Abstract T P89: Curcumin Encapsulated Stem Cell Exosomes Attenuate Ischemic Brain Injury in Type 1 Diabetic Akita Mice

Abstract

Background and Purpose: Stroke in type-1 diabetes mellitus (T1DM) is severe in terms of exacerbated brain damage and severe functional decline as compared to non-diabetic stroke. Curcumin possesses remarkable medicinal properties and stem cells exosomes (nano-vesicles; 40-100 nm) have paracrine effects with neovascularization properties. The therapy available for stroke (tissue plasminogen activator) is not effective in diabetic stroke and leads to excessive vasodilation and hemorrhagic transformations. Therefore, we tested the hypothesis that encapsulating curcumin to mouse embryonic stem cell exosomes mitigates type-1 diabetic stroke injury. Methods: We employed 8-10 weeks old male genetic T1DM Ins2+/- Akita mice. Ischemia was performed for 40 min and reperfusion for 7 days in the following mice groups: 1) Sham Akita , 2) Sham Akita + cur-exo , 3) IR Akita , 4) IR Akita + cur-exo . Exosomes were isolated from mouse embryonic stem cells culture conditioned media and encapsulated with curcumin ( cur-exo ). Therapeutic exo-cur units were used for mice treatment intranasally for 7 days. Brain cryo-sections were analyzed for vascular (VCAM, VE-cadherin), glial (GFAP), neuronal (Tuj1, nNOS) coupling in ipsilateral area. Neuronal loss, neurodegeneration was analyzed with NeuN, fluorojade-C staining. White matter damage was examined with luxol fast blue. Intra-carotid FITC-BSA infusion was used to assess venular leakage. Passive avoidance and auditory brainstem response tests were used to determine cognitive functions. Results: Treatment with cur-exo alleviated Infarct volume, edema, and vascular damage in IR Akita + cur-exo mice as compared to IR Akita mice. The axonal-glia damage and venular permeability were exacerbated in IR Akita mice, as compared to sham Akita , which were mitigated after cur-exo treatment. Cur-exo also ameliorated neurodegeneration and promoted neuronal survival as determined through immunolocalization studies. Further, cur-exo remarkably restored cognitive functions (p<0.001, n=6). Conclusion: Our results suggested that combining the therapeutic efficacy of curcumin and stem cells exosomes represent a novel treatment for stroke during T1DM. Acknowledgement: This work was supported by NIH grant HL107640.