Evidence for oxidative damage in a murine leukemia virus-induced neurodegeneration

Abstract

Vacuolation in cellular organelles within the central nervous system is a common manifestation of oxidative injury. We found that the spongiform vacuolation observed in PVC‐211 murine leukemia virus (PVC‐MuLV) neurodegeneration was associated with oxidative damage as detected by immunoreactivity for 3‐nitrotyrosine and protein carbonyl groups. This oxidative injury was present in brain before or concomitant with the appearance of activated microglia, vacuolation, and gliosis that characterize PVC‐MuLV neuropathology. Treatment of infected F344 rat pups with the antioxidant vitamin E transiently protected and prolonged the latency of PVC‐MuLV neurodegeneration. Taken together, these findings implicate oxidative damage and lipid peroxidation in the pathogenesis of PVC‐MuLV neurodegeneration. This animal model may be useful for studies of mechanisms and potential therapies for progressive neurodegeneration following a well‐defined insult. J. Neurosci. Res. 62:440–450, 2000. Published 2000 Wiley‐Liss, Inc.

Microglial response to murine leukemia virus-induced encephalopathy is a good indicator of neuronal perturbations

“…Here we sought to identify sites of neuronal damage using microglial reactivity as an indirect marker. Consistent with prior studies (Hoffman et al, 1992; Wilt et al, 2000), our findings on microglial activation reveal that the brain areas most sensitive to the consequences of viral infection are the spinal cord and brainstem primarily. This preferential involvement of the hindbrain, including the selective loss of rubrospinal neurons, is consistent with the neurological symptoms present in infected animals.…”

“…PVC-211 MuLV is a neuropathogenic, paralysis–inducing virus that produces a neurodegenerative syndrome characterized by tremor, loss of splay reflex, ataxia, and hindlimb weakness/paralysis after intracerebral inoculation into neonatal rats or mice (Hoffman et al, 1992; Kai and Furuta, 1984; Wilt et al, 2000). However, the neuropathology of this infection paradigm is not well defined or even controversial to date.…”

“…More recently, neuronal loss was reported to occur in the cerebellum and brainstem during end stage disease (Li et al, 2009). In addition, activation of microglia has been reported (Wilt et al, 2000) indicating that while not a blatantly inflammatory condition, an endogenous neuroinflammatory component does exist. In light of these disparate findings, we sought to further characterize the neuropathology of PVC-211 infection by performing a comprehensive analysis of microglial reactivity with a number of cell markers.…”

“…In previous studies (Li et al, 2009; Wilt et al, 2000), the microglial reaction to neonatal PVC-211 infection, was assessed using immunostaining with ED1 antibody, which is a macrophage marker that recognizes an intracytoplasmic, lysosomal antigen whose expression increases during phagocytic activity in monocytes and other tissue macrophages, including in microglia (Bauer et al, 1994; Dijkstra et al, 1985; Graeber et al, 1998). Thus, the endogenous neuroinflammatory response in PVC-211-infected rats has not been characterized with markers directed against microglial surface antigens to delineate non-activated (resting), as well as activated but non-phagocytic microglia which are ED1-negative (Graeber et al, 1998).…”

Experimental evidence that bioenergetics disruption is not mainly involved in the brain injury of glutaryl-CoA dehydrogenase deficient mice submitted to lysine overload

“…It is of note that a high protein intake is more damaging than Lys overload to GcdhÀ/À mice causing a higher mortality and morbidity (Zinnanti et al, 2006). Although it is difficult to determine the exact pathomechanisms of vacuole formation as observed in the present investigation, these pathophysiological findings may be a consequence of energy metabolism disruption , excitotoxicity (Forstner et al, 1999;Goodman et al, 1977; Hoffmann and Zschocke, 1999) or oxidative stress (Cubells et al, 1994;Saxena et al, 2010;Wilt et al, 2000). Interestingly, vacuolation characteristic of glutamate-mediated brain injury has been observed in post mortem examination of the basal ganglia and cerebral cortex of patients with GA I, suggesting excitotoxicity as a relevant mechanism underlying these histopathological findings (Goodman et al, 1977).…”