LoPachin R M, Lehning E J
Department of Anesthesiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA.
Neurotoxicology. 1997;18(1):7-22.
Traditionally, gamma-diketone neuropathy is classified as a distal axonopathy and has been characterized by giant axonal swellings in CNS and PNS tissues. These swellings contain neurofilamentous masses and are associated with thinning and retraction of the myelin sheath. It has been proposed that this axonopathy is caused by direct gamma-diketone modification of neurofilaments (NFs) involving pyrrolation of epsilon-amino groups on NF lysyl residues and possibly secondary autoxidation of the pyrrole rings with creation of covalent NF-NF crosslinks. Neurofilaments are thought to undergo chemical modification as they progress along the axonal axis and, eventually, accumulate at distal nodes of Ranvier where their proximodistal movement is impeded. Development of swelling presumably initiates axonal degeneration and subsequent functional deficits. However, other research suggests that axonal swellings are a non-specific effect related to subchronic gamma-diketone exposure. Such evidence draws into question the mechanistic relevance of these swellings. In contrast, research conducted over the past decade indicates axonal atrophy is a specific morphologic component of gamma-diketone neuropathy which might have both functional and mechanistic importance. In this overview, the potential neurotoxicological significance of both axonal swellings and atrophy are evaluated critically. Based on the evidence to be presented, we propose that axonal atrophy is the morphological consequence of the molecular mechanism of gamma-diketone neuropathy. Accordingly, several mechanistic scenarios related to the development of atrophy will be discussed. It is hoped that this Forum will stimulate scientific debate and initiate laboratory investigations which will either confirm or refute the involvement of axonal atrophy in gamma-diketone neurotoxicity. Investigating gamma-diketone atrophy might provide insight into the mechanism of other toxic axonopathies which are also associated with reduced axon caliber; e.g., acrylamide and carbon disulfide neuropathies.
传统上，γ-二酮神经病被归类为远端轴索性神经病，其特征是中枢神经系统和周围神经系统组织中出现巨大的轴突肿胀。这些肿胀包含神经丝团块，并与髓鞘变薄和退缩有关。有人提出，这种轴索性神经病是由神经丝（NFs）的直接γ-二酮修饰引起的，涉及NF赖氨酸残基上ε-氨基的吡咯化，并且吡咯环可能会发生继发自氧化，从而形成共价的NF-NF交联。神经丝在沿轴突轴前进时会发生化学修饰，并最终在Ranvier远端节段积聚，在那里它们的近远侧移动受到阻碍。肿胀的发展可能引发轴突变性及随后的功能缺陷。然而，其他研究表明，轴突肿胀是与亚慢性γ-二酮暴露相关的非特异性效应。此类证据使这些肿胀的机制相关性受到质疑。相比之下，过去十年进行的研究表明，轴突萎缩是γ-二酮神经病的一种特定形态学成分，可能具有功能和机制上的重要性。在本综述中，对轴突肿胀和萎缩的潜在神经毒理学意义进行了批判性评估。基于所提供的证据，我们提出轴突萎缩是γ-二酮神经病分子机制的形态学后果。因此，将讨论与萎缩发展相关的几种机制情况。希望这个论坛能激发科学辩论并启动实验室研究，以证实或反驳轴突萎缩与γ-二酮神经毒性的关联。研究γ-二酮萎缩可能有助于深入了解其他也与轴突管径减小相关的毒性轴索性神经病的机制，例如丙烯酰胺和二硫化碳神经病。
