LAUSR

ETHNOPHARMACOLOGICAL RELEVANCE Ginkgo biloba L. is a kind of traditional Chinese medicinal material with a long history. Its main active components, ginkgolides, can be used for the treatment of stroke and other cardio-cerebrovascular diseases. Ginkgo Diterpene Lactone Meglumine Injection (GDLI) as a modernized TCM attracted much attention because of its neuroprotective and anti-inflammatory properties. AIM OF THE STUDY To uncover the effects of GDLI on ischemic stroke patients, as well as the underlying biomarkers involved in sub-acute stroke. MATERIALS AND METHODS We used a state-of-the-art targeted proteomics chip to investigate the association between a large number of serum proteins (1101 proteins) and the sub-acute phase post ischemic stroke. Then, the relative proteins of anti-apoptosis, anticoagulant, and neuroprotection of GDLI were confirmed in the animal models. RESULTS Compared with serum from healthy volunteers, we identified 18 up-regulated proteins (FC ≥ 1.5) involved in the inflammatory response, and 55 down-regulated proteins involved in the immune response and nervous system development in the sub-acute ischemic stroke. The pro-inflammatory proteins, such as IL17A MST1R, CSF2, CSF3R, TLR3, CCL19, TNFRSF19 and TNFRSF12, were significantly increased in serum, illustrating that the lasting chronic inflammatory status was evident in sub-acute phase post stoke. However, the common pro-inflammatory proteins, such as IL-1B, IL-6, IL-8, TNF- alpha, IFN-γ and IL-10, known to be up-regulated in acute stroke, had close or lightly lower levels than health human (FC ≥ 1.5, P > 0.05). And some cytokines (TNFRSF6B, IL3, CCL13, LTBR, IL10RB, HLA-A, IL36B, TNFRSF8, CCL18, IL37) also were markedly down-regulated in sub-acute phase of stroke. These proteins are highly associated with onset of stroke-induced immunosuppression and post-stroke infection. Moreover, we noticed that Ginkgo Diterpene Lactone Meglumine Injection (GDLI) treatment for 14 days was helpful to recovery in patients with sub-acute phase of stroke. After the treatment of GDLI, it was observed that several inflammatory cytokines (i.e. IL-17A and IL-28A), chemokine (i.e. HCC-1) and Coagulation Factor III were reduced, meanwhile the anti-inflammatory cytokines (IL-10 R alpha, GREMLIN, and Activin C) and neurotrophic factors (Neurturin and IGFBP2) were found to be up-regulated in stroke patients through self-control observation. Finally, we validated the IGFBP2 as novel markers in the animal models. CONCLUSIONS In summary, the potential markers in sub-acute stroke patients were highly different from known protein markers in acute phase of ischemic stroke. The serum protein IGFBP2 could be novel biomarkers for the treatment of GDLI in sub-acute stroke patients. Our present findings provide an innovative insight into the novel treatment of GDLI in ischemic stroke therapy.