Laboratory of Pharmacology and Brain Biostructure, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
Pharmacol Rep. 2009 Nov-Dec;61(6):1008-16. doi: 10.1016/s1734-1140(09)70162-8.
The present study investigated the potential role of the extracellular signal-regulated kinase (ERK) pathway in the alternation of polysialylated neural cell adhesion molecule (PSA-NCAM) expression and proliferation rates in the dentate gyrus (DG) evoked by activation of the CB1 receptor. When given at a dose of 0.1 mg/kg, the CB1 receptor agonist, 3-(1,1-dimethylheptyl)-11-hydroxy-Delta(8)-tetrahydrocannabinol (HU-210), increased the levels of the phosphorylated forms of ERK (pERK1 and pERK2) in the hippocampus when measured 30 min after injection. This HU-210-induced effect was inhibited by alpha-{amino[(4-aminophenyl)thio]methylene}-2-(trifluoromethyl) benzeneacetonitrile (SL327, 30 mg/kg) - an inhibitor of mitogen-activated protein kinase kinase (MEK1/2), the upstream kinase of ERK - given 1 h before HU-210 administration. Additionally, SL327 alone significantly attenuated the basal level of both pERK1 and pERK2. HU-210 (0.1 mg/kg) decreased the number of PSA-NCAM-immunoreactive (IR) cells but did not affect the rate of proliferation, which was analyzed as the number of Ki-67-IR cells measured in the DG 2 days after HU-210 administration. The data indicated that SL327 (30 mg/kg) alone decreased the number of PSA-NCAM-IR cells 2 days after treatment. Joint administration of SL327 and HU-210 decreased the number of PSA-NCAM cells more robustly than did the administration of either alone. In addition, SL327 did not decrease the number of Ki-67-IR cells, while pretreatment with SL327 1 h before HU-210 administration did. These results suggest that stimulation of the ERK cascade caused by CB1 receptor activation is not involved in hippocampal plasticity governed by PSA-NCAM expression.
本研究探讨了细胞外信号调节激酶（ERK）通路在外源性大麻素受体 1（CB1）受体激活引起齿状回（DG）中多聚唾液酸神经细胞黏附分子（PSA-NCAM）表达和增殖率改变中的潜在作用。当给予 0.1mg/kg 的剂量时，CB1 受体激动剂 3-（1,1-二甲基庚基）-11-羟基-Delta(8)-四氢大麻醇（HU-210）在注射后 30 分钟测量时增加了海马中磷酸化 ERK（pERK1 和 pERK2）的水平。这种 HU-210 诱导的效应被α-（氨基[（4-氨基苯基）硫基]亚甲基）-2-（三氟甲基）苯乙腈（SL327，30mg/kg）-ERK 的上游激酶丝裂原活化蛋白激酶激酶（MEK1/2）的抑制剂-在 HU-210 给药前 1 小时给予，被抑制。此外，SL327 本身显著减弱了 pERK1 和 pERK2 的基础水平。HU-210（0.1mg/kg）减少了 PSA-NCAM-免疫反应性（IR）细胞的数量，但不影响增殖率，这是在 HU-210 给药后 2 天在 DG 中测量的 Ki-67-IR 细胞的数量来分析的。数据表明，SL327（30mg/kg）单独给药 2 天后减少了 PSA-NCAM-IR 细胞的数量。SL327 和 HU-210 的联合给药比单独给药更显著地减少了 PSA-NCAM 细胞的数量。此外，SL327 没有减少 Ki-67-IR 细胞的数量，而在 HU-210 给药前 1 小时用 SL327 预处理则没有。这些结果表明，CB1 受体激活引起的 ERK 级联的刺激不参与由 PSA-NCAM 表达调节的海马可塑性。
