Inhibition of SOD1 expression by mitomycin C is a non-specific consequence of cellular toxicity
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition that results in the death of the large motor neurons of the brain and spinal cord. Familial ALS accounts for 10% of all ALS cases. Approximately 25% of these cases are due to mutations in the SOD1 gene. Several lines of evidence argue that mutant SOD1 causes ALS by a toxic gain of function. We therefore anticipate that measures that reduce the levels of mutant SOD1 expression should be beneficial in mutant SOD1-associated ALS patients. Mitomycin C (MC) is an antitumor antibiotic previously demonstrated to reduce SOD1 expression in a reporter gene system. We investigated whether MC reduces endogenous SOD1 expression levels both in vitro and in vivo. MC reduced human and rat SOD1 protein levels in vitro, with a concomitant decrease in actin and increase in p53 protein levels, as detected by Western blotting. However, this decrease in SOD1 protein levels was paralleled by a similar decrease in cell viability. In contrast, intracerebroventricular administration of MC to rats and mice failed to produce any effect on brain or spinal cord SOD1 protein levels. Our data indicate the apparent inhibition of SOD1 expression by MC is a non-specific consequence of MC-induced cellular toxicity.
- [Show abstract] [Hide abstract] ABSTRACT: Extensive epidural fibrosis after lumbar spine surgery might be an important underlying cause of failed-back syndrome. Based on previously obtained data, the effect of mitomycin C (MMC) in a concentration of 0.1 mg/ml on spinal epidural fibrosis in a rat laminectomy model was investigated in a large series. Eighty adult Wistar rats underwent lumbar laminectomy. In 40 rats, MMC in a concentration of 0.1 mg/ml was locally applied to the laminectomy sites. No similar treatment was performed in the other 40 rats. At intervals from one to 12 weeks after laminectomy, both macroscopic and histological evaluations were performed. For radiological investigation, 10 rats underwent magnetic resonance (MR) imaging at 6 weeks postoperatively. Furthermore, the concentration of MMC in cerebrospinal fluid (CSF) and serum was determined 12 hours postoperatively in seven rats. Due to ease of absorption, high levels of MMC were rapidly detectable in serum, whereas the values obtained from the CSF were markedly lower. In the majority of MMC-treated laminectomy sites, epidural scarring was significantly reduced and dural adhesions were absent, in comparison with control sites (p < 0.001), as confirmed by MR images. Accordingly, the macroscopic dissection of epidural fibrous tissue to reexpose the dura mater was performed more easily and without severe bleeding in these rats. The healing of skin and the lumbar fascia was not affected, and dural leakage was not observed. All control sites showed dense epidural fibrosis with marked dural adherence. In this experimental model, it was shown that locally applied MMC in a concentration of 0.1 mg/ml effectively reduces epidural fibrosis and dural adherence without side effects in rats that underwent lumbar laminectomy.0Comments 11Citations
- [Show abstract] [Hide abstract] ABSTRACT: The number of genes associated with motor neuron degeneration has increased considerably over the past few years. As more gene mutations are identified, the hope arises that certain common themes and/or pathways become clear. In this overview, we focus on recent discoveries related to amyotrophic lateral sclerosis (ALS), spinal muscular atrophies (SMA), and distal hereditary motor neuropathies (dHMN). It is striking that many of the mutated genes that were linked to these diseases encode proteins that are either directly or indirectly involved in axonal transport or play a role in RNA metabolism. We hypothesize that both phenomena are not only crucial for the normal functioning of motor neurons, but that they could also be interconnected. In analogy with the situation after acute stress, axonal mRNA translation followed by retrograde transport of the signal back to the nucleus could play an important role in chronic motor neuron diseases. We hope that information on the genetic causes of these diseases and the insight into the pathologic processes involved could ultimately lead to therapeutic strategies that prevent or at least slow this degenerative process.0Comments 21Citations
- [Show abstract] [Hide abstract] ABSTRACT: The authors conducted a study to determine the effectiveness of mitomycin C (MMC) in preventing epidural fibrosis in rats which underwent craniectomy. Craniectomies were performed in the right frontoparietal region; after the procedure the animals had been divided in 2 groups of 10 each. Cotton pads soaked with 0.1 mg/ml MMC or saline (control) were applied to the operative sites. Four weeks after craniectomy the rats were sacrificed, and epidural fibrosis was evaluated histologically. The dura mater thickness, the density of epidural fibrosis, arachnoidal involvement, and bone regeneration were determined. No obvious adhesion formed in the rats in the MMC group, but severe epidural adhesions were found in control group. The duramater thickness, the density of epidural fibrosis, and arachnoidal involved rat number in the MMC group were significantly lower than in control groups. Epidural fibrosis can be a devastating condition that forms after craniectomy. Topical application of mitomycin C may be a successful method of preventing epidural fibrosis following craniectomy.0Comments 4Citations