Glutamate reduces secretion of l-serine in astrocytes isolated from stroke-prone spontaneously hypertensive rats.
In the CNS, l-serine (l-Ser) plays an essential role in neuronal survival by evoking a variety of biological responses in glial cells. Initially, we examined whether glutamate, hydrogen peroxide (H(2)O(2)), interleukin-1 (IL-1) beta, and sodium nitroprusside (SNP) induce the secretion of l-Ser in astrocytes isolated from Wistar Kyoto rats (WKY). The secretion of l-Ser was significantly induced with glutamate and SNP in cultured astrocytes. Next, to gain insight into the involvement of l-Ser in glutamate-induced neuroprotection, we compared the secretion of l-Ser in astrocytes isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive rats, WKY. We also examined the mRNA expression of the enzyme that produces l-Ser, 3-phosphoglycerate dehydrogenase (PHGDH), and a neural amino acid transporter, ASCT1, in the cultured astrocytes. A dose-dependent study of glutamate in astrocytes of SHRSP indicated differences in the secretion of l-Ser, and gene expression of PHGDH and ASCT1, compared with levels in the WKY astrocytes. We demonstrated that both the secretion and the gene expression were significantly attenuated in glutamate-treated astrocytes from SHRSP. Cerebral ischemia in SHRSP induced a massive efflux of glutamate, causing delayed neuronal death in region CA1 of the hippocampus. The results suggest that the attenuated secretion of l-Ser in astrocytes is involved in neuronal vulnerability and survival in SHRSP during the production of glutamate, as the secretion of l-Ser, which is stimulated by glutamate, is closely related to the protective effect against glutamate-mediated neurotoxicity. We conclude that glutamate and SNP up-regulate the secretion of l-Ser in primary astrocytes. Secretion of l-Ser is regulated in astrocytes in response to glutamate and nitric oxide and may correspond to the level of l-Ser needed for neuronal survival during brain insults such as ischemic stroke in SHRSP.
Yamagata
K
K
Department of Food Science and Technology, College of Bioresource Sciences, Nihon University (NUBS), Fujisawa-shi, Fujisawa, Kanagawa, Japan. kyamagat@brs.nihon-u.ac.jp
Shoji
Y
Y
Terashima
T
T
Yokogoshi
H
H
D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D017077:Culture Media, Conditioned / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012694:Serine / Q000378:metabolism*; D013045:Species Specificity; D013997:Time Factors
D017077:Culture Media, Conditioned; D006360:Heat-Shock Proteins; D007375:Interleukin-1; D010446:Peptide Fragments; D012333:RNA, Messenger; C063820:SNP nonapeptide; D018698:Glutamic Acid; D012694:Serine; D006861:Hydrogen Peroxide