Aluminum-induced neurofilamentous changes in cultured rat dorsal root ganglia explants.
Intrathecal administration of aluminum (AI) salts to susceptible species causes prominent accumulations of neurofilaments (NFs) in neurons of the CNS. Involved nerve cells display abnormal phosphorylation of perikaryal NFs, impaired axonal transport of NFs, and reduced levels of mRNA for NF proteins. Further understanding of the pathogenesis of AI toxicity has been limited by difficulties inherent in the available in vivo systems. For this reason, we have developed a model to study the effects of AI on cultured sensory neurons. Explant cultures of rat dorsal root ganglia (DRG) were exposed to 1 mM aluminum lactate for 1 d, 3 d, or 7 d and then examined morphologically. Accumulations of NFs were noted as early as 1 d after exposure, and prominent masses of NFs were seen at 3 and 7 d. Northern analysis of mRNA extracted from the cultured ganglia showed that high, medium, and low molecular weight NF protein mRNA levels were markedly reduced compared to control values by 1 d of exposure. Class II beta-tubulin mRNA was also moderately decreased. Reversibility of toxicity was assessed by removing the aluminum lactate from the medium after a 3 d exposure and examining the cultures 1 week later. The perikaryal masses of NFs dispersed and the levels of mRNA coding for the NF proteins and class II beta-tubulin increased. The neurotoxic effects of AI on cultured DRG recapitulates the effects of intrathecal administration of AI on animals; this model produces similar changes in neuronal morphology with neurofilamentous masses and similar modifications of NF gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)
Gilbert
M R
MR
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Harding
B L
BL
Hoffman
P N
PN
Griffin
J W
JW
Price
D L
DL
Troncoso
J C
JC
D000535:Aluminum / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D066298:In Vitro Techniques; D008854:Microscopy, Electron; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats
D016900:Neurofilament Proteins; D012333:RNA, Messenger; D000535:Aluminum