A single dose of neuron-binding human monoclonal antibody improves spontaneous activity in a murine model of demyelination

Aleksandar Denic, Slobodan I Macura, Arthur E. Warrington, Istvan Pirko, Brandon R. Grossardt, Larry R Pease, Moses Rodriguez

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Our laboratory demonstrated that a natural human serum antibody, sHIgM12, binds to neurons in vitro and promotes neurite outgrowth. We generated a recombinant form, rHIgM12, with identical properties. Intracerebral infection with Theiler's Murine Encephalomyelitis Virus (TMEV) of susceptible mouse strains results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis. To study the effects of rHIgM12 on the motor function of TMEV-infected mice, we monitored spontaneous nocturnal activity over many weeks. Nocturnal behavior is a sensitive measure of rodent neurologic function because maximal activity changes are expected to occur during the normally active night time monitoring period. Mice were placed in activity boxes eight days prior to treatment to collect baseline spontaneous activity. After treatment, activity in each group was continuously recorded over 8 weeks. We chose a long 8-week monitoring period for two reasons: (1) we previously demonstrated that IgM induced remyelination is present by 5 weeks post treatment, and (2) TMEV-induced demyelinating disease in this strain progresses very slowly. Due to the long observation periods and large data sets, differences among treatment groups may be difficult to appreciate studying the original unfiltered recordings. To clearly delineate changes in the highly fluctuating original data we applied three different methods: (1) binning, (2) application of Gaussian low-pass filters (GF) and (3) polynomial fitting. Using each of the three methods we showed that compared to control IgM and saline, early treatment with rHIgM12 induced improvement in both horizontal and vertical motor function, whereas later treatment improved only horizontal activity. rHIgM12 did not alter activity of normal, uninfected mice. This study supports the hypothesis that treatment with a neuron-binding IgM not only protects neurons in vitro, but also influences functional motor improvement.

Original languageEnglish (US)
Article numbere26001
JournalPLoS One
Volume6
Issue number10
DOIs
StatePublished - Oct 12 2011

Fingerprint

Theilovirus
Demyelinating Diseases
Viruses
Neurons
Immunoglobulin M
monoclonal antibodies
neurons
animal models
Monoclonal Antibodies
nocturnal activity
mice
dosage
nervous system
Monitoring
Low pass filters
neurites
filters
monitoring
sclerosis
Neurologic Manifestations

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

A single dose of neuron-binding human monoclonal antibody improves spontaneous activity in a murine model of demyelination. / Denic, Aleksandar; Macura, Slobodan I; Warrington, Arthur E.; Pirko, Istvan; Grossardt, Brandon R.; Pease, Larry R; Rodriguez, Moses.

In: PLoS One, Vol. 6, No. 10, e26001, 12.10.2011.

Research output: Contribution to journalArticle

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