenças , Feminino , Fibroblastos/metabolismo , Gangliosídeos/metabolismo , Glicosaminoglicanos/metabolismo , Glicosaminoglicanos/urina , Hexosaminidase A , Hexosaminidase B , Humanos , Isoenzimas , Fígado/enzimologia , Masculino , Camundongos , Esfingolipídeos/química , Esfingolipídeos/metabolismo , Baço/patologiaRESUMO
Tay-Sachs and Sandhoff diseases are clinically similar neurodegenerative disorders. These two sphingolipidoses are characterized by a heritable absence of beta-hexosaminidase A resulting in defective GM2 ganglioside degradation. Through disruption of the Hexa and Hexb genes in embryonic stem cells, we have established mouse models corresponding to each disease. Unlike the two human disorders, the two mouse models show very different neurologic phenotypes. Although exhibiting biochemical and pathologic features of the disease, the Tay-Sachs model showed no neurological abnormalities. In contrast, the Sandhoff model was severely affected. The phenotypic difference between the two mouse models is the result of differences in the ganglioside degradation pathway between mice and humans.
Assuntos
Encéfalo/patologia , Gangliosídeos/metabolismo , Neurônios/patologia , Doença de Sandhoff/genética , Medula Espinal/patologia , Doença de Tay-Sachs/genética , beta-N-Acetil-Hexosaminidases/deficiência , beta-N-Acetil-Hexosaminidases/genética , Animais , Encéfalo/fisiopatologia , Sequência de Carboidratos , Modelos Animais de Doenças , Hexosaminidase A , Hexosaminidase B , Humanos , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Neurônios/metabolismo , Fenótipo , Mapeamento por Restrição , Doença de Sandhoff/metabolismo , Doença de Sandhoff/patologia , Medula Espinal/metabolismo , Células-Tronco/fisiologia , Doença de Tay-Sachs/metabolismo , Doença de Tay-Sachs/patologiaRESUMO
The present study investigated the relationships among oxidative stress, beta-amyloid and cognitive abilities in the APP/PSEN1 double-transgenic mouse model of Alzheimer's disease. In two experiments, long-term dietary supplements were given to aged APP/PSEN1 mice containing vitamin C alone (1 g/kg diet; Experiment 1) or in combination with a high (750 IU/kg diet, Experiments 1 and 2) or lower (400 IU/kg diet, Experiment 2) dose of vitamin E. Oxidative stress, measured by F(4)-neuroprostanes or malondialdehyde, was elevated in cortex of control-fed APP/PSEN1 mice and reduced to wild-type levels by vitamin supplementation. High-dose vitamin E with C was less effective at reducing oxidative stress than vitamin C alone or the low vitamin E+C diet combination. The high-dose combination also impaired water maze performance in mice of both genotypes. In Experiment 2, the lower vitamin E+C treatment attenuated spatial memory deficits in APP/PSEN1 mice and improved performance in wild-type mice in the water maze. Amyloid deposition was not reduced by antioxidant supplementation in either experiment.
Assuntos
Doença de Alzheimer/metabolismo , Antioxidantes/administração & dosagem , Memória , Estresse Oxidativo , Envelhecimento , Precursor de Proteína beta-Amiloide/deficiência , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Antioxidantes/efeitos adversos , Antioxidantes/análise , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/efeitos adversos , Ácido Ascórbico/análise , Comportamento Animal/fisiologia , Química Encefálica , Cognição , Dieta , Modelos Animais de Doenças , Feminino , Fígado/química , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/metabolismo , Presenilina-1/deficiência , Presenilina-1/genética , Presenilina-1/fisiologia , Vitamina E/administração & dosagem , Vitamina E/efeitos adversos , Vitamina E/análiseRESUMO
Mice co-expressing the Swedish amyloid precursor protein mutation (APP(Swe)) and exon 9 deletion (DeltaE9) of the PSEN1 gene begin to develop amyloid plaques at 6-7 months of age. We demonstrate here a spatial learning deficit in 7-month-old APP(Swe) + PSEN1DeltaE9 bigenic mice using an adaptation of the Barnes maze. Mice were first trained on a cued target followed by a hidden-target condition. Although bigenic mice quickly learned the cued-target version of the task, they were significantly impaired when switched to the hidden-target version. In contrast, a separate group of double-transgenic mice trained first on the spatial hidden-target version of the task were unimpaired relative to wild-type controls. We propose that processes such as general rule learning, context learning and exploratory habituation exert a greater influence when the testing environment is novel and overshadow the spatial memory deficit in naive bigenic mice. However, when cued-target training is conducted first, these processes habituate and the spatial learning deficit is unmasked. Seven-month-old APP(Swe) + PSEN1DeltaE9 mice were unimpaired on tests of memory that did not involve learning the rules governing spatial associations.
Assuntos
Doença de Alzheimer/metabolismo , Ansiedade/metabolismo , Aprendizagem em Labirinto/fisiologia , Presenilina-1/metabolismo , Comportamento Espacial/fisiologia , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ansiedade/genética , Encéfalo/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Deleção de Genes , Masculino , Camundongos , Camundongos Mutantes Neurológicos , Camundongos Transgênicos , Presenilina-1/genética , Percepção Espacial/fisiologiaRESUMO
Cholinergic neurons elaborate a hemicholinium-3 (HC-3) sensitive choline transporter (CHT) that mediates presynaptic, high-affinity choline uptake (HACU) in support of acetylcholine (ACh) synthesis and release. Homozygous deletion of CHT (-/-) is lethal shortly after birth (Ferguson et al. 2004), consistent with CHT as an essential component of cholinergic signaling, but precluding functional analyses of CHT contributions in adult animals. In contrast, CHT+/- mice are viable, fertile and display normal levels of synaptosomal HACU, yet demonstrate reduced CHT protein and increased sensitivity to HC-3, suggestive of underlying cholinergic hypofunction. We find that CHT+/- mice are equivalent to CHT+/+ siblings on measures of motor co-ordination (rotarod), general activity (open field), anxiety (elevated plus maze, light/dark paradigms) and spatial learning and memory (Morris water maze). However, CHT+/- mice display impaired performance as a result of physical challenge in the treadmill paradigm, as well as reduced sensitivity to challenge with the muscarinic receptor antagonist scopolamine in the open field paradigm. These behavioral alterations are accompanied by significantly reduced brain ACh levels, elevated choline levels and brain region-specific decreased expression of M1 and M2 muscarinic acetylcholine receptors. Our studies suggest that CHT hemizygosity results in adequate baseline ACh stores, sufficient to sustain many phenotypes, but normal sensitivities to physical and/or pharmacological challenge require full cholinergic signaling capacity.
Assuntos
Acetilcolina/metabolismo , Comportamento Exploratório/fisiologia , Proteínas de Membrana Transportadoras/fisiologia , Atividade Motora/fisiologia , Receptores Muscarínicos/metabolismo , Comportamento Espacial/fisiologia , Animais , Ansiedade/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Colinérgicos/farmacologia , Hemicolínio 3/farmacologia , Heterozigoto , Aprendizagem em Labirinto/fisiologia , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Muscarínicos/efeitos dos fármacos , Teste de Desempenho do Rota-Rod , Escopolamina/farmacologiaRESUMO
Inherited defects in the degradation of glycosphingolipids (GSLs) cause a group of severe diseases known as GSL storage disorders. There are currently no effective treatments for the majority of these disorders. We have explored a new treatment paradigm, substrate deprivation therapy, by constructing a genetic model in mice. Sandhoff's disease mice, which abnormally accumulate GSLs, were bred with mice that were blocked in their synthesis of GSLs. The mice with simultaneous defects in GSL synthesis and degradation no longer accumulated GSLs, had improved neurologic function, and had a much longer life span. However, these mice eventually developed a late-onset neurologic disease because of accumulation of another class of substrate, oligosaccharides. The results support the validity of the substrate deprivation therapy and also highlight some limitations.
Assuntos
Glicoesfingolipídeos/metabolismo , Modelos Genéticos , N-Acetilgalactosaminiltransferases/fisiologia , Doença de Sandhoff/terapia , beta-N-Acetil-Hexosaminidases/fisiologia , Animais , Comportamento Animal , Modelos Animais de Doenças , Feminino , Glicolipídeos/metabolismo , Masculino , Camundongos , Camundongos Knockout , N-Acetilgalactosaminiltransferases/genética , Oligossacarídeos/metabolismo , Projetos de Pesquisa , Doença de Sandhoff/genética , Doença de Sandhoff/metabolismo , Especificidade por Substrato , beta-N-Acetil-Hexosaminidases/genética , Polipeptídeo N-AcetilgalactosaminiltransferaseRESUMO
The GM2 gangliosidoses are a group of severe, neurodegenerative conditions that include Tay-Sachs disease, Sandhoff disease, and the GM2 activator deficiency. Bone marrow transplantation (BMT) was examined as a potential treatment for these disorders using a Sandhoff disease mouse model. BMT extended the life span of these mice from approximately 4.5 mo to up to 8 mo and slowed their neurologic deterioration. BMT also corrected biochemical deficiencies in somatic tissues as indicated by decreased excretion of urinary oligosaccharides, and lower glycolipid storage and increased levels of beta-hexosaminidase activity in visceral organs. Even with neurologic improvement, neither clear reduction of brain glycolipid storage nor improvement in neuronal pathology could be detected, suggesting a complex pathogenic mechanism. Histological analysis revealed beta-hexosaminidase-positive cells in the central nervous system and visceral organs with a concomitant reduction of colloidal iron-positive macrophages. These results may be important for the design of treatment approaches for the GM2 gangliosidoses.
Assuntos
Transplante de Medula Óssea , Doença de Sandhoff/terapia , beta-N-Acetil-Hexosaminidases/deficiência , Animais , Comportamento Animal , Química Encefálica , Córtex Cerebral/patologia , Modelos Animais de Doenças , Glicolipídeos/análise , Longevidade , Camundongos , Camundongos Mutantes , Oligossacarídeos/urina , Doença de Sandhoff/mortalidade , Análise de Sobrevida , beta-N-Acetil-Hexosaminidases/genéticaRESUMO
Parkinson's disease is a debilitating neurodegenerative condition for which there is no cure. Converging evidence implicates gangliosides in the pathogenesis of several neurodegenerative diseases, suggesting a potential new class of therapeutic targets. We have shown that interventions that simultaneously increase the neuroprotective GM1 ganglioside and decrease the pro-apoptotic GD3 ganglioside - such as inhibition of GD3 synthase (GD3S) or administration of sialidase - are neuroprotective in vitro and in a number of preclinical models. In this study, we investigated the effects of GD3S deletion on parkinsonism induced by 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP was administered to GD3S-/- mice or controls using a subchronic regimen consisting of three series of low-dose injections (11 mg/kg/day × 5 days each, 3 weeks apart), and motor function was assessed after each. The typical battery of tests used to assess parkinsonism failed to detect deficits in MPTP-treated mice. More sensitive measures - such as the force-plate actimeter and treadmill gait parameters - detected subtle effects of MPTP, some of which were absent in mice lacking GD3S. In wild-type mice, MPTP destroyed 53% of the tyrosine-hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc) and reduced striatal dopamine 60.7%. In contrast, lesion size was only 22.5% in GD3S-/- mice and striatal dopamine was reduced by 37.2%. Stereological counts of Nissl-positive SNc neurons that did not express TH suggest that neuroprotection was complete but TH expression was suppressed in some cells. These results show that inhibition of GD3S has neuroprotective properties in the MPTP model and may warrant further investigation as a therapeutic target.
Assuntos
Deleção de Genes , Intoxicação por MPTP/genética , Sialiltransferases/genética , Animais , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Locomoção , Camundongos , Camundongos Endogâmicos C57BL , Substância Negra/metabolismo , Substância Negra/patologia , Substância Negra/fisiopatologiaRESUMO
Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed childhood psychiatric disorder. We have found that a transgenic mouse bearing a human mutant thyroid receptor (TRbeta1) expresses all of the defining symptoms of ADHD--inattention, hyperactivity, and impulsivity--as well as a 'paradoxical' response to methylphenidate (MPH). As with ADHD, the behavioral phenotypes expressed by the TRbeta transgenic mice are dynamic and sensitive to changes in environmental conditions, stress, and reinforcement. TRbeta transgenic mice are euthyroid except for a brief period during postnatal development, but the behavioral phenotypes, elevated dopamine turnover, and paradoxical response to MPH persist into adulthood. Thus, like the vast majority of children with ADHD, the TRbeta transgenic mice exhibit the symptoms of ADHD in the complete absence of thyroid abnormalities. This suggests that even transient perturbations in developmental thyroid homeostasis can have long-lasting behavioral and cognitive consequences, including producing the full spectrum of symptoms of ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Atenção/fisiologia , Hipercinese/genética , Comportamento Impulsivo/genética , Receptores beta dos Hormônios Tireóideos/genética , Fatores Etários , Análise de Variância , Animais , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Genes erbA/genética , Predisposição Genética para Doença , Humanos , Comportamento Impulsivo/metabolismo , Masculino , Metilfenidato/farmacologia , Camundongos , Camundongos Transgênicos , Mutação , Receptores beta dos Hormônios Tireóideos/metabolismo , Síndrome da Resistência aos Hormônios Tireóideos/complicações , Síndrome da Resistência aos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/metabolismo , Transgenes/genéticaRESUMO
The study of anxiety and fear involves complex interrelationships between psychiatry and the autonomic nervous system. Altered noradrenergic signaling is linked to certain types of depression and anxiety disorders, and treatment often includes specific transporter blockade. The norepinephrine transporter is crucial in limiting catecholaminergic signaling. Norepinephrine transporter-deficient mice have increased circulating catecholamines and elevated heart rate and blood pressure. We hypothesized, therefore, that reduced norepinephrine clearance would heighten the autonomic cardiovascular response to anxiety and fear. In separate experiments, norepinephrine transporter-deficient (norepinephrine transporter-/-) mice underwent tactile startle and trace fear conditioning to measure hemodynamic responses. A dramatic tachycardia was observed in norepinephrine transporter-/- mice compared with controls following both airpuff or footshock stimuli, and pressure changes were also greater. Interestingly, in contrast to normally elevated home cage levels in norepinephrine transporter-deficient mice, prestimulus heart rate and blood pressure were actually higher in norepinephrine transporter+/+ animals throughout behavioral testing. Upon placement in the behavioral chamber, norepinephrine transporter-deficient mice demonstrated a notable bradycardia and depressor effect that was more pronounced in females. Power spectral analysis indicated an increase in low frequency oscillations of heart rate variability; in mice, suggesting increased parasympathetic tone. Finally, norepinephrine transporter-/- mice exhibited sexual dimorphism in freeze behavior, which was greatest in females. Therefore, while reduced catecholamine clearance amplifies immediate cardiovascular responses to anxiety- or fear-inducing stimuli in norepinephrine transporter-/- mice, norepinephrine transporter deficiency apparently prevents protracted hemodynamic escalation in a fearful environment. Conceivably, chronic norepinephrine transporter blockade with transporter-specific drugs might attenuate recognition of autonomic and somatic distress signals in individuals with anxiety disorders, possibly lessening their behavioral reactivity, and reducing the cardiovascular risk factors associated with persistent emotional arousal.
Assuntos
Ansiedade/fisiopatologia , Bradicardia/etiologia , Medo/fisiologia , Hipertensão/etiologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/deficiência , Animais , Condicionamento Clássico , Feminino , Masculino , Camundongos , Camundongos Knockout , Reflexo de Sobressalto/fisiologiaRESUMO
The noradrenergic system is involved in the regulation of many physiological and psychological processes, including the modulation of mood. The alpha(2)-adrenergic receptors (alpha(2)-ARs) modulate norepinephrine release, as well as the release of serotonin and other neurotransmitters, and are therefore potential targets for antidepressant and anxiolytic drug development. The current studies were undertaken to examine the role of the alpha(2A) subtype of alpha(2)-AR in mouse behavioral models of depression and anxiety. We have observed that the genetic knock-out of the alpha(2A)-AR makes mice less active in a modified version of Porsolt's forced swim test and insensitive to the antidepressant effects of the tricyclic drug imipramine in this paradigm. Furthermore, alpha(2A)-AR knock-out mice appear more anxious than wild-type C57 Bl/6 mice in the rearing and light-dark models of anxiety after injection stress. These findings suggest that the alpha(2A)-AR may play a protective role in some forms of depression and anxiety and that the antidepressant effects of imipramine may be mediated by the alpha(2A)-AR.
Assuntos
Ansiedade/metabolismo , Depressão/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Inibidores da Captação Adrenérgica/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Escuridão , Modelos Animais de Doenças , Feminino , Fluoxetina/farmacologia , Imipramina/farmacologia , Luz , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Adrenérgicos alfa 2/deficiência , Receptores Adrenérgicos alfa 2/genética , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia , Estresse Fisiológico/metabolismo , Natação/fisiologiaRESUMO
We have recently disrupted Slc12a2, the gene encoding the secretory Na-K-2Cl cotransporter in mice (NKCC1) (Delpire et al., 1999). Gramicidin perforated-patch and whole-cell recordings were performed to study GABA-induced currents in dorsal root ganglion (DRG) neurons isolated from wild-type and homozygote NKCC1 knock-out mice. In wild-type DRG neurons, strong GABA-evoked inward current was observed at the resting membrane potential, suggesting active accumulation of Cl(-) in these cells. This GABA-induced current was blocked by picrotoxin, a GABA(A) receptor blocker. The strong Cl(-) accumulation that gives rise to depolarizing GABA responses is caused by Na-K-2Cl cotransport because reduction of external Cl(-) or application of bumetanide induced a decrease in [Cl(-)](i), whereas an increase in external K(+) caused an apparent [Cl(-)](i) accumulation. In contrast to control neurons, little or no net current was observed at the resting membrane potential in homozygote NKCC1 mutant DRG neurons. E(GABA) was significantly more negative, demonstrating the absence of Cl(-) accumulation in these cells. Application of bumetanide induced a positive shift of E(GABA), suggesting the presence of an outward Cl(-) transport mechanism. In agreement with an absence of GABA depolarization in DRG neurons, behavioral analysis revealed significant alterations in locomotion and pain perception in the knock-out mouse. Our results clearly demonstrate that the Na-K-2Cl cotransporter is responsible for [Cl(-)](i) accumulation in DRG neurons and that via regulation of intracellular Cl(-), the Na-K-2Cl cotransporter participates in the modulation of GABA neurotransmission and sensory perception.
Assuntos
Proteínas de Transporte/genética , Gânglios Espinais/metabolismo , Neurônios/metabolismo , Receptores de GABA-A/metabolismo , Animais , Comportamento Animal , Bumetanida/farmacologia , Células Cultivadas , Cloretos/metabolismo , Contraindicações , Feminino , Antagonistas GABAérgicos/farmacologia , Antagonistas de Receptores de GABA-A , Transtornos Neurológicos da Marcha/genética , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Gramicidina/farmacologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Knockout , Neurônios/citologia , Neurônios/efeitos dos fármacos , Medição da Dor , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Potássio/metabolismo , Simportadores de Cloreto de Sódio-Potássio , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologiaRESUMO
This paper reviews the current literature on animal models of the memory impairments of Alzheimer's disease (AD). The authors suggest that modeling of the mnemonic deficits in AD be limited to the amnesia observed early in the course of the disease, to eliminate the influence of impairments in non-mnemonic processes. Tasks should be chosen for their specificity and selectivity to the behavioral phenomena observed in early-stage AD and not for their relevance to hypothetical mnemonic processes. Tasks that manipulate the delay between learning and remembering are better able to differentiate Alzheimer patients from persons with other disorders, and better able to differentiate effects of manipulations in animals. The most commonly used manipulations that attempt to model the amnesia of AD are reviewed within these constraints. The authors conclude that of the models examined, lesions of the medial septal nucleus produce behavioral deficits that are most similar to the mnemonic impairments in the earliest stage of AD. However, the parallel is not definitive and more work is needed to clarify the relationship between neurobiology and behavior in AD.
Assuntos
Doença de Alzheimer/psicologia , Transtornos da Memória/psicologia , Animais , Modelos Animais de Doenças , Humanos , Transtornos da Memória/induzido quimicamenteRESUMO
Galanin is a 29-amino acid neuropeptide that coexists with acetylcholine in the medial septum/diagonal band in the rat and impairs choice accuracy on an operant delayed-nonmatching-to-position (DNMTP) working-memory task. M40, a peptidergic galanin antagonist, has previously been shown to block several physiological actions of galanin. The present experiments tested the ability of M40 to block the effects of galanin on DNMTP performance. M40 completely blocked choice-accuracy deficits induced by galanin administration in both the lateral ventricle and ventral hippocampus, at doses of M40 approximately 5-fold the molar dose of galanin. M40 appears to be an effective galanin antagonist in a rodent memory paradigm, indicating that this compound may prove useful in investigating the role of endogenous galanin in learning and memory.
Assuntos
Encéfalo/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Galanina/farmacologia , Rememoração Mental/efeitos dos fármacos , Orientação/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Animais , Mapeamento Encefálico , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Galanina/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Injeções Intraventriculares , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Receptores de GalaninaRESUMO
Galanin is a 29-amino-acid neuropeptide that is overexpressed in Alzheimer's disease (AD) and impairs performance on rodent learning and memory tasks. M40, a peptidergic galanin receptor ligand, blocks galanin-induced impairments on delayed non-matching-to-position (DNMTP). The present experiments used the 192IgG-saporin lesion model of AD to evaluate the actions of galanin and M40 on DNMTP when cholinergic transmission was reduced. Hippocampal choline acetyltransferase levels were correlated with DNMTP choice accuracy in lesioned rats. Intracerebroventricular (icv) galanin reduced choice accuracy in both the lesioned and sham groups. M40 alone, either icv or intrahippocampal, did not affect choice accuracy in either group. These results suggest that excess galanin can produce further deficits in DNMTP performance in a lesion model of AD, but blocking endogenous galanin is not sufficient alone to improve performance in lesioned rats.
Assuntos
Doença de Alzheimer/fisiopatologia , Anticorpos Monoclonais/farmacologia , Aprendizagem por Discriminação/efeitos dos fármacos , Galanina/farmacologia , Imunotoxinas/farmacologia , Rememoração Mental/efeitos dos fármacos , Orientação/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores Colinérgicos/efeitos dos fármacos , Animais , Mapeamento Encefálico , Aprendizagem por Discriminação/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Galanina/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Masculino , Rememoração Mental/fisiologia , N-Glicosil Hidrolases , Orientação/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Colinérgicos/fisiologia , Receptores de Galanina , Receptores dos Hormônios Gastrointestinais/efeitos dos fármacos , Receptores dos Hormônios Gastrointestinais/fisiologia , Proteínas Inativadoras de Ribossomos Tipo 1 , SaporinasRESUMO
Central administration of galanin produces performance deficits on a variety of rodent learning and memory tasks. Galanin impairs acquisition and/or retention of the Morris water task, delayed nonmatching to position, T-maze delayed alternation, starburst radial maze, and passive avoidance in normal rats. A primary site of action is the ventral hippocampus, with an additional modulatory site in the medial septum-diagonal band. The behavioral actions of galanin at rat septohippocampal sites mediating cognitive processes are consistent with previous reports of inhibitory actions of galanin on acetylcholine release and cholinergically activated transduction at the M1 muscarinic receptor in rat hippocampus. The peptidergic galanin receptor antagonist M40 blocks the inhibitory actions of galanin on memory tasks. Treatment combinations of M40 with an M1 agonist, TZTP, improves performance on delayed nonmatching to position, in rats with 192IgG-saporin-induced cholinergic lesions of basal forebrain neurons. Nonpeptide, bioavailable, subtype-selective galanin receptor antagonists may provide tools to test the hypothesis that antagonism of endogenous galanin, which is overexpressed in the basal forebrain in Alzheimer's patients, can contribute to the alleviation of the cognitive deficits associated with Alzheimer's disease.
Assuntos
Galanina/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Receptores de Neuropeptídeos/fisiologia , Animais , Galanina/farmacologia , Memória/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Fragmentos de Peptídeos/farmacologia , Ratos , Receptores de Galanina , Receptores Muscarínicos/fisiologia , Receptores de Neuropeptídeos/agonistas , Análise e Desempenho de TarefasRESUMO
BACKGROUND: Hürthle cell carcinomas of the thyroid are unusual variants of well-differentiated thyroid cancers. Considered more aggressive tumors, their optimal treatment is controversial. Our institution's half century of experience, the largest series to date, includes 40 patients with Hürthle cell carcinomas of 1000 well-differentiated thyroid cancers. METHODS: A retrospective study was carried out on 40 patients. RESULTS: Seventy-two percent were female, with a median age of 53 years. Median follow-up was 9 years. With the AMES risk stratification (age, distant metastasis, capsular extent, tumor size), among the 21 high-risk patients, 10 (48%) had a recurrence or died, with median time to recurrence 3 years (range, 0.5 to 14 years). Of these 10, 5 died of disease, one died of unrelated causes with disease, and 4 are alive with disease. Five recurrences presented as distant metastases. Extent at operation was the strongest predictor of recurrence, occurring in 66% of those with gross extraglandular involvement. CONCLUSIONS: The AMES criteria are useful in predicting recurrence and death. Although more aggressive surgery is appropriate for high-risk patients, in general their outlook remains grim.
Assuntos
Adenocarcinoma/cirurgia , Neoplasias da Glândula Tireoide/cirurgia , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Resultado do TratamentoRESUMO
Changes in arterial and cardiopulmonary baroreflex function and cardiac structure were followed throughout 10 wk of moderate endurance training [60 min of cycling, 3 days/wk, 60% maximal O2 uptake (VO2max)] in sedentary normotensive men (22-34 yr old). Subjects were randomly assigned to an exercise training group (ET; n = 9) or to a control group (UT; n = 4). Decreases in resting heart rate (8.9 +/- 2.6%, P < 0.01) and mean arterial pressure (7.0 +/- 2.3%, P < 0.05) and an increase in VO2max occurred after 10 wk in ET. An increase in the gain or slope of the spontaneous baroreflex response at rest was found after 10 wk in ET (50.1 +/- 6.3%, P < 0.01) but not in UT. An upward shift in the resting carotid-cardiac baroreflex response curve also occurred after 10 wk in ET, although the maximum range and gain of the response and the vagally mediated peak reflex sinus node responses were unchanged. Cardiopulmonary baroreflex function (reflex changes in forearm vascular conductance) and measured indexes of left ventricular structure were not altered in either ET or UT, although peak transmitral inflow velocity increased in ET (P < 0.05). These findings demonstrate that moderate exercise training results in an enhancement in the ability to reflexly adjust heart rate with spontaneous changes in arterial pressure within the operating range. This occurs independently of any changes in carotid-cardiac baroreflex function over the full response range in cardiopulmonary baroreflex function or in cardiac structure.