Abstract
BackgroundMultiple sclerosis is widely accepted as an inflammatory disease. However, studies indicate that degenerative processes in the CNS occur prior to inflammation. In the widely used animal model experimental autoimmune encephalomyelitis (EAE), we investigated the significance of degenerative processes from mitochondrial membrane potentials, reactive oxidative species, cell death markers, chemokines, and inflammatory cell types in brain, spinal cord, and optic nerve tissue during the effector phase of the disease, before clinical disease was evident.MethodsSixty-two rats were placed in eight groups, n = 6 to 10. Four groups were immunized with spinal cord homogenate emulsified in complete Freund’s adjuvant (one served as EAE group), three groups were immunized with complete Freund’s adjuvant only, and a control group was injected with phosphate buffered saline only. Groups were sacrificed 3, 5, 7, or 12–13 days after the intervention and analyzed for early signs of CNS degeneration.ResultsLoss of mitochondrial membrane potential and oxidative changes was observed days before clinical disease debut at day 9.75 ± 0.89. The early mitochondrial changes were not associated with cytochrome C release, cleavage of caspases 9 (38/40 kDa) and 3 (17/19 kDa), and cleavage of PARP (89 kDa) or spectrin (120/150 kDa), and apoptosis was not initiated. Axonal degeneration was only present at disease onset. Increases in a range of cytokines and chemokines were observed systemically as a consequence of immunization with complete Freund’s adjuvant, whereas the encephalitogenic emulsion induced an upregulation of the chemokines Ccl2, Ccl20, and Cxcl1, specifically in brain tissue, 7 days after immunization.ConclusionFive to seven days after immunization, subtle decreases in the mitochondrial membrane potential and an increased reactive oxygen species burden in brain tissue were observed. No cell death was detected at these time-points, but a specific expression pattern of chemokines indicates activity in the CNS, several days before clinical disease debut.
Highlights
Multiple sclerosis is widely accepted as an inflammatory disease
This typically coincides with the release of cytochrome C from the mitochondrial intramembrane space to the cytoplasm resulting in apoptosome formation, activation of caspase 9, and induction of apoptosis [20]
No differences in Δψ m were found between phosphate buffered saline (PBS), complete Freund’s adjuvant (CFA) 5, and the 3 days postimmunization (DPI) animals, whereas a significant decrease—15– 19 % reduction in area under the curve—was observed in the brain at days 5 and 7 post-immunization (Fig. 1b) and in the spinal cord at 7 days after immunization (Fig. 1c)
Summary
Multiple sclerosis is widely accepted as an inflammatory disease. In the widely used animal model experimental autoimmune encephalomyelitis (EAE), we investigated the significance of degenerative processes from mitochondrial membrane potentials, reactive oxidative species, cell death markers, chemokines, and inflammatory cell types in brain, spinal cord, and optic nerve tissue during the effector phase of the disease, before clinical disease was evident. In the clinic and according to the Revised McDonald Criteria, a diagnosis of MS may be supported by optical coherence tomography to detect early optic neuritis, magnetic resonance imaging for observation of multiple central nervous system (CNS) areas with neuronal damage, a cerebrospinal fluid analysis to investigate presence of non-specific inflammation markers, and visual evoked potentials to examine brain processing speed, the diagnosis is a clinical diagnosis [2]. Early diagnosis is paramount in order to provide optimal treatment, thereby implicating a need to establish reliable translational experimental models for MS disease induction
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