Inhibiting scrapie neuroinvasion by polyene antibiotic treatment of SCID mice
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Published on: November 6, 2013
Abstract:
The polyene antibiotic MS-8209 is currently one of the most effective drugs in the treatment of experimental scrapie. However, its mechanism of action and its site of intervention in the pathogenetical process of scrapie infection are largely unknown. It has been shown previously that the infection of immunodeficient SCID mice by the peripheral route provides a reliable model for direct scrapie neuroinvasion, bypassing the lymphoreticular system. Indeed, a proportion of SCID mice develop scrapie after a similar time to immunocompetent mice, despite their severe immune impairment. This model is now used to clarify the targets of MS-8209. In SCID mice, MS-8209 treatment protected against infection but did not prolong survival time. In SCID mice immunologically reconstituted prior to inoculation, the drug delayed the disease without an effect on the attack rate. These findings strongly suggest that MS-8209 acts by hampering the first step of the neuroinvasion process, i.e. the uptake of the infectious agent by peripheral nerve endings. The mechanism leading to the inhibition of agent propagation to nervous cells is discussed with regard to the properties of polyene antibiotics.
Insights
The polyene antibiotic MS-8209 effectively treats experimental scrapie by blocking the initial entry of the infectious agent into nerve endings. This study clarifies its mechanism, targeting neuroinvasion in SCID mice.
Area of Science:
- Neuroscience
- Infectious Diseases
- Pharmacology
Background:
- Scrapie is a fatal neurodegenerative disease caused by prions.
- The polyene antibiotic MS-8209 shows efficacy in experimental scrapie models.
- The precise mechanism of action and target of MS-8209 in scrapie pathogenesis remain unclear.
Purpose of the Study:
- To elucidate the mechanism of action and identify the target of the polyene antibiotic MS-8209 in experimental scrapie.
- To investigate the role of neuroinvasion in scrapie pathogenesis using a SCID mouse model.
- To determine if MS-8209 interferes with the initial uptake of the infectious agent by peripheral nerves.
Main Methods:
- Utilized immunodeficient SCID mice for modeling direct peripheral scrapie neuroinvasion.
- Administered MS-8209 to SCID mice and immunologically reconstituted SCID mice.
- Assessed the effects of MS-8209 on protection against infection, survival time, and disease onset.
Main Results:
- MS-8209 treatment protected SCID mice from scrapie infection but did not extend survival.
- In reconstituted SCID mice, MS-8209 delayed disease onset without altering the attack rate.
- These results indicate MS-8209 targets the initial step of neuroinvasion.
Conclusions:
- MS-8209 likely inhibits scrapie by preventing the infectious agent's uptake by peripheral nerve endings.
- The drug's mechanism involves hampering the early stages of neuroinvasion.
- Further investigation into polyene antibiotic properties may reveal more about inhibiting prion propagation.
