Effects of the AMPA receptor modulator S 18986 on measures of cognition and oxidative stress in aged rats
- 105 Downloads
Development of cognitive-enhancing drugs that delay or halt mild cognitive impairment progression to Alzheimer’s disease would be of great benefit.
The aim of this study was to examine the ability of (S)-2,3-dihydro-[3,4]-cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S 18986), a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, to improve behavioral performance and alleviate age-related deficits in oxidative stress status in the prelimbic cortex and hippocampus.
Materials and methods
Daily administration of S 18986 (0.1, 0.3, and 1.0 mg/kg) or vehicle was given to separate groups of male rats starting at 12 months of age. Additionally, daily vehicle administration was given to a group of rats starting at 3 months of age. Four months after initiation of drug administration, rats were trained and tested in an operant-delayed alternation task and a reinforcer devaluation task. Upon completion of testing, oxidative stress status was assessed in the prelimbic cortex and hippocampus.
S 18986 dose-dependently altered responses in the reinforcer devaluation task such that aged rats came to resemble young rats. There were no age or drug effects in the operant-delayed alternation task. Levels of the lipid peroxidation product 4-hydroxy-nonenal (HNE) were increased, and Cu/Zn–superoxide dismutase (SOD) levels were decreased in prelimbic cortex in aged rats, changes that were reversed by S 18986. Similarly, age-related increases in hippocampal HNE levels were prevented by S 18986.
Positive modulation of AMPA receptor activity may be a therapeutic approach to halt or slow progression of mild cognitive impairment via improvement in oxidative stress status in the hippocampus and prelimbic cortex.
KeywordsCognitive enhancer Aging Oxidative stress Superoxide dismutase Prelimbic cortex Reinforcer devaluation Lipid peroxidation Hippocampus
This research was funded by a grant from the Institute de Recherches Internationales Servier to L.P.R.
- Burgmans S, van Boxtel MP, Smeets F, Vuurman EF, Gronenschild EH, Verhey FR, Uylings HB, Jolles J (2008) Prefrontal cortex atrophy predicts dementia over a six-year period. Neurobiol Aging (in press)Google Scholar
- Colombrita C, Calabrese V, Stella AM, Mattei F, Alkon DL, Scapagnini G (2003) Regional rat brain distribution of heme oxygenase-1 and manganese superoxide dismutase mRNA: relevance of redox homeostasis in the aging processes. Exp Biol Med (Maywood) 228:517–524Google Scholar
- Lockhart B, Iop F, Closier M, Lestage P (2000) (S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide: (S18986–1) a positive modulator of AMPA receptors enhances (S)-AMPA-mediated [3H]noradrenaline release from rat hippocampal and frontal cortex slices. Eur J Pharmacol 401:145–153PubMedCrossRefGoogle Scholar
- Moron I, Ballesteros MA, Candido A, Gallo M (2002) Taste aversion learning and aging: a comparison with the effect of dorsal hippocampal lesions in rats. Physiol Res 51 Suppl 1:S21–S27Google Scholar