Nishizaki T, Nomura T, Matuoka T, Kondoh T, Enikolopov G, Sumikawa K, Watabe S, Shiotani T, Yoshii M
Department of Physiology, Kobe University School of Medicine, Japan.
Brain Res Mol Brain Res. 2000 Aug 14;80(1):53-62. doi: 10.1016/s0169-328x(00)00117-0.
Nefiracetam, a pyrrolidone derivative developed as an anti-dementia drug, persistently potentiated currents through neuronal nicotinic acetylcholine (ACh) receptors (alpha7, alpha4beta2) expressed in Xenopus oocytes, and the potentiation was blocked by either the selective protein kinase C (PKC) inhibitors, GF109203X and staurosporine, or co-expressed active PKC inhibitor peptide. In primary cultures of rat hippocampal neurons, nefiracetam increased the rate of nicotine-sensitive miniature excitatory postsynaptic currents, without affecting the amplitude, and the increase was inhibited by GF109203X. In addition, the drug caused a marked increase in the glutamate release from electrically stimulated guinea pig hippocampal slices, and the effect was abolished by the nicotinic ACh receptor antagonists, alpha-bungarotoxin and mecamylamine. Nefiracetam induced a long-lasting facilitation of synaptic transmission in both the CA1 area and the dentate gyrus of rat hippocampal slices, and the facilitation was inhibited by alpha-bungarotoxin and mecamylamine. Such facilitatory action was still found in the hippocampus with selective cholinergic denervation. The results of the present study, thus, suggest that nefiracetam enhances activity of nicotinic ACh receptors by interacting with a PKC pathway, thereby increasing glutamate release from presynaptic terminals, and then leading to a sustained facilitation of hippocampal neurotransmission. This may represent a cellular mechanism underlying the cognition-enhancing action of nefiracetam. The results also provide the possibility that nefiracetam could be developed as a promising therapeutic drug for senile dementia or Alzheimer's disease.
奈非西坦是一种作为抗痴呆药物开发的吡咯烷酮衍生物，它能持续增强通过非洲爪蟾卵母细胞中表达的神经元烟碱型乙酰胆碱（ACh）受体（α7、α4β2）的电流，并且这种增强作用可被选择性蛋白激酶C（PKC）抑制剂GF109203X和星形孢菌素或共表达的活性PKC抑制肽阻断。在大鼠海马神经元的原代培养中，奈非西坦增加了对烟碱敏感的微小兴奋性突触后电流的频率，而不影响其幅度，且这种增加被GF109203X抑制。此外，该药物使电刺激的豚鼠海马切片中的谷氨酸释放显著增加，并且该作用被烟碱型ACh受体拮抗剂α-银环蛇毒素和美加明消除。奈非西坦在大鼠海马切片的CA1区和齿状回中均诱导了突触传递的持久易化，并且这种易化被α-银环蛇毒素和美加明抑制。在选择性胆碱能去神经支配的海马中仍发现这种易化作用。因此，本研究结果表明，奈非西坦通过与PKC途径相互作用增强烟碱型ACh受体的活性，从而增加突触前终末的谷氨酸释放，进而导致海马神经传递的持续易化。这可能代表了奈非西坦认知增强作用的细胞机制。这些结果还提供了奈非西坦可被开发成为治疗老年痴呆或阿尔茨海默病的有前景的治疗药物的可能性。
