Virmani M A, Conti R, Spadoni A, Rossi S, Arrigoni-Martelli E
Research & Development, Neuroendocrinology, Sigma-Tau, Pomezia, Italy.
Pharmacol Res. 1995 Mar-Apr;31(3-4):211-5. doi: 10.1016/1043-6618(95)80020-4.
L-carnitine plays a central role in mitochondrial function and is found to be differentially distributed in the brain. We have shown before that the uptake of L-carnitine into cultured rat cortical neurones was temperature-dependent, as well as potently inhibited by factors affecting the sodium gradient as well as by molecules resembling its structure, e.g. D-carnitine, acetyl-L-carnitine and gamma-aminobutyric acid (GABA). GABA was the most potent inhibitor of L-carnitine uptake. In the present study we have found that specific GABA uptake blockers, nipecotic acid, cis-4-hydroxynipecotic (HNA), guvacine, 2,4-diaminobutyric acid (DABA) and NO 711 inhibit L-carnitine uptake even more potently than GABA. However, apart from NO 711, they caused about the same maximal inhibition, 67.4% at 50 microM for guvacine, compared to 60.5% by GABA. NO 711 was extremely potent and blocked 80.5% of the L-carnitine uptake. In contrast, the GABAA receptor agonists, isonipecotic acid and isoguvacine, or the antagonist bicuculline, at similar concentrations (50 microM), did not significantly inhibit the uptake of the L-carnitine. However, bicuculline at relatively high concentration (500 microM) was inhibitory (38%). The GABAB receptor agonist, baclofen, or antagonist, phaclofen, were ineffective, although 5-aminovaleric acid did significantly inhibit uptake at both 50 and 500 microM, causing 22 and 48% inhibition respectively. Like bicuculline, it was not as effective as GABA or the specific GABA uptake blockers. The results indicate that the uptake of L-carnitine by rat cortical neurones occurs in part by a process that can be potently inhibited by GABA and GABA uptake blockers.
左旋肉碱在线粒体功能中起核心作用，且在大脑中呈差异分布。我们之前已表明，左旋肉碱进入培养的大鼠皮层神经元的摄取过程是温度依赖性的，并且会受到影响钠梯度的因素以及结构类似分子（如D - 肉碱、乙酰 - 左旋肉碱和γ-氨基丁酸（GABA））的强烈抑制。GABA是左旋肉碱摄取的最有效抑制剂。在本研究中，我们发现特异性GABA摄取阻滞剂，如尼克酸、顺式 - 4 - 羟基尼克酸（HNA）、胍基乙酸、2,4 - 二氨基丁酸（DABA）和NO 711，比GABA更有效地抑制左旋肉碱摄取。然而，除NO 711外，它们引起的最大抑制作用大致相同，胍基乙酸在50μM时最大抑制率为67.4%，而GABA为60.5%。NO 711极其有效，可阻断80.5%的左旋肉碱摄取。相比之下，在相似浓度（50μM）下，GABAA受体激动剂异尼克酸和异胍基乙酸，或拮抗剂荷包牡丹碱，并未显著抑制左旋肉碱摄取。然而，相对高浓度（500μM）的荷包牡丹碱具有抑制作用（38%）。GABAB受体激动剂巴氯芬或拮抗剂巴氯芬无效，尽管5 - 氨基戊酸在50和500μM时均显著抑制摄取，分别导致22%和48%的抑制。与荷包牡丹碱一样，其效果不如GABA或特异性GABA摄取阻滞剂。结果表明，大鼠皮层神经元对左旋肉碱的摄取部分是通过一个可被GABA和GABA摄取阻滞剂强烈抑制的过程进行的。
