Restorative effect of insulin-like growth factor-I gene therapy in the hypothalamus of senile rats with dopaminergic dysfunction
Restorative effect of insulin-like growth factor-I gene therapy in the hypothalamus of senile rats with dopaminergic dysfunction
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DOI：
10.1038/sj.gt.3302870
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发表时间：
2007-02-01
期刊：
影响因子：
5.1
通讯作者：
Goya, R. G.
中科院分区：
文献类型：
--
作者：
Herenu, C. B.;Cristina, C.;Goya, R. G.
胰岛素样生长因子-I (IGF-I) 正在成为一种强大的神经保护分子，在不同的损伤后会在中枢神经系统中强烈诱导。我们构建了一种含有大鼠 IGF-I 基因的重组腺病毒载体 (RAd-IGFI)，并用它对老年雌性大鼠的下丘脑实施 IGF-I 基因治疗，这些大鼠表现出下丘脑多巴胺能 (DA) 神经变性，并因此导致慢性高催乳素血症。在年轻（5个月）和老年（28个月）雌性大鼠中进行恢复性IGF-I基因治疗，这些大鼠接受单次下丘脑内注射3 x 10(9)斑块形成单位的RAd-bgal（表达β-半乳糖苷酶的对照腺病毒载体）或RAd-IGFI，并在注射后17天处死。在幼年动物中，两种载体均未改变血清催乳素水平，但在注射 RAd-IGFI 的老年大鼠中，记录到其高催乳素血症状态几乎完全逆转。形态分析显示，与对照老年动物相比，实验下丘脑中酪氨酸羟化酶阳性细胞总数显着增加（分别为5874+/-486和3390+/-498）。我们的结果表明，老年雌性大鼠的 IGF-I 基因治疗对于恢复其下丘脑 DA 功能障碍，从而逆转其慢性高催乳素血症非常有效。
Insulin-like growth factor-I (IGF-I) is emerging as a powerful neuroprotective molecule that is strongly induced in the central nervous system after different insults. We constructed a recombinant adenoviral vector (RAd-IGFI) harboring the gene for rat IGF-I and used it to implement IGF-I gene therapy in the hypothalamus of senile female rats, which display hypothalamic dopaminergic (DA) neurodegeneration and as a consequence, chronic hyperprolactinemia. Restorative IGF-I gene therapy was implemented in young (5 months) and senile (28 months) female rats, which received a single intrahypothalamic injection of 3 x 10(9) plaque-forming units of RAd-bgal (a control adenoviral vector expressing beta-galactosidase) or RAd-IGFI and were killed 17 days post-injection. In the young animals, neither vector modified serum prolactin levels, but in the RAd-IGFI-injected senile rats a nearly full reversion of their hyperprolactinemic status was recorded. Morphometric analysis revealed a significant increase in the total number of tyrosine hydroxylase-positive cells in the hypothalamus of experimental as compared with control senile animals (5874 +/- 486 and 3390 +/- 498, respectively). Our results indicate that IGF-I gene therapy in senile female rats is highly effective for restoring their hypothalamic DA dysfunction and thus reversing their chronic hyperprolactinemia.