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The use of protease inhibitors in experimental allergic neuritis
M Schabet1, J N Whitaker, K Schott
1Department of Neurology, Klinikum Schnarrenberg, University of Tübingen, F.R.G.
Abstract:
In experimental allergic neuritis (EAN) break-down of myelin is attributed to macrophages, which among other factors contain and secrete proteases. In vitro studies have shown that cathepsin D, an acidic aspartyl endopeptidase, and plasmin can degrade myelin proteins. In order to elucidate a potential therapeutic effect of protease inhibitors we treated Lewis rats, immunized with bovine peripheral nervous system myelin, with epsilon-amino-caproic acid (EACA) or pepstatin. EACA or pepstatin was administered twice daily by intraperitoneal injection beginning on day 6 postimmunization or from the onset of disease (on day 12) through day 24. Compared to saline-treated controls, animals treated with either of the inhibitors showed delayed development of clinical signs and electrophysiological abnormalities. Maximal severity and the further course of disease, however, were not different in control and treated groups. Immunohistological evaluation of sciatic nerve specimens on day 24 postimmunization showed equal numbers of cells positive for ED1 (macrophages) and cathepsin D in all animal groups. There was also no difference in the spontaneous proteolytic activity of the sciatic nerve homogenates at pH 2.8, 5.0, and 7.4. Incubation of the homogenates with pepstatin, however, significantly reduced proteolytic activity at pH 2.8 and 5.0, while EACA had no effect at any pH tested. These results imply that treatment to limit the infiltration of cathepsin D-positive cells or to reduce the induction or activity of cathepsin D may provide a therapeutic avenue for treating inflammatory demyelination of the peripheral nervous system.
Insights
Protease inhibitors like pepstatin delayed disease onset in experimental allergic neuritis, a model for peripheral nervous system demyelination. However, they did not alter disease severity, suggesting cathepsin D inhibition as a potential therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Experimental allergic neuritis (EAN) involves myelin breakdown by macrophages secreting proteases.
- Cathepsin D and plasmin are identified as myelin-degrading proteases in vitro.
- Protease inhibitors offer a potential therapeutic strategy for EAN.
Purpose of the Study:
- To investigate the therapeutic potential of protease inhibitors epsilon-amino-caproic acid (EACA) and pepstatin in EAN.
- To assess the impact of these inhibitors on clinical signs, electrophysiology, and sciatic nerve pathology.
Main Methods:
- Lewis rats were immunized with myelin and treated with EACA or pepstatin starting at different disease stages.
- Clinical and electrophysiological parameters were monitored.
- Immunohistology (ED1, cathepsin D) and proteolytic activity assays were performed on sciatic nerve samples.
Main Results:
- Pepstatin and EACA treatment delayed the onset of clinical and electrophysiological abnormalities in EAN.
- Maximal disease severity and progression were not affected by inhibitor treatment.
- Pepstatin significantly reduced proteolytic activity at acidic pH in nerve homogenates, while EACA had no effect.
Conclusions:
- Cathepsin D activity contributes to myelin degradation in EAN.
- Targeting cathepsin D-positive cells or inhibiting cathepsin D activity may offer a therapeutic approach for peripheral nervous system inflammatory demyelination.