J Korean Neurosurg Soc.  2015 Sep;58(3):167-174. 10.3340/jkns.2015.58.3.167.

Role of a Burr Hole and Calvarial Bone Marrow-Derived Stem Cells in the Ischemic Rat Brain: A Possible Mechanism for the Efficacy of Multiple Burr Hole Surgery in Moyamoya Disease

• Nam TK
• Park SW
• Park YS
• Kwon JT
• Min BK
• Hwang SN

• KMID: 2191352
• DOI: http://doi.org/10.3340/jkns.2015.58.3.167

Abstract

OBJECTIVE
This study investigates the role of a burr hole and calvarial bone marrow-derived stem cells (BMSCs) in a transient ischemic brain injury model in the rat and postulates a possible mechanism for the efficacy of multiple cranial burr hole (MCBH) surgery in moyamoya disease (MMD).
METHODS
Twenty Sprague-Dawley rats (250 g, male) were divided into four groups : normal control group (n=5), burr hole group (n=5), ischemia group (n=5), and ischemia+burr hole group (n=5). Focal ischemia was induced by the transient middle cerebral artery occlusion (MCAO). At one week after the ischemic injury, a 2 mm-sized cranial burr hole with small cortical incision was made on the ipsilateral (left) parietal area. Bromodeoxyuridine (BrdU, 50 mg/kg) was injected intraperitoneally, 2 times a day for 6 days after the burr hole trephination. At one week after the burr hole trephination, brains were harvested. Immunohistochemical stainings for BrdU, CD34, VEGF, and Doublecortin and Nestin were done.
RESULTS
In the ischemia+burr hole group, BrdU (+), CD34 (+), and Doublecortin (+) cells were found in the cortical incision site below the burr hole. A number of cells with Nestin (+) or VEGF (+) were found in the cerebral parenchyma around the cortical incision site. In the other groups, BrdU (+), CD34 (+), Doublecortin (+), and Nestin (+) cells were not detected in the corresponding area. These findings suggest that BrdU (+) and CD34 (+) cells are bone marrow-derived stem cells, which may be derived from the calvarial bone marrow through the burr hole. The existence of CD34 (+) and VEGF (+) cells indicates increased angiogenesis, while the existence of Doublecortin (+), Nestin (+) cells indicates increased neurogenesis.
CONCLUSION
Based on these findings, the BMSCs through burr holes seem to play an important role for the therapeutic effect of the MCBH surgery in MMD.

Keyword

Burr hole; Bone marrow; Stem cell; Moyamoya disease; Angiogenesis; Neurogenesis

MeSH Terms

Animals
Bone Marrow
Brain Injuries
Brain*
Bromodeoxyuridine
Infarction, Middle Cerebral Artery
Ischemia
Moyamoya Disease*
Nestin
Neurogenesis
Rabeprazole
Rats*
Rats, Sprague-Dawley
Stem Cells*
Trephining
Vascular Endothelial Growth Factor A
Bromodeoxyuridine
Vascular Endothelial Growth Factor A

Figure

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  Fig. 1 Possible treatment mechanism for multiple cranial burr hole surgery. In moyamoya disease, calvarial bone marrow-derived stem cells migrate into the ischemic cerebral cortex through multiple cranial burr holes and play a role in angiogenesis and neurogenesis.

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  Fig. 2 The site of burr hole trephination. A 2-mm-diameter burr hole trephination was made 3 mm lateral and 3 mm posterior to the bregma.

• 

  Fig. 3 Schematic flow sheet for this study. BrdU : 5-bromodeoxyuridine, IP : intraperitoneal.

• 

  Fig. 4 Immunohistochemical stain with BrdU. A : Normal control group. B : Burr hole group. C : Ischemia group. D : Ischemia+burr hole group. In the ischemia+burr hole group, BrdU (+) cells (arrow) were found at the cortical injury site beneath the burr hole in the coronal section. In the burr hole group, a few BrdU (+) cells were detected. Original magnification ×200. BrdU : 5-bromodeoxyuridine.

• 

  Fig. 5 Immunohistochemical stain with CD34 in the ischemia+burr-hole group. CD34 (+) cells (arrow) were detected at the site of the burr hole. A : Original magnification ×100. B : Black rectangle in A, original magnification ×400.

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  Fig. 6 Immunohistochemical stain with VEGF in the ischemia+burr hole group. Many VEGF (+) cells (arrow) were found under the burr hole. A : Original magnification ×100. VEGF (+) cells markedly increased at the cerebral parenchyma adjacent to the cortical incision site below the burr hole. B : Black rectangle in A, original magnification ×400. VEGF : vascular endothelial growth factor.

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  Fig. 7 Immunohistochemical stain with Doblecortin (DCX). In the ischemia +burr hole group, many DCX (+) cells (arrow) are observed at the burr hole site. A : Original magnification ×100. B : Black rectangle in A, original magnification ×400.

• 

  Fig. 8 Immunohistochemical stain with Nestin in the ischemia+burr hole group. Numerous Nestin (+) cells (arrow) were present at the cerebral parenchyma adjacent to the cortical incision site below the burr hole. A : Original magnification ×100. B : Black rectangle in A, original magnification ×400.

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