RESUMEN
Sporadic Alzheimer's disease (sAD) represents a serious and growing worldwide economic and healthcare burden. Almost 95% of current AD patients are associated with sAD as opposed to patients presenting with well-characterized genetic mutations that lead to AD predisposition, i.e., familial AD (fAD). Presently, the use of transgenic (Tg) animals overexpressing human versions of these causative fAD genes represents the dominant research model for AD therapeutic development. As significant differences in etiology exist between sAD and fAD, it is perhaps more appropriate to develop novel, more sAD-reminiscent experimental models that would expedite the discovery of effective therapies for the majority of AD patients. Here we present the oDGal mouse model, a novel model of sAD that displays a range of AD-like pathologies as well as multiple cognitive deficits reminiscent of AD symptomology. Hippocampal cognitive impairment and pathology were delayed with N-acetyl-cysteine (NaC) treatment, which strongly suggests that reactive oxygen species (ROS) are the drivers of downstream pathologies such as elevated amyloid beta and hyperphosphorylated tau. These features demonstrate a desired pathophenotype that distinguishes our model from current transgenic rodent AD models. A preclinical model that presents a phenotype of non-genetic AD-like pathologies and cognitive deficits would benefit the sAD field, particularly when translating therapeutics from the preclinical to the clinical phase.
Asunto(s)
Enfermedad de Alzheimer , Trastornos del Conocimiento , Ratones , Humanos , Animales , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Memoria , Animales Modificados Genéticamente , Modelos Animales de EnfermedadRESUMEN
Clinical evaluation of tachykinin NK(3) receptor antagonists has provided support for the therapeutic utility of this target in schizophrenia. However, these studies have not been entirely conclusive, possibly because of the pharmacokinetic limitations of these molecules. In the search for tachykinin NK(3) receptor antagonists with improved properties, we have discovered GSK172981 and GSK256471. Both compounds demonstrated high affinity for recombinant human (pK(i) values 7.7 and 8.9, respectively) and native guinea pig (pK(i) values 7.8 and 8.4, respectively) tachykinin NK(3) receptors. In vitro functional evaluations revealed GSK172981 to be a competitive antagonist (pA(2)=7.2) at cloned human tachykinin NK(3) receptor whereas GSK256471 diminished the neurokinin B-induced E(max) response, indicative of non-surmountable antagonist pharmacology (pA(2)=9.2). GSK172981 also exhibited a competitive profile in antagonizing neurokinin B-stimulated neuronal activity recorded from the guinea pig medial habenula slices (apparent pK(B)=8.1), whilst GSK256471 abolished the agonist-induced response. Central nervous system penetration by GSK172981 and GSK256471 was indicated by dose-dependent ex vivo tachykinin NK(3) receptor occupancy in medial prefrontal cortex (ED(50) values of 0.8 and 0.9 mg/kg, i.p., respectively) and the dose-dependent attenuation of agonist-induced "wet dog shake" behaviours in guinea pigs. Finally, in vivo microdialysis studies demonstrated that acute GSK172981 (30 mg/kg, i.p.) and GSK256471 (1mg/kg, i.p.) attenuated haloperidol-induced increases in extracellular dopamine in the guinea pig nucleus accumbens. Taken together, these in vitro and in vivo characterisations of the tachykinin NK(3) receptor antagonists GSK172981 and GSK256471 support their potential utility in the treatment of schizophrenia.
Asunto(s)
Aminoquinolinas/metabolismo , Aminoquinolinas/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Quinolinas/metabolismo , Quinolinas/farmacología , Receptores de Taquicininas/antagonistas & inhibidores , Aminoquinolinas/farmacocinética , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/citología , Encéfalo/fisiología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Clonación Molecular , Dopamina/metabolismo , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Cobayas , Habénula/citología , Haloperidol/farmacología , Humanos , Fosfatos de Inositol/metabolismo , Masculino , Microdiálisis , Neuroquinina B/farmacología , Neuronas/citología , Neuronas/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Fragmentos de Péptidos/farmacología , Péptidos/química , Quinolinas/farmacocinética , Ratas , Receptores de Taquicininas/genética , Receptores de Taquicininas/metabolismo , Sustancia P/análogos & derivados , Sustancia P/farmacologíaRESUMEN
The mechanism of action of standard drug treatments for psychiatric disorders remains fundamentally unknown, despite intensive investigation in academia and the pharmaceutical industry. So far, little is known about the effects of psychotropic medications on brain metabolism in either humans or animals. In this study, we investigated the effects of a range of psychotropic drugs on rat brain metabolites. The drugs investigated were haloperidol, clozapine, olanzapine, risperidone, aripiprazole (antipsychotics); valproate, carbamazapine (mood stabilizers) and phenytoin (antiepileptic drug). The relative concentrations of endogenous metabolites were determined using high-resolution proton nuclear magnetic resonance (1H NMR) spectroscopy. The results revealed that different classes of psychotropic drugs modulated a range of metabolites, where each drug induced a distinct neurometabolic profile. Some common responses across several drugs or within a class of drug were also observed. Antipsychotic drugs and mood stabilizers, with the exception of olanzapine, consistently increased N-acetylaspartate (NAA) levels in at least one brain area, suggesting a common therapeutic response on increased neuronal viability. Most drugs also altered the levels of several metabolites associated with glucose metabolism, neurotransmission (including glutamate and aspartate) and inositols. The heterogenic pharmacological response reflects the functional and physiological diversity of the therapeutic interventions, including side effects. Further study of these metabolites in preclinical models should facilitate the development of novel drug treatments for psychiatric disorders with improved efficacy and side effect profiles.
Asunto(s)
Encéfalo/fisiología , Oligodendroglía/fisiología , Psicotrópicos/farmacología , Animales , Encéfalo/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Oligodendroglía/efectos de los fármacos , RatasRESUMEN
Haloperidol and olanzapine are widely used antipsychotic drugs in the treatment of schizophrenia and other psychotic disorders. Despite extensive research efforts within the biopharmaceutical industry and academia, the exact molecular mechanisms of their action remain largely unknown. Since the response of patients to existing medications can be variable and often includes severe side effects, it is critical to increase our knowledge on their mechanism of action to guide clinical usage and new drug development. In this study, we have employed the label-free liquid chromatography tandem mass spectrometry (LC-MSE) to identify differentially expressed proteins in rat frontal cortex following subchronic treatment with haloperidol or olanzapine. Subcellular fractionation was performed to increased proteomic coverage and provided insight into the subcellular location involved in the mechanism of drug action. LC-MSE profiling identified 531 and 741 annotated proteins in fractions I (cytoplasmic-) and II (membrane enriched-) in two drug treatments. Fifty-nine of these proteins were altered significantly by haloperidol treatment, 74 by olanzapine and 21 were common to both treatments. Pathway analysis revealed that both drugs altered similar classes of proteins associated with cellular assembly/organization, nervous system development/function (particularly presynaptic function) and neurological disorders, which indicate a common mechanism of action. The top affected canonical signaling pathways differed between the two treatments. The haloperidol data set showed a stronger association with Huntington's disease signaling, while olanzapine treatment showed stronger effects on glycolysis/gluconeogenesis. This could either relate to a difference in clinical efficacy or side effect profile of the two compounds. The results were consistent with the findings reported previously by targeted studies, demonstrating the validity of this approach. However, we have also identified many novel proteins which have not been found previously to be associated with these drugs. Further study of these proteins could provide new insights into the etiology of the disease or the mechanism of antipsychotic medications.
Asunto(s)
Antipsicóticos/farmacología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Lóbulo Frontal/efectos de los fármacos , Animales , Benzodiazepinas/farmacología , Cromatografía Liquida/métodos , Detergentes/farmacología , Haloperidol/farmacología , Masculino , Espectrometría de Masas/métodos , Sistema Nervioso/efectos de los fármacos , Olanzapina , Proteómica/métodos , Ratas , Ratas Wistar , Transmisión SinápticaRESUMEN
MRI has been used to measure hindlimb muscle volume in female and male transgenic mice overexpressing the Gly93Ala (G93A) mutant human superoxide dismutase 1 (SOD1), a widely used model of familial amyotrophic lateral sclerosis (FALS), over the first 4 months of life. Significant decreases in the hindlimb muscle volume of the female G93A SOD1 mice were evident from 11 weeks of age, before other overt pathology appeared. By 15 weeks volume had decreased by 37% compared with 7 weeks, from 0.84+/-0.04 cm(3) (mean+/-standard deviation, n = 6) to 0.54+/-0.07 cm(3), (p < 0.05), despite an increase in body weight of ca. 12% (from 16.2 +/- 1.4 to 18.1 +/- 0.7 g). Female wild-type volume increased by ca. 30% whilst the body weight increased by 15%. Muscle wasteage was less (0.82+/-0.1 to 0.65+/-0.02 cm(3), p < 0.05, n = 6) in male G93A SOD1 mice between 8 and 16 weeks of age, against a body weight increase trend from 20.7 +/- 0.4 to 21.6 +/- 0.5 g, (p > 0.05). Wild-type male muscle volume did not change significantly over this period, with an increase in body weight of 20%. Longitudinal MRI hindlimb muscle volume measurements may provide a straightforward, rapid, non-invasive and sensitive, way of monitoring outcome of experimental ALS treatments.