Complement inhibition abrogates nerve terminal injury in Miller Fisher syndrome.

Abstract

A large body of clinical and experimental data indicate that complement activation is an important mechanism for neuronal and glial injury in Guillain-Barré syndromes. Inhibition of complement activation therefore might be expected to limit the progression of the disease. Using in vitro and in vivo models of the Guillain-Barré syndrome variant, Miller Fisher syndrome, we have shown previously that anti-GQ1b ganglioside antibodies target the presynaptic motor nerve terminal axon and surrounding perisynaptic Schwann cells, thereby mediating destructive injury through deposition of membrane attack complex. Here, we have used this model to investigate the effects of a novel therapeutic inhibitor of complement activation, APT070 (Mirococept), both in vitro and in vivo. In these models, APT070 completely prevents membrane attack complex formation, and thereby has a major neuroprotective effect at the nerve terminal, as assessed by immunohistology of perisynaptic Schwann cell and axonal integrity. These data provide a rationale for considering clinical trials of APT070 in Guillain-Barré syndrome, its variant forms, and other complement dependent neuromuscular disorders.

• Authors: Susan K Halstead, Peter D Humphreys, John A Goodfellow, Eric R Wagner, Richard A G Smith, Hugh J Willison
• Journal: Annals of neurology (Ann Neurol) Vol. 58 Issue 2 Pg. 203-10 (Aug 2005) ISSN: 0364-5134 [Print] United States
• PMID: 16049921 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Complement Inactivator Proteins
• Complement Membrane Attack Complex
• Glycoproteins
• Neurofilament Proteins
• Pregnancy Proteins
• Psg19 protein, rat
• S100 Proteins
• Complement C3c

Topics

• Animals
• Chi-Square Distribution
• Complement C3c (metabolism)
• Complement Inactivator Proteins (therapeutic use)
• Complement Membrane Attack Complex (metabolism)
• Diagnostic Imaging (methods)
• Diaphragm (drug effects, immunology, metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Glycoproteins (immunology)
• Immunization, Passive (methods)
• Immunohistochemistry (methods)
• In Vitro Techniques
• Male
• Mice
• Mice, Inbred BALB C
• Miller Fisher Syndrome (complications, drug therapy)
• Neurofilament Proteins (metabolism)
• Neuromuscular Junction (drug effects, immunology, metabolism)
• Pregnancy Proteins (immunology)
• S100 Proteins (metabolism)
• Trauma, Nervous System (drug therapy, etiology)