NeuropharmacologyResearch PaperEffects of memantine on soluble Αβ25-35-induced changes in peptidergic and glial cells in Alzheimer's disease model rat brain regions
Section snippets
Materials
Male Wistar rats (10–11 weeks) weighing 300–320 g were obtained from Sankyo Laboratory (Tokyo, Japan). Memantine, dithiothreitol, and Tris base were purchased from Sigma, Chemical Co. (Tokyo). Αβ25-35, 7-amino-4-methylcoumarin (AMC) and 7-(succinyl–Gly–Pro)-4-methylcoumarinamide (Suc–Gly–Pro-MCA), 7-methoxycoumarin-4-acetyl-Pro–Leu–Gly–Leu-A2pr(Dnp)-Ala–Arg-NH2 (QFS), MCA-Pro–Leu–Gly, anti-rabbit SS were from Peptide Institute Inc. (Osaka, Japan). Ac-Asp–Glu–Val–Asp-AMC and the specific
Effects of Aβ and Aβ-plus memantine on the neuropeptide levels
As shown in Fig. 1A, SP-like immunoreactivity (SP-LI) measured by EIA, significantly decreased in the hippocampus (F(2,15)=4.530; P<0.05) following administration of soluble Αβ25-35 as compared with the control group, whereas no change was observed in the frontal cortex and striatum. On the other hand, SS-like immunoreactivity (SS-LI) in the hippocampus and frontal cortex of Aβ-treated rats decreased 35% and 23%, respectively (Fig. 1B). Co-administration of memantine substantially
Discussion
The results presented here indicate for the first time that repeated i.c.v. infusion of soluble Aβ alters the levels of neuropeptides and their degrading enzymes in the brain, with a concomitant increase in glial cells and a loss of spine density. Co-treatment with memantine in the Aβ-induced changes of peptidergic system and glial cells suggest a molecular basis of the protective effect of memantine in AD pathology. In the current study, we used Aβ25-35, which is the shorter, biologically
Conclusion
Our findings suggest that glial cell-mediated increases in brain peptidases, as well as oxidative stress, promote the spine loss, and this is a contributing mechanism of peptidergic change in the absence of neuronal loss. Furthermore, memantine treatment could suppress glutamate activation via a blockade of NMDA receptors, reduced glial activation, as well as glial-mediated changes in neuropeptides and their degrading enzymes. Ultimately, these findings indicate a possible role of glial and
Acknowledgments
The authors thank to Professor Michiyuki Yamada, Yokohama City University for his valuable comments and encouragement throughout the work. We also thank to Dr. Toshifumi Yamamoto and Professor Shinji Hayashi of Yokohama City University for donating iNOS antibody and helping in Golgi staining, respectively. This work was supported in part by Grants-in-Aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
References (59)
- et al.
Effect of memantine on the levels of glial cells, neuropeptides, and peptide-degrading enzymes in rat brain regions of the ibotenic acid-treated Alzheimer's disease model
Neuroscience
(2004) - et al.
Inflammation and Alzheimer's disease
Neurobiol Aging
(2000) - et al.
Clozapine but not haloperidol suppresses the changes in the levels of neuropeptides in MK-801-treated rat brain regions
Neurochem Int
(2006) - et al.
Suppressive effect of clozapine but not haloperidol on the increases of neuropeptide-degrading enzymes and glial cells in (+) MK-801-treated rat brain regions
Neurosci Res
(2007) - et al.
Glial cells and neurotransmission: an inclusive view of synaptic function
Neuron
(2003) - et al.
Somatostatin and Alzheimer's disease
Mol Cell Endocrinol
(2008) - et al.
The association of metalloendopeptidase EC 3.4.24.15 at the extracellular surface of the AtT-20 cell plasma membrane
Brain Res
(1999) - et al.
Correlations of synaptic and pathological markers with cognition of the elderly
Neurobiol Aging
(1995) - et al.
Neuropeptide deficits in schizophrenia vs. Alzheimer's disease cerebral cortex
Biol Psychiatry
(1996) - et al.
Neuropeptides and Alzheimer's disease
Eur Neuropsychopharamacol
(1995)