RESUMO
Age-related development of behavioral disorders in transgenic mice with modeled Alzheimer's disease carrying V6S3-Tg(APP695)85Dbo Tg(PSENI)85Dbo) genotype was assessed at the age of 7.5, 10 and 20 months in the following tests: open-field, plus maze, T-maze, conditioned passive avoidance response, rotarod, conflict situation with water deprivation, behavioral despair, and arecoline tremor. The main behavioral disorder in transgenic mice at all observation terms was memory impairment in conditioning with positive (but not negative) reinforcement. At the age of 7.5 and 10 months, transgenic mice also showed signs of nonspecific excitement and anxiety, depression-like state, and symptoms of cholinergic deficit. Our results suggest that appropriate age for behavioral tests in studies of effects of potential anti-Alzheimer drugs in transgenic V6S3-Tg(APP695)85Dbo Tg(PSENI)85Dbo) mice is 7.5-10 months.
Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/genética , Animais , Ansiedade/tratamento farmacológico , Ansiedade/patologia , Ansiedade/fisiopatologia , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/uso terapêuticoRESUMO
Nootropic non-anticholinesterase organophosphorus preparation CAPAH and substance P produced similar and dose-dependent effects on the amplitude and temporal parameters of miniature endplate potentials in mammalian neuromuscular synapse. Neurokinin receptor antagonist Win-51.708 abolished the effects of these agents. In behavioral experiments substance P moderated the mnemotropic and antidepressant effects of CAPAH. It was assumed that neurokinin receptors are the targets of CAPAH and substance P in CNS and neuromuscular synapse.
Assuntos
Acetatos/farmacologia , Sistema Nervoso Central/metabolismo , Hidrazinas/farmacologia , Compostos Organofosforados/farmacologia , Receptores da Neurocinina-1/metabolismo , Substância P/metabolismo , Androstanos/farmacologia , Animais , Benzimidazóis/farmacologia , Relação Dose-Resposta a Droga , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Antagonistas dos Receptores de Neurocinina-1 , Ligação Proteica , Ratos , SinapsesRESUMO
In vivo and in vitro experiments revealed the neuroprotective activity of CAPAH, a representative of the new nootropic class phosphorylated carboxylic acid hydrazides. The mechanisms of this action, which were due to the membranous stabilizing activity of the drug and its affinity for glycine strychnine-sensitive sites of MMDA receptors (Ki = 8.8.10(-5) M). Six analogues of CAPAH have been also found to have affinity for these types of receptors; based on the examination of structure-affinity relationship, putative pharmacophores (only radicals of the benzene ring of a molecule in the para position exerted effects on affinity changes) were revealed. The findings give a deep insight into the mechanism of nootropic activity and open vistas for synthesizing phosphorylated carboxylic acid hydrazides as potential neuroprotective agents interacting with glycine strychnine-sensitive sites of MMDA receptor.
