Abstract
This study was designed to determine 1) whether repeated exposures to the acetylcholinesterase inhibitors (AChEIs) galantamine (GAL) or donepezil (DON) resulted in positive effects on nerve growth factor (NGF) and its receptors, cholinergic proteins, and cognitive function in the aged rat, and 2) whether GAL had any advantages over DON given its allosteric potentiating ligand (APL) activity at nicotinic acetylcholine receptors. Behavioral tests (i.e., water maze and light/dark box) were conducted in aged Fisher 344 rats during 15 days of repeated (subcutaneous) exposure to either GAL (3.0 or 6.0 mg/kg/day) or DON (0.375 or 0.75 mg/kg/day). Forty-eight hours after the last drug injection, cholinergic receptors were measured by [125I]-(±)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([125I]IPH; epibatidine analog), 125I-α-bungarotoxin (125I-BTX), [3H]pirenzepine ([3H]PRZ), and [3H]-5,11-dihydro-11-[((2-(2-((dipropylamino)methyl)-1-piperidinyl)ethyl)amino)carbonyl]-6H-pyrido(2,3-b)(1,4)-benzodiazepin-6-one methanesulfonate ([3H]AFDX-384, or [3H]AFX) autoradiography. Immunochemical methods were used to measure NGF, high (TrkA and phospho-TrkA)- and low (p75 neurotrophin receptor)-affinity NGF receptors, choline acetyltransferase (ChAT), and the vesicular acetylcholine transporter (VAChT) in memory-related brain regions. Depending on dose, both GAL and DON enhanced spatial learning (without affecting anxiety levels) and increased [125I]IPH, [3H]PRZ, and [3H]AFX (but decreased 125I-BTX) binding in some cortical and hippocampal brain regions. Neither AChEI was associated with marked changes in NGF, NGF receptors, or VAChT, although DON did moderately increase ChAT in the basal forebrain and hippocampus. The results suggest that repeated exposures to either GAL or DON results in positive (and sustained) behavioral and cholinergic effects in the aged mammalian brain but that the APL activity of GAL may not afford any advantage over acetylcholinesterase inhibition alone.
Footnotes
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This work was supported in part by the Janssen Research Foundation and by the American Foundation for Pharmaceutical Education's Predoctoral Fellowship program.
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doi:10.1124/jpet.105.093047.
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ABBREVIATIONS: AD, Alzheimer's disease; AChE, acetylcholinesterase; AChEI, acetylcholinesterase inhibitor; DON, donepezil; GAL, galantamine; APL, allosteric potentiating ligand; nAChR, nicotinic acetylcholine receptor; NGF, nerve growth factor; TrkA, tropomyosin-receptor kinase A; ELISA, enzyme-linked immunosorbent assay; ChAT, choline acetyltransferase; VAChT, vesicular acetylcholine transporter; p75NTR, p75 neurotrophin receptor; IPH, (±)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane; BTX, α-bungarotoxin; PRZ, pirenzepine; AFX, 5,11-dihydro-11-[((2-(2-((dipropylamino)methyl)-1-piperidinyl)ethyl)amino)carbonyl]-6H-pyrido(2,3-b)(1,4)-benzodiazepin-6-one methanesulfonate (AFDX-384); HRP, horseradish peroxidase; TMB, 3,3′,5,5′-tetramethylbenzidine; IHC, immunohistochemical; mAChR, muscarinic acetylcholine receptor; OD, optical density; PBS, phosphate-buffered saline; PBS-T20, PBS with 0.05% Tween 20; DG, dentate gyrus; MOD, mean OD; RIPA, radioimmunoprecipitation assay; M-PBST, 1% (w/v) nonfat dry milk in PBS with 0.05% (v/v) Triton X-100; ANOVA, analysis of variance; phospho-TrkA, phosphorylated TrkA.
- Received July 21, 2005.
- Accepted October 6, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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