Combination therapy with bone marrow stromal cells and FK506 enhanced amelioration of ischemic brain damage in rats

• Published in: Life sciences (1973) 2011-07, Vol.89 (1-2), p.50-56
• Main Authors: Suda, Satoshi, Shimazaki, Kuniko, Ueda, Masayuki, Inaba, Toshiki, Kamiya, Nobuo, Katsura, Ken-ichiro, Katayama, Yasuo
• Format: Article
• Language: English
• Subjects: Acute transplantation; Allografts; Analysis of Variance; Animals; anti-inflammatory activity; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Bax protein; Bcl-2 protein; bcl-2-Associated X Protein - metabolism; Bone marrow; bone marrow transplant; Bone Marrow Transplantation - methods; brain; brain damage; Brain injury; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Brain Ischemia - pathology; Brain Ischemia - surgery; Cell activation; Cell survival; Cerebral blood flow; Cerebral focal ischemia; Combined Modality Therapy - methods; Edema; Immunohistochemistry; Immunosuppressive agents; In Situ Nick-End Labeling; infarction; Inflammation; Intravenous administration; intravenous injection; Ischemia; macrophage activation; Macrophages; Male; MSC; neuroglia; Neuroprotection; neuroprotective effect; neutrophils; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Rats, Sprague-Dawley; Stroke; stromal cells; Stromal Cells - transplantation; Tacrolimus; Tacrolimus - pharmacology; Tacrolimus - therapeutic use; Transplantation; Treatment Outcome
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2011.05.001

Transplantation of bone marrow stromal cells (MSCs) has been shown to ameliorate ischemic brain injury in animals. In the present study, we investigated whether the transplantation of MSCs combined with FK506, a clinically used immunosuppressant, enhanced neuroprotective effects in rat experimental stroke. Male Sprague–Dawley rats underwent transient 90min middle cerebral artery occlusion (MCAO). Two or 6h after ischemia onset, the rats were randomly assigned to receive intravenous administration of MSCs plus FK506, MSCs alone, FK506 alone, or vehicle. Infarct volume, and neurological and immunohistological assessments were performed to examine the effects of these therapies. In 2-hour post-ischemia treatment groups, significant improvement of infarct volume and neurological scores were observed 1day after combination therapy compared with monotherapy, and this neuroprotection continued for 7days. Combination therapy significantly reduced the number of TUNEL-positive apoptotic cells, increased Bcl-2 expression, decreased Bax expression, and suppressed neutrophil infiltration and microglia/macrophage activation compared to monotherapy. In 6-hour post-ischemia treatment groups, a significant reduction of infarct volume, edema index, and neurological score was observed only in the combination therapy group. Moreover, the number of engrafted MSCs on day 7 with combination therapy was significantly higher than with MSCs alone. Combination therapy using FK506 enhanced the anti-apoptotic and anti-inflammatory effects of MSCs and increased the survival of transplanted cells, leading to expansion of the therapeutic time window for MSCs.