Department of Pharmacology and Neuroscience, University of
North Texas Health Science Center at Fort Worth (UNTHSC), Fort Worth, Texas.
Discovery of treatments to protect axonal function of neurons
and prevent permanent disability associated with progressive multiple sclerosis
(MS) has faced the uphill challenge of assessing relatively small changes in
accumulated axon damage within a background environment that is disorganized by
CNS inflammation. We hypothesized that transient immunosuppression after
initiation of MS-like autoimmune mechanisms would disassociate development of
MS-like myelinated axon pathology from development of CNS inflammation in a rat
model of autoimmune optic neuritis (AON). A rat model of myelin oligodendrocyte
glycoprotein peptide-induced AON was transiently treated (on days 3-7 after
antigen exposure) with 5-(4-phenylbutoxy)psoralen (PAP-1), an immunomodulatory
drug previously shown specifically to suppress proliferation of effector memory
T-cells and immunoglobulin class-switched B-cells. Thirteen days after antigen
exposure, optic nerves were harvested for quantitative assessment of 12
MS-associated pathologies using microfluorimetry. With one exception, the
immunoreactivities (-ir) for eight markers of MS-like neuroinflammation and
immune infiltration were significantly reduced (P < 0.05) by transient PAP-1
treatment, often to levels significantly below those detected in normal control
rat optic nerves. With one exception, four immunoreactive markers of MS-like
myelinated axon pathology were detected at levels indicating increased
axon/myelin pathology compared with vehicle-treated rats with AON (P < 0.05).
These data suggest the conclusion that early causative mechanisms in CNS
autoimmunity initiate signaling mechanisms that diverge into two separate
pathways, one that is strongly associated with inflammatory responses and one
that is associated predominantly with disturbed axon-myelin interactions and
impaired fast axonal transport. (c) 2008 Wiley-Liss, Inc.
