title: A novel effect of rivastigmine on pre-synaptic proteins and neuronal viability in a neurodegeneration model of fetal rat primary cortical cultures and its implication in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized by deposition of amyloid-beta peptide plaque, disrupted amyloid-beta-precursor protein (APP) metabolism, hyperphosphorylation of Tau leading to neurofibrillary tangles and associated neurotoxicity. Moreover, there is synaptic loss in AD, which occurs early and may precede frank amyloidosis. The central cholinergic system is especially vulnerable to the toxic events associated with AD, and reduced acetylcholine levels in specific brain regions is thought to be central to memory deficits in AD. First-generation cholinesterase inhibitors have provided only symptomatic relief to patients with AD by prolonging the action of remaining acetylcholine with little or no change in the course of the disease. Some second-generation cholinesterase inhibitors are multifunctional drugs that may provide more than purely palliative results. To evaluate the effects of the dual acetylcholinesterase and butyrylcholinesterase inhibitor rivastigmine on key aspects of AD, embryonic day 16 rat primary cortical cultures were treated with rivastigmine under media conditions observed to induce time-dependent neurodegeneration. Samples were subjected to western blotting and immunocytochemistry techniques to determine what influence this drug may have on synaptic proteins and neuronal morphology. There was a strong increase in relative cell viability associated with rivastigmine treatment. Significant dose-dependent increases were observed in the levels of synaptic markers synaptosomal-associated protein of 25 kDa (SNAP-25) and synaptophysin, as well as the neuron-specific form of enolase. Together with an observed enhancement of neuronal morphology, our results suggest a rivastigmine-mediated novel neuroprotective and/or neurorestorative effects involving the synapse. Our observations may explain the potential for rivastigmine to alter the course of AD, and warrant further investigations into using butyrylcholinesterase inhibition as a therapeutic strategy for AD, especially with regard to restoration of synaptic function.
authors.affiliation: Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Bailey
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
mesh_terms: D000199:Actins / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000544:Alzheimer Disease; D000818:Animals; D049108:Cell Enlargement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004996:Ethidium / Q000031:analogs & derivatives; D005786:Gene Expression Regulation / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007211:Indoles; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000517:prevention & control*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D048448:Phenylcarbamates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068836:Rivastigmine; D016708:Synaptophysin / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D018696:Neuroprotective Agents; D048448:Phenylcarbamates; D016708:Synaptophysin; D050825:Synaptosomal-Associated Protein 25; D016875:tau Proteins; C007293:DAPI; C018533:ethidium homodimer; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D004996:Ethidium; D000068836:Rivastigmine