CNS inflammation: Mechanisms of damage and strategies for prevention

Axonal damage in the central nervous system (CNS) is an important pathological process in multiple sclerosis (MS). I established an acute demyelination model in the rat optic nerve through the microinjection of anti-galactocerebroside antibody and complement. Neurofilament (NF) and microtubule (MT) immunoreactivity was markedly reduced within large demyelination lesions that had little inflammation at 24 hours after the injection. Between 3 and 7 days post-injection, there was a gradual increase of macrophages/activated microglia in demyelinated areas. NF and MT immunoreactivity almost disappeared within severe inflammatory lesions, and numerous axonal spheroids appeared at the lesion edges. Axonal cytoskeleton changes were further characterized on the ultrastructural level. It is concluded that acute demyelination may by itself induce local axonal cytoskeleton breakdown and that macrophages/activated microglia may cause axonal transection in CNS demyelination areas.; I next explored other neurodegenerative features in experimental autoimmune encephalomyelitis (EAE). Extensive dendritic beading were observed in the white matter of lumbosacral spinal cord (LSSC) during acute and chronic EAE attacks, but recovered almost completely after clinical EAE recovery. In addition, synaptophysin, synapsin I, and PSD-95 immunoreactivity were markedly reduced in both the gray and white matter of LSSC during acute and chronic EAE attacks, but showed partial recovery after clinical EAE recovery. At various EAE stages, both dendritic beading and synaptic protein loss were correlated with the degree of inflammation in the LSSC. The dendritic and synaptic damage thus represents novel neuronal pathology that is associated with CNS autoimmune inflammation.; Finally, I examined whether CNS autoimmune inflammation could be prevented through the potentiation of CNS immunoprivilege. Intrathecal infusion of recombinant Fas ligand (rFasL) before the onset of acute EAE dose-dependently suppressed EAE severity and alleviated pathological inflammation in LSSC. This treatment markedly increased apoptosis in CNS inflammatory cells, but did not suppress systemic immune response to the EAE-inducing antigen. No damage to spinal cord neural cells was detected after rFasL infusion. It is concluded that intrathecal infusion of rFasL is able to eliminate early-infiltrating inflammatory cells within the CNS, and therefore blocks the later recruitment of inflammatory cells into the CNS.