Pharmacology Post Graduate Program, Physiology Department, Health Sciences Center, Federal University of Santa Maria, 97105-900, RS, Santa Maria, Brazil.
Amino Acids. 2012 Dec;43(6):2491-503. doi: 10.1007/s00726-012-1329-4. Epub 2012 Jun 5.
Although Creatine (Cr) and Phosphocreatine (PCr) systems play a key role in cellular energy and energy transport in neuronal cells, its implications for learning and memory are still controversial. Thus, we decided to investigate the involvement of cAMP-dependent protein kinase A (PKA), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and cAMP responsive element binding protein (CREB) in the spatial consolidation after an intrahippocampal injection of Cr. Statistical analysis revealed that Cr (2.5 nmol/hippocampus) (post-training) decreased the latency for escape and the mean number of errors on Barnes maze test. Post-training co-administration of the PKA inhibitor (H-89 25 ρmol/hippocampus) did not alter the facilitatory effect of Cr in this memory test. On the other hand, Cr-induced spatial retention was reverted by co-administration of the CaMKII inhibitor (STO-609 5 nmol/hippocampus). Neurochemical analysis revealed that intrahippocampal injection of Cr, when analyzed after 30 min rather than after 3 h, increased the levels of pCREB and pCaMKII but not pPKA levels. Statistical analysis also revealed that the post-training co-administration of STO-609 but not H-89 reversed the increase of pCREB levels induced by Cr. The results presented in this report suggest that intracellular CaMKII/CREB pathway plays a key role in the Cr-induced spatial retention. Thus, it is plausible to propose that Cr plays a putative role as a neuromodulator in the brain, and that at least some of its effects may be mediated by intracellular CaMKII/CREB pathway.
虽然肌酸（Cr）和磷酸肌酸（PCr）系统在神经元细胞的细胞能量和能量转运中发挥着关键作用，但其对学习和记忆的影响仍存在争议。因此，我们决定研究 cAMP 依赖性蛋白激酶 A（PKA）、Ca2+/钙调蛋白依赖性蛋白激酶 II（CaMKII）和 cAMP 反应元件结合蛋白（CREB）在海马内注射 Cr 后空间巩固中的作用。统计分析显示，Cr（2.5 nmol/海马）（训练后）降低了逃避潜伏期和在 Barnes 迷宫测试中的平均错误数。训练后共同给予 PKA 抑制剂（H-89 25 ρmol/海马）不会改变 Cr 在该记忆测试中的促进作用。另一方面，Cr 诱导的空间保留被 CaMKII 抑制剂（STO-609 5 nmol/海马）共同给药逆转。神经化学分析显示，海马内注射 Cr 后 30 分钟而不是 3 小时后分析，增加了 pCREB 和 pCaMKII 的水平，但 pPKA 水平没有增加。统计分析还显示，训练后共同给予 STO-609 但不是 H-89 逆转了 Cr 诱导的 pCREB 水平的增加。本报告中的结果表明，细胞内 CaMKII/CREB 途径在 Cr 诱导的空间保留中起着关键作用。因此，可以提出 Cr 在大脑中作为一种神经调质发挥作用，其至少部分作用可能是通过细胞内 CaMKII/CREB 途径介导的。
