TREATMENTS FOR ACUTE FATAL ALPHAVIRAL ENCEPHALOMYELITIS

Inflammation;acute viral encephalomyelitis;alphavirus;Sindbis;neuroinflammatory diseases;AMPA;CNS;virus;IL-2;immunosuppressive;RNA virus;neuroprotection;6-diazo-5-oxo-l-norleucine;DON;GYKI-52466;GYKI-53655;AMPA receptor antagonist;not listed

Manivannan, SivabalanCulotta, Valeria L. ;

Johns Hopkins University

关键词: Inflammation;    acute viral encephalomyelitis;    alphavirus;    Sindbis;    neuroinflammatory diseases;    AMPA;    CNS;    virus;    IL-2;    immunosuppressive;    RNA virus;    neuroprotection;    6-diazo-5-oxo-l-norleucine;    DON;    GYKI-52466;    GYKI-53655;    AMPA receptor antagonist;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/39349/MANIVANNAN-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Inflammation in the nervous system is a necessary part of the response to CNS infection, but can also cause neuronal damage in both infectious and autoimmune diseases of the CNS. Sindbis virus is an enveloped, positive-strand RNA virus that infects neurons andcauses acute encephalomyelitis and fatal paralysis in mice. Adult C57BL/6 mice inoculated with the neurovirulent strain of Sindbis virus (NSV) succumb to fatal paralysis despite clearing infectious virusfrom the central nervous system.The anti-viral immune response rather than viral replication is a major contributor to neuronal damage in NSV infection.Thisstudy has evaluated two potential methods for treatment of alphavirus encephalomyelitis.Both methods involve small molecules with neuroprotective properties that also inhibit the peripheral immune response indistinct ways.DON (6-diazo-5-oxo-l-norleucine) is a glutamine antagonist initially studied as a chemotherapeutic for various cancers. Because glutamine is necessary for the synthesis of glutamate by glutaminase, proliferating primary T-cells are very sensitive to perturbations in glutamine metabolism. Daily intraperitoneal administration of DON to NSV-infected C57BL/6 mice inhibited the peripheral immune response to NSV, delayed viral clearance,decreased inflammation in the CNS, and protected NSV infected mice from fatal paralysis.However, once treatment was stopped, CNS inflammation appeared, infectious virus was cleared, andmice developed fatal paralysis.Protection was associated with failure to induce an adaptive immune response in the draining cervical lymph nodes and decreased leukocyte infiltration, lower levels of inflammatory cytokines, and delayed viral clearance in the brain. In vitro and in vivo studies showed that DON inhibited stimulus-induced proliferation of lymphocytes.GYKI-52466, an AMPA receptor antagonist,was previously shownto protect against NSV-induced fatal paralysis by being both neuroprotective and anti-inflammatory. GYKI belongs to a class of 2,3 benzodiazepines that allosterically inhibits glutamate gated AMPA receptors in the CNS.In this study, we demonstrated that AMPA receptor antagonists directly affect lymphocyte proliferation by preventing T-cell activation and the synthesis of IL-2. This non-canonical effect of an AMPA receptor antagonisthas implications for use in neuroinflammatory diseases.Both treatments providenew approaches totreatment of alphavirus induced encephalomyelitis.