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P2X7: a target for neuroprotection and neuroinflammation in multiple sclerosis
Author(s): ,
R. Gruber
Affiliations:
Neuroinflammation and MS Research, Sanofi Neuroscience, Framingham, MA, United States
,
L. Woodworth
Affiliations:
Neuroinflammation and MS Research, Sanofi Neuroscience, Framingham, MA, United States
,
K. Radzwill
Affiliations:
Neuroinflammation and MS Research, Sanofi Neuroscience, Framingham, MA, United States
,
M. LaMorte
Affiliations:
Neuroinflammation and MS Research, Sanofi Neuroscience, Framingham, MA, United States
,
P. Pevarello
Affiliations:
Chemistry, Axxam S.p.A., Milan, Italy
D. Ofengeim
Affiliations:
Neuroinflammation and MS Research, Sanofi Neuroscience, Framingham, MA, United States
ECTRIMS Online Library. Gruber R. Oct 12, 2018; 229066; P1226
Ross Gruber
Ross Gruber
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Abstract: P1226

Type: Poster Sessions

Abstract Category: Therapy - Neuroprotection and Repair

Background: The pathological hallmarks of Multiple Sclerosis (MS) include demyelinated lesions. Active MS lesions exhibit myelin and oligodendrocyte loss, dense infiltration with debris-laden CD68+ macrophages and/or microglia and lymphocytes. Within active lesions, axons are largely devoid of myelin, and are vulnerable to injury. P2X7 is a purinergic receptor activated by high levels of ATP (high µM) and is expressed by macrophages and several brain cell types, including microglia and oligodendrocyte precursor cells (OPCs). While extracellular ATP levels are typically low, cytosolic concentrations of ATP range between 5 and 10 mM. Therefore, CNS insults such as inflammation, trauma, stroke, and neurodegeneration can cause a marked release of intracellular ATP into the extracellular space, making ATP an important danger signal. P2X7 activation contributes to the release of IL-1β and other inflammatory cytokines, and plays a direct role in OPC death.
Objective: We hypothesized that inhibition of P2X7 activation in the CNS will reduce neuroinflammation, promote protection of oligodendrocytes, and attenuate disease pathology.
Results: In vitro, P2X7 antagonism prevents BzATP-mediated OPC cell death. Additionally, in vitro P2X7 antagonism strongly disrupts the release of IL-1β in mouse microglia, human macrophages and in a human whole blood assay. Finally, we have observed therapeutic efficacy of P2X7 antagonism in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS, with a corresponding reduction in demyelinating lesions and plasma neurofilament heavy (NFH), as a biomarker of neurodegeneration.
Conclusion: Our data suggest that P2X7 antagonism may be a viable therapeutic strategy in MS.
Disclosure: Study was supported by Sanofi. RG, LW, KR, ML, DO are employees of Sanofi, PP is an employee of Axxam S.p.A

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