Cytotherapy. 2018 May 15. pii: S1465-3249(18)30508-5. doi: 10.1016/j.jcyt.2018.04.004. [Epub ahead of print]

The combination of mannitol and temozolomide increases the effectiveness of stem cell treatment in a chronic stroke model.

Choi C¹, Kim HM¹, Shon J¹, Park J¹, Kim HT¹, Kang SH², Oh SH¹, Kim NK³, Kim OJ⁴.

Abstract

BACKGROUND:

The blood-brain barrier (BBB) presents a significant challenge to the therapeutic efficacy of stem cells in chronic stroke. Various methods have been developed to increase BBB permeability, but these are associated with adverse effects and are, therefore, not clinically applicable. We recently identified that combination drug treatment of mannitol and temozolomide improved BBB permeability in vitro. Here, we investigated whether this combination could increase the effectiveness of stem cell treatment in an animal model of chronic ischemic stroke.

METHODS:

Chronic stroke was induced in rats by middle cerebral artery occlusion (MCAo). After then, rats were administered human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) by intravenous injection with or without combination drug treatment of mannitol and temozolomide. To evaluate the therapeutic efficacy, behavioral and immunohistochemical tests were performed, and the differences among control, stem cell only, combination drug only and stem cell with combination drug treatment were analyzed.

RESULTS:

Although no hUC-MSCs were detected in any group, treatment with stem cells and combination drug of mannitol and temozolomide increased the intracerebral delivery of hCD63-positive microvesicles compared with stem cell only treatment. Furthermore, treatment with stem cells and drug combination ameliorated behavioral deficits and increased bromodeoxyuridine-, doublecortin- and Reca-1-positive cells in the perilesional area as compared with other groups.

DISCUSSION:

The combination drug treatment of mannitol and temozolomide allowed for the efficient delivery of hUC-MSC-derived microvesicles into the brain in a chronic stroke rat model. This attenuated behavioral deficits, likely by improving neural regeneration and angiogenesis. Thus, combination drug treatment of mannitol and temozolomide could be a novel therapeutic option for patients with chronic ischemic stroke.