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P2‐124: Chronic subcutaneous application of sodium azide to muscarinic M2 receptors: Knockout mice and animal modeling of Alzheimer's disease
Author(s) -
Ripova Daniela,
Kristofikova Zdena,
Holubova Katerina,
Stuchlik Ales,
Vales Karel
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.829
Subject(s) - morris water navigation task , sodium azide , knockout mouse , endocrinology , nitric oxide synthase , medicine , open field , water maze , subcutaneous injection , elevated plus maze , chemistry , receptor , pharmacology , nitric oxide , biochemistry , hippocampus , anxiety , psychiatry
Background:A primary cause of Alzheimer disease is not known yet, however, it seems that mitochondrial dysfunction could play a role. Chronic application of sodium azide, a selective inhibitor of cytochrome c oxidase, leads to deficits in learning and memory task and is used in animal modeling of different neurodegenerative disorders including Alzheimer disease. Marked changes of cholinergic neurotransmitter system especially in its presynaptic part were observed in demented people, in addition. Methods: Chronic subcutaneous application of sodium azide (0.5 mg/kg/day for 28 days) via osmotic minipumps Alzet model 1004 was used on adult (6 months) or older (11 months) male mice (129J1/CF-1 wild type controls or corresponding M2 autoreceptor knockaut animals). Behavioral tests (open field, elevated plus maze andMorris water maze) were performed during the application, biochemical analysis of the brains (activities of neuronal, endothelial and inducible nitric oxide synthases) closely after the application. Results: Behavioral tests did not indicate significant differences between wild types and knockout groups. The activity of neuronal synthase in wild type mice was increased in sham operated when compared to intact animals but decreased in sodium azide when compared to sham operated animals (however, no significant changes were observed on young or old knockout animals). No changes were observed in endothelial synthase. And finally, the activity of inducible synthase was unchanged in groups of wild type mice but significantly increased in young sham operated/sodium azide when compared to young intact knockout mice (however, it was not observed in old knockout animals). Conclusions: Our results support direct links among M2 autoreceptors and nitric oxide synthases (especially in the case of neuronal/inducible enzymes). However, although our biochemical results suggest a possible dysregulation of a nitric oxide pathway in young M2 knockout mice with mitochondrial dysfunction, missing alterations in behavioral tests or a missing progression of biochemical changes during aging do not support a validity of this model of Alzheimer disease.