Extracellular matrix peptides as theranostic mediators of ischemic stroke neuroprotection and repair: lessons from studies in remote ischemic preconditioning and exercise

Ischemic stroke remains one of the leading causes of long-term disability and death worldwide, despite being a preventable neurological injury. Efforts in prevention have included urging patients toward a healthier lifestyle, including a healthy diet and regular exercise. Experimental and clinical evidence supporting these healthy-living recommendations found that systemic interventions like exercise impart protection for both rodents and humans. Despite these data, patients who are at the highest risk for stroke are unlikely to make these long-term lifestyle changes. Herein lies a challenge for clinicians and researchers alike to identify pharmaceutical or physical substitutions for exercise (e.g. limb remote ischemic conditioning (RIC)) that can be administered upon identification of a stroke, or a high risk of stroke, in the clinic. One impact of exercise is to promote vascular remodeling in the skeletal muscle. A chief component of this remodeling is proteolysis of the vascular extracellular matrix. Likewise, similar remodeling of the extracellular matrix occurs in the brain following focal ischemia. Among the most heavily proteolyzed matrix components is perlecan, a heparan sulfate proteoglycan. Importantly, we found that this proteolysis generates neuroprotective fragments, including the LG3 peptide, following experimental stroke. Exercise also increases LG3 peptide levels in urine and serum, making this not only a mediator of exercise-mediated neuroprotection, but also a potential theranostic biomarker for an efficacious delivery of systemic interventions like exercise. In this review, we discuss the potential benefits and mechanisms of exercise and RIC, and propose that the LG3 peptide could be a theranostic for stroke recovery.