Mattson M P, Murrain M, Guthrie P B, Kater S B
Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky Medical Center, Lexington 40536.
J Neurosci. 1989 Nov;9(11):3728-40. doi: 10.1523/JNEUROSCI.09-11-03728.1989.
Neuritic regression and cell death (neurodegeneration) are common features of both normal nervous system development and neurodegenerative disorders. Growth factors and excitatory amino acid neurotransmitters have been suggested independently to play roles in neurodegenerative processes. The present study investigated the combined effects of fibroblast growth factor (FGF) and glutamate on the development and degeneration of cultured hippocampal neurons. Consistent with previous data, we found that FGF, but not NGF, promoted neuronal survival and dendritic outgrowth. In contrast, a low level of glutamate (50 microM) caused a reduction in dendritic outgrowth, and high levels (100 microM-1 mM) reduced neuronal survival in a dose-dependent manner. When cultures were maintained in the presence of FGF, there was a striking reduction in neuronal death normally caused by 100-500 microM glutamate. FGF raised the threshold for glutamate neurotoxicity. FGF also antagonized the outgrowth-inhibiting actions of glutamate. Measurements of intracellular calcium levels with fura-2 demonstrated a direct relationship between glutamate-induced rises in intracellular calcium and neurodegeneration. FGF reduced the glutamate-induced increases in intracellular calcium levels. However, when cultures were pretreated with the RNA synthesis inhibitor actinomycin D or with the protein synthesis inhibitor cycloheximide, FGF did not prevent glutamate-induced increases in intracellular calcium or neurodegeneration. Taken together, these results suggest that (1) interactions between growth factors and neurotransmitters may be important in brain development; (2) imbalances in these systems may lead to neurodegeneration; and (3) cellular calcium-regulating systems may be a common focus of growth factor and neurotransmitter actions.
神经突退化和细胞死亡（神经退行性变）是正常神经系统发育和神经退行性疾病的共同特征。生长因子和兴奋性氨基酸神经递质已被分别提出在神经退行性过程中发挥作用。本研究调查了成纤维细胞生长因子（FGF）和谷氨酸对培养的海马神经元发育和退化的联合作用。与先前的数据一致，我们发现FGF促进神经元存活和树突生长，而神经生长因子（NGF）则无此作用。相反，低水平的谷氨酸（50微摩尔）导致树突生长减少，高水平（100微摩尔至1毫摩尔）则以剂量依赖的方式降低神经元存活率。当培养物在FGF存在下维持时，通常由100 - 500微摩尔谷氨酸引起的神经元死亡显著减少。FGF提高了谷氨酸神经毒性的阈值。FGF还拮抗谷氨酸的生长抑制作用。用fura - 2测量细胞内钙水平表明，谷氨酸诱导的细胞内钙升高与神经退行性变之间存在直接关系。FGF降低了谷氨酸诱导的细胞内钙水平升高。然而，当培养物用RNA合成抑制剂放线菌素D或蛋白质合成抑制剂环己酰亚胺预处理时，FGF不能阻止谷氨酸诱导的细胞内钙升高或神经退行性变。综上所述，这些结果表明：（1）生长因子和神经递质之间的相互作用在大脑发育中可能很重要；（2）这些系统的失衡可能导致神经退行性变；（3）细胞钙调节系统可能是生长因子和神经递质作用的共同焦点。
