Axonal degeneration is an early pathological feature in autoimmune‐mediated demyelination in mice

Abstract

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system (CNS), characterised by focal destruction of myelin. Although it is evident that the immune system contributes to tissue destruction in MS, it is still unclear as to whether this immune response is a cause or a consequence of the disease process. In addition, there is debate over the contribution of axonal damage to clinical progression. We have described a murine model of relapsing-remitting MS (RR-MS), the most common form of the disease, following immunisation with the myelin component, myelin oligodendrocyte glycoprotein (MOG). We showed that a single injection of a MOG peptide (MOG(35-55)) in NOD/Lt mice induces a paralytic relapsing disease with extensive plaque-like demyelination. This model also mimics many of the immunological features associated with RR-MS. To investigate the relationship between clinical episodes, inflammation, and demyelination/remyelination, we analysed lesions during each attack and remission over the course of the disease, using histological, immunocytochemical, and electron microscopy (EM) techniques. We show that morphological features of lesions in our model resemble those observed in MS. Indeed, severe inflammation and demyelination coincide with the peak of clinical episodes while remissions are characterised by quiescent plaques. Furthermore, axonal damage is evident from the earliest stage of the disease and increases in severity with subsequent relapses. These data establish that in the model of MS-like disease, the peak of clinical episodes coincides with severe inflammation and demyelination and that axonal pathology correlates with clinical progression.

Effects of progesterone in the spinal cord of a mouse model of multiple sclerosis

“…Mice were monitored daily for weight loss and neurological signs of EAE. Disease severity was scored as previously published for EAE mice [25,30]: grade 0 = no signs, grade 1 = partial loss of tail tonicity, grade 2 = loss of tail tonicity, difficulty in righting, grade 3 = unsteady gait and mild paralysis, grade 4 = hind-limb paralysis and incontinence, grade 5 = moribund or death. EAE in hormone-free animals developed approximately on day 10 and they were sacrificed on day 16 when the disease was still in an acute phase.…”

“…EAE may be induced with a number of myelin proteins, including myelin oligodendrocyte glycoprotein (MOG). MOG is expressed on the outer surface of oligodendrocytes and its administration has many features in common with MS [25]. Rodents with EAE present spinal cord demyelination, inflammatory cell infiltration, microglial activation, axonal loss, astrocytosis, proliferation of oligodendrocyte precursor cells and neuronal dysfunction [26][27][28][29].…”

“…Rodents with EAE present spinal cord demyelination, inflammatory cell infiltration, microglial activation, axonal loss, astrocytosis, proliferation of oligodendrocyte precursor cells and neuronal dysfunction [26][27][28][29]. Clinically, afflicted mice show typical neurological deficits, ranging from loss of tail tonicity to several degrees of paralysis to death [25,26,30].…”

Effect of aqueous extract of Achillea millefolium on the development of experimental autoimmune encephalomyelitis in C57BL/6 mice

“…The severity of disease among EAE mice were scored (6 grades) based on the method reported by Onuki et al ., as follows: Grade 0 = if there was no sign of disease, grade 1 = if there was partial loss of tail tonicity, grade 2 = if there was loss of tail tonicity along with tail righting disabilities, grade 3 = if there was unsteady gait and mild paralysis of one hind limb, grade 4 = if there were both hind-limb paralysis and incontinence, grade 5 = if there was quadriplegia, and grade 6 = death. [12] The mice were humanely sacrificed 21 days after immunization with MOG35-55.…”

Stem Cell and Gene Therapeutic Strategies for the Treatment of Multiple Sclerosis

“…For example, adult oligodendrocytes divide slower and require longer exposure to mobilizing cytokines in comparison to younger oligodendrocytes [268,269]. Finally, given that cross-talk interactions between oligodendrocytes and axons are paramount for their respective maintenance and survival [270,271], the extensive axonal transections that been demonstrated in acute MS and EAE lesions [9,272,273] may impede the remyelination process. As insurmountable as these blockades may seem, a number of therapeutic strategies have been devised where they attempt to overcome these barriers in addition to rescuing the oligodendrocyte and axonal pathology that is at the heart of MS.…”