During Matthew J, Cao Lei, Zuzga David S, Francis Jeremy S, Fitzsimons Helen L, Jiao Xiangyang, Bland Ross J, Klugmann Matthias, Banks William A, Drucker Daniel J, Haile Colin N
Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland 86716, New Zealand.
Nat Med. 2003 Sep;9(9):1173-9. doi: 10.1038/nm919. Epub 2003 Aug 17.
Glucagon-like peptide-1 (GLP-1) is a gut peptide that, together with its receptor, GLP-1R, is expressed in the brain. Here we show that intracerebroventricular (i.c.v.) GLP-1 and [Ser(2)]exendin(1-9) (HSEGTFTSD; homologous to a conserved domain in the glucagon/GLP-1 family) enhance associative and spatial learning through GLP-1R. [Ser(2)]exendin(1-9), but not GLP-1, is also active when administered peripherally. GLP-1R-deficient mice have a phenotype characterized by a learning deficit that is restored after hippocampal Glp1r gene transfer. In addition, rats overexpressing GLP-1R in the hippocampus show improved learning and memory. GLP-1R-deficient mice also have enhanced seizure severity and neuronal injury after kainate administration, with an intermediate phenotype in heterozygotes and phenotypic correction after Glp1r gene transfer in hippocampal somatic cells. Systemic administration of [Ser(2)]exendin(1-9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons. Brain GLP-1R represents a promising new target for both cognitive-enhancing and neuroprotective agents.
胰高血糖素样肽-1（GLP-1）是一种肠道肽，它与其受体GLP-1R一起在大脑中表达。在此我们表明，脑室内（i.c.v.）注射GLP-1和[Ser(2)]艾塞那肽（1-9）（HSEGTFTSD；与胰高血糖素/GLP-1家族中的一个保守结构域同源）可通过GLP-1R增强联想学习和空间学习能力。[Ser(2)]艾塞那肽（1-9）在外周给药时也具有活性，但GLP-1没有。GLP-1R缺陷型小鼠具有学习缺陷的表型，海马Glp1r基因转移后这种缺陷得以恢复。此外，海马中过表达GLP-1R的大鼠学习和记忆能力得到改善。GLP-1R缺陷型小鼠在注射红藻氨酸后癫痫发作严重程度增加且神经元损伤加重，杂合子表现出中间型表型，海马体细胞进行Glp1r基因转移后表型得到纠正。在野生型动物中全身给药[Ser(2)]艾塞那肽（1-9）可防止红藻氨酸诱导的海马神经元凋亡。脑GLP-1R是认知增强剂和神经保护剂一个有前景的新靶点。
