In vivo effects of beta-amyloid implants in rodents: lack of potentiation of damage associated with transient global forebrain ischemia.
Recent studies have shown that the principal component of the senile plaque in Alzheimer's disease (AD), beta-amyloid protein (beta AP) can exert direct and indirect neurotoxicity in vitro. Because of the studies that demonstrated potentiation of excitatory amino acid toxicity by beta AP, we decided to test whether beta AP was able to potentiate damage in an in vivo model where excitotoxic damage is thought to be important. The present study evaluated the in vivo effects of beta AP implants in the brain of rats before and after being subjected to 10 min of transient global forebrain ischemia by 4-vessel occlusion (4-VO). Implants of either synthetic beta AP or prolactin (PRL), which was used as a control protein, were made into the striatum and the hippocampus of either the left (beta AP) or the right (PRL) cerebral hemisphere. The implants were made in a lipophilic, non-toxic vehicle so as to try and achieve sustained beta AP exposure. One group of animals was evaluated for direct in vivo effects within 1 week following implantation; the other group was subjected to 4-VO 3-4 days post-implantation for evaluation of potential indirect effects. This latter group was compared to the histopathology of animals subjected to 4-VO without prior implantation. In the group of animals evaluated for direct effects, no evidence of neurotoxicity was observed. Bielschowsky silver staining and immunostaining for ubiquitin were unremarkable in all lesions. beta AP was detected by immunocytochemistry in the parenchymal tissue that received beta AP implants. Marked glial activation was observed to be associated with experimental and control implants. Under the experimental conditions employed in this study, significant protection from ischemia rather than potentiation of damage was observed. These results suggest that beta AP may not be neurotoxic in rodents in vivo and that the lesions and/or trauma produced by the implantation procedure 3-4 days prior to 4-VO may have induced factors that were protective against ischemia-induced damage.
Stephenson
D T
DT
Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285.
Clemens
J A
JA
D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004343:Drug Implants; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002546:Ischemic Attack, Transient / Q000473:pathology* / Q000503:physiopathology; D011388:Prolactin / Q000008:administration & dosage / Q000494:pharmacology; D016548:Prosencephalon / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D011712:Pyramidal Tracts / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051381:Rats
D016229:Amyloid beta-Peptides; D004343:Drug Implants; D011388:Prolactin