Ladostigil prevents gliosis, oxidative-nitrative stress and memory deficits induced by intracerebroventricular injection of streptozotocin in rats.
Glial activation and oxidative-nitrative stress occur at an early stage in Alzheimer's disease (AD). In a rat model of AD, deficits in cerebral glucose utilization and memory were seen 3-4 weeks after intracerebroventricular (icv) injection of streptozotocin (STZ). This study examined whether icv STZ induced glial activation and oxidative-nitrative stress preceded the memory deficits and whether they could be prevented by ladostigil a novel drug, a cholinesterase and monoamine oxidase inhibitor with neuroprotective activity. One week after STZ injection activated microglia and astrocytes were seen in the cortex, around the cannula penetration area, in the hippocampal CA1 region, corpus callosum, medial and lateral septum. The activated astrocytes showed a significant increase in nitrotyrosine immunoreactivity, a measure of oxidative-nitrative stress. Only 3 weeks later were deficits in episodic (object recognition test) and spatial memory (place recognition) seen in STZ-injected rats. Daily oral administrations of ladostigil (1mg/kg) for 1 week, before and after STZ prevented the glial changes, increase in nitrotyrosine immunoreactivity and memory deficits. Taken together the data support the role of glial activation and oxidative-nitrative stress in discrete brain areas in the aetiology of memory deficits and indicate a potential mechanism for their prevention by drug treatment.
Shoham
Shai
S
Research Department, Herzog Hospital, Jerusalem, Israel.
Bejar
Corina
C
Kovalev
Eugenia
E
Schorer-Apelbaum
Donna
D
Weinstock
Marta
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count / Q000379:methods; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced / Q000517:prevention & control*; D007150:Immunohistochemistry; D007189:Indans / Q000627:therapeutic use*; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
C423264:(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate; D005904:Glial Fibrillary Acidic Protein; D007189:Indans; C493461:Slc18a3 protein, rat; D050494:Vesicular Acetylcholine Transport Proteins; C002744:3-nitrotyrosine; D014443:Tyrosine; D013311:Streptozocin; D002795:Choline O-Acetyltransferase