Gass P, Herdegen T, Bravo R, Kiessling M
Department of Neuropathology, University of Heidelberg, Germany.
Neuroscience. 1993 Apr;53(3):749-58. doi: 10.1016/0306-4522(93)90621-l.
The expression pattern of six different immediate early gene-encoded proteins was examined in the rat forebrain after intraperitoneal administration of MK-801, a non-competitive N-methyl-D-aspartate receptor antagonist, at doses of 3 mg/kg and 0.3 mg/kg, respectively. Following MK-801 treatment, the presence of c-FOS, FOS B, KROX-24, c-JUN, JUN B, and JUN D were investigated by immunocytochemistry with specific antisera at different time intervals up to 48 h. Selective induction of all six immediate early genes was found in layer III neurons of the posterior cingulate and retrosplenial cortex. More complex effects were observed in the neocortex: MK-801 did not influence constitutive expression of different FOS and JUN proteins, but caused marked induction of c-FOS, FOS B, JUN B and JUN D, mainly in layer IV, but also in layers V and VI. In contrast, strong neocortical constitutive expression of KROX-24 was almost abolished by MK-801 administration, and replaced by an expression pattern similar to that of FOS and JUN proteins. Subcortical areas such as the hypothalamus and thalamus demonstrated an induction of a subset of immediate early genes (c-fos, fos B, Krox-24, jun B). Injection of MK-801 caused the same distributional pattern of immediate early gene expression irrespective of the dose given, but the extent of changes was stronger after 3 mg/kg, and altered levels of immunoreactivity persisted longer. In many experimental paradigms, immediate early genes are induced by N-methyl-D-aspartate receptor-mediated mechanisms. This induction can readily be blocked by N-methyl-D-aspartate receptor antagonists like MK-801. Our data, however, indicate that MK-801 itself causes immediate early gene expression in specific neuronal populations. In the present study MK-801-elicited expression of immediate early gene-encoded proteins seems to identify reversibly injured neurons, mainly in layer III of the posterior cingulate and retrosplenial cortex. These neurons have previously been shown to be the principal target of N-methyl-D-aspartate receptor antagonist toxicity. Since immediate early gene induction precedes heat-shock protein expression as well as pathomorphological changes, and is induced in additional cortical cell populations, it seems to be a more rapid and more sensitive indicator of non-lethal neuronal injury.
分别以3mg/kg和0.3mg/kg的剂量腹腔注射非竞争性N-甲基-D-天冬氨酸受体拮抗剂MK-801后，检测大鼠前脑六种不同即早基因编码蛋白的表达模式。MK-801处理后，在长达48小时的不同时间间隔，用特异性抗血清通过免疫细胞化学法研究c-FOS、FOS B、KROX-24、c-JUN、JUN B和JUN D的存在情况。发现在后扣带回和压后皮质的III层神经元中所有六种即早基因均有选择性诱导。在新皮质中观察到更复杂的效应：MK-801不影响不同FOS和JUN蛋白的组成性表达，但主要在IV层以及V层和VI层引起c-FOS、FOS B、JUN B和JUN D的显著诱导。相反，MK-801给药几乎消除了新皮质中KROX-24的强组成性表达，并被一种类似于FOS和JUN蛋白的表达模式所取代。下丘脑和丘脑等皮质下区域显示出一部分即早基因（c-fos、fos B、Krox-24、jun B）的诱导。注射MK-801后，即早基因表达的分布模式与给药剂量无关，但3mg/kg后变化程度更强，免疫反应性改变水平持续时间更长。在许多实验范式中，即早基因是由N-甲基-D-天冬氨酸受体介导的机制诱导的。这种诱导很容易被MK-801等N-甲基-D-天冬氨酸受体拮抗剂阻断。然而，我们的数据表明，MK-801本身可导致特定神经元群体中即早基因表达。在本研究中，MK-801诱导的即早基因编码蛋白表达似乎可识别可逆性损伤的神经元，主要位于后扣带回和压后皮质的III层。这些神经元先前已被证明是N-甲基-D-天冬氨酸受体拮抗剂毒性的主要靶点。由于即早基因诱导先于热休克蛋白表达以及病理形态学变化，并且在额外的皮质细胞群体中被诱导，它似乎是非致死性神经元损伤更快速、更敏感的指标。
