Neuroprotection by rasagiline in thiamine deficient rats.
Thiamine deficiency (TD) in rats is a model of chronic impairment of oxidative metabolism leading to neuronal loss. TD rats exhibit neuropathological, behavioral and cognitive abnormalities. The aim of this study was to use this syndrome to assess the neuroprotective potential of drugs in a whole animal model. TD was produced in rats using the following protocol: thiamine deficient diet, daily injections of the central thiamine antagonist, pyrithiamine (0.5 mg/kg), and the test drugs, the selective monoamine oxidase (MAO) B inhibitors, rasagiline (1 or 3 mg/kg/day) and selegiline (2.4 or 8 mg/kg/day). Normal rats and untreated TD rats served as controls. Upon the appearance of neurological symptoms, the TD protocol was suspended, rats were transferred to a regular diet, pyrithiamine and test drug injections were terminated and rats were injected with 3 daily doses of thiamine (100 mg/kg). Neuroprotective potential was assessed by: general behavioral observations, cognitive testing using the Morris water maze and histopathological examination of the brains. Rasagiline but not selegiline significantly delayed the onset and severity of the neurological symptoms of TD. In the Morris water maze, TD-untreated rats displayed severe cognitive impairment while rasagiline-treated rats were similar to control rats and significantly different from TD-untreated rats. The effects were dose related. Selegiline treatment had no significant protective effect. TD-untreated brains displayed extensive gliotic and necrotic lesions mainly in the thalamus and posterior collicular nucleus, which were significantly reduced in the rasagiline-treated TD rats. These findings demonstrate significant neuroprotection by rasagiline with possible implications for clinical neurodegenerative disorders.
Eliash
Sarah
S
Dept. of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel. seliash@post.tau.ac.il
Dror
Vered
V
Cohen
Sasson
S
Rehavi
Moshe
M
D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D007189:Indans / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000627:therapeutic use; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000627:therapeutic use; D013832:Thiamine Deficiency / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; C031967:rasagiline; D012642:Selegiline; D008995:Monoamine Oxidase