A chronic Alzheimer's model evoked by mitochondrial poison sodium azide for pharmacological investigations.
Alzheimer's disease (AD) is a neurodegenerative disorder and accounts for 50-70% of all dementia cases affecting more than 12 million people worldwide. The primary cause of the disease is presently unknown; however, much evidence suggests the involvement of mitochondrial damage. Selective reduction of complex IV activity is present in post-mortem AD brains. Inhibition of this complex could be evoked by chronic sodium azide (NaN(3)) administration in animals. Partial inhibition of the mitochondrial respiratory chain produces free radicals, diminishes aerobic energy metabolism and causes excitotoxic damage creating a deleterious spiral causing neurodegeneration, a pathological process considered to underlie AD. In the present study SPRD rats were treated by various doses of NaN(3) (24-51 mg/kg per day) for 31 days via subcutaneously implanted osmotic minipumps. We have found the proper dose and duration of NaN(3) treatment which was able to cause easily detectable and reproducible cognitive changes. Animals receiving Na-azide doses under 45 mg/kg daily did not show cognitive deficits, but minor histopathological changes were already present. Doses above 45 mg/kg per day proved to be toxic in 4-week-long application causing mortality. NaN(3) dose of 45 mg/kg per day caused cognitive deficit in Morris water maze and passive avoidance tests and a decrease of spontaneous exploratory activity in open field. Histopathological but not biochemical changes were present: dendritic thickening, nerve cell loss, corkscrew-like dendrites and pycnotic nerve cells. The cognitive, behavioural and histopathological features were reproducible. The chronic Na-azide-induced mitochondrial poisoning is suitable for producing AD-like symptoms in rats and testing neuroprotective drug candidates by preventive or curative applications.
Szabados
Tamás
T
CNS Pharmacology, Biorex Research and Development Company, P.O.B. 348, H-8201 Veszprém, Hungary. t.szabados@richter.hu
Dul
Csaba
C
Majtényi
Katalin
K
Hargitai
Judit
J
Pénzes
Zoltán
Z
Urbanics
Rudolf
R
D000544:Alzheimer Disease / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D005106:Exploratory Behavior / Q000187:drug effects; D007260:Infusion Pumps; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019810:Sodium Azide / Q000008:administration & dosage / Q000633:toxicity*; D036401:Toxicity Tests, Chronic
D004791:Enzyme Inhibitors; D019810:Sodium Azide; D003576:Electron Transport Complex IV