Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein

Area of Science:

• Neuroscience
• Immunology
• Biochemistry

Background:

• Selectins mediate tissue injury in stroke by promoting adhesion of inflammatory cells.
• Ischemic neurons express C1q, potentially marking them for complement-mediated damage or clearance.

Purpose of the Study:

• To develop and evaluate a hybrid molecule inhibiting both complement activation and selectin-mediated adhesion for stroke treatment.

Main Methods:

• Created a hybrid molecule by glycosylating soluble complement receptor-1 (sCR1) with sialyl Lewis x (sCR1sLex).
• Administered sCR1 and sCR1sLex to ischemic stroke models.
• Assessed molecule colocalization, inflammatory cell accumulation, and infarct volumes.

Main Results:

• sCR1 and sCR1sLex localized to ischemic cerebral microvessels and C1q-expressing neurons.
• Both molecules inhibited neutrophil and platelet accumulation.
• sCR1sLex significantly reduced cerebral infarct volumes, with additional benefit from sialyl Lewis x glycosylation.

Conclusions:

• Simultaneous inhibition of complement activation and selectin-mediated adhesion is a viable therapeutic strategy for ischemic stroke.
• The hybrid molecule sCR1sLex demonstrates efficacy in reducing stroke-related brain injury.