Comparison of galantamine and donepezil for effects on nerve growth factor, cholinergic markers, and memory performance in aged rats

Caterina M. Hernandez, D. A. Gearhart, V. Parikh, E. J. Hohnadel, L. W. Davis, M. L. Middlemore, S. P. Warsi, Jennifer L Waller, Alvin V Terry

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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.

Original languageEnglish (US)
Pages (from-to)679-694
Number of pages16
JournalJournal of Pharmacology and Experimental Therapeutics
Volume316
Issue number2
DOIs
StatePublished - Feb 1 2006

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Galantamine
Nerve Growth Factor
Cholinergic Agents
Nerve Growth Factor Receptors
Vesicular Acetylcholine Transport Proteins
Bungarotoxins
epibatidine
Choline O-Acetyltransferase
Cholinesterase Inhibitors
Brain
Ligands
Pirenzepine
Nerve Growth Factor Receptor
Nicotinic Receptors
Cholinergic Receptors
Acetylcholinesterase
Autoradiography
Cognition
donepezil
Hippocampus

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Comparison of galantamine and donepezil for effects on nerve growth factor, cholinergic markers, and memory performance in aged rats. / Hernandez, Caterina M.; Gearhart, D. A.; Parikh, V.; Hohnadel, E. J.; Davis, L. W.; Middlemore, M. L.; Warsi, S. P.; Waller, Jennifer L; Terry, Alvin V.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 316, No. 2, 01.02.2006, p. 679-694.

Research output: Contribution to journalArticle

Hernandez, Caterina M. ; Gearhart, D. A. ; Parikh, V. ; Hohnadel, E. J. ; Davis, L. W. ; Middlemore, M. L. ; Warsi, S. P. ; Waller, Jennifer L ; Terry, Alvin V. / Comparison of galantamine and donepezil for effects on nerve growth factor, cholinergic markers, and memory performance in aged rats. In: Journal of Pharmacology and Experimental Therapeutics. 2006 ; Vol. 316, No. 2. pp. 679-694.
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