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Hideyuki Yoshida, Isao Date, Tetsuro Shingo, Kenjiro Fujiwara, Kazuki Kobayashi, Yasuyuki Miyoshi, and Takashi Ohmoto

Object. The PC12 cells are well known for their ability to secrete dopamine and levodopa. In multiple animal models encapsulated PC12 cells have been shown to ameliorate parkinsonian symptoms when transplanted into the striatum; this technique is expected to be effective clinically as well. The present study was performed using nonhuman primates to ensure that the transplantation of encapsulated PC12 cells is likely to be both safe and effective in human clinical trials.

Methods. Unencapsulated or encapsulated PC12 cells were implanted into the brains of Japanese monkeys (Macaca fuscata). Histological and immunocytochemical analyses were performed 1, 2, 4, and 8 weeks posttransplantation on the unencapsulated cells and 2, 4, and 8 weeks after transplantation on the encapsulated cells. The survival of the PC12 cells inside the capsule was determined by measuring the amounts of dopamine and levodopa released from the capsules after removal from the striatum. Magnetic resonance imaging was performed in both unencapsulated and encapsulated PC12 cell—grafted groups.

Due to the immunological reaction of the host brain no unencapsulated PC12 cells remained in the grafted area 8 weeks after transplantation. On the contrary, encapsulated PC12 cells retrieved from the host brain continued to release dopamine and levodopa even 8 weeks after implantation. The host's reaction to the PC12-loaded capsule was much weaker than that to the unencapsulated PC12 cells.

Conclusions. These results suggest that the transplantation of encapsulated PC12 cells could be a safe and effective treatment modality for Parkinson disease in human patients.

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Yosuke Sato, Yoshihito Tsuji, Yuta Kawauchi, Kazuki Iizuka, Yusuke Kobayashi, Ryo Irie, Tatsuya Sugiyama, and Tohru Mizutani


In epilepsy surgery for cavernoma with intractable focal epilepsy, removal of the cavernoma with its surrounding hemosiderin deposition and other extended epileptogenic zone has been shown to improve postsurgical seizures. However, there has been no significant association between such an epileptogenic zone and intraoperative electrocorticography (ECoG) findings. The authors recently demonstrated that high regular gamma oscillation (30–70 Hz) regularity (GOR) significantly correlates with epileptogenicity.


The authors evaluated the utility of intraoperative GOR analysis in epilepsy surgery for cavernomas. The authors also analyzed intraoperative ECoG data from 6 patients with cavernomas. The GOR was calculated using a sample entropy algorithm. In 4 patients, the GOR was significantly high in the area with the pathological hemosiderin deposition. In 2 patients with temporal cavernoma, the GOR was significantly high in both the hippocampus and the area with the pathological hemosiderin deposition. ECoG showed no obvious epileptic waveforms in 3 patients, whereas extensive spikes were observed in 3 patients. All patients underwent cavernoma removal plus resection of the area with significantly high GOR. The 2 patients with temporal cavernomas underwent additional hippocampal transection. All patients were seizure free after surgery.


The high GOR may be a novel intraoperative marker of the epileptogenic zone in epilepsy surgery for cavernomas.

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Kenjiro Fujiwara, Isao Date, Tetsuro Shingo, Hideyuki Yoshida, Kazuki Kobayashi, Akira Takeuchi, Akimasa Yano, Takashi Tamiya, and Takashi Ohmoto

Object. This study was conducted to evaluate the effects of grafting encapsulated basic fibroblast growth factor (bFGF)—secreting cells in rat brains subjected to ischemic injury.

Methods. Two cell lines were used for encapsulated grafting in this experiment, namely, a bFGF-secreting cell line established by genetic manipulation of baby hamster kidney (BHK) cells, and a naive BHK cell line. Forty-seven Sprague—Dawley rats were used in this experiment. The animals were divided into the following three groups: those receiving grafts of encapsulated bFGF-secreting cells (BHK-bFGF group); those with grafts of encapsulated naive BHK cells (naive BHK group); and those with no grafts (control group). The authors implanted encapsulated cells into the right striatum of host rats in the BHK-bFGF and naive BHK groups. Six days after grafting, the host and control animals underwent permanent right middle cerebral artery occlusion (MCAO) with an intraluminal suture procedure. The infarct volume was evaluated using 2,3,5-triphenyltetrazolium chloride staining and computerized image analysis 24 hours after MCAO. Fragmentations of DNA in the host brains were analyzed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling 12 hours after MCAO.

The authors found that the infarct volume in the BHK-bFGF group was reduced by approximately 30% compared with that in the naive BHK and control groups. In the ischemic penumbral area, the number of apoptotic cells in the BHK-bFGF group was significantly decreased compared with that in the other groups.

Conclusions. The grafting of encapsulated BHK bFGF-secreting cells protected the brain from ischemic injury. Encapsulation and grafting of genetically engineered cells such as bFGF-secreting cells is thus thought to be a useful method for protection against cerebral ischemia.

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Akimasa Yano, Tetsuro Shingo, Akira Takeuchi, Takao Yasuhara, Kazuki Kobayashi, Kazuya Takahashi, Kenichiro Muraoka, Toshihiro Matsui, Yasuyuki Miyoshi, Hirofumi Hamada, and Isao Date


The authors evaluated the neuroprotective and angiogenic effects of a continuous and low-dose infusion of vascular endothelial growth factor (VEGF)-165 on cerebral ischemia in rats.


The authors introduced VEGF complementary (c)DNA into baby hamster kidney (BHK) cells and established a cell line that produces human VEGF165 (BHK-VEGF). The BHK-VEGF cells and BHK cells that had been transfected with an expression vector that did not contain human VEGF165 cDNA (BHK-control) were encapsulated. Both capsules were implanted into rat striata. Six days after capsule implantation, the right middle cerebral artery (MCA) was occluded. Some animals were killed 24 hours after occlusion to measure the volume of the resulting infarct and to perform immunohistochemical studies. Other animals were used for subsequent behavioral studies 1, 7, and 14 days after MCA occlusion.

The encapsulated BHK-VEGF cell grafts significantly reduced the volume of the infarct and the number of apoptotic cells in the penumbral area when compared with the effect of the BHK-control cell capsule. In addition, angiogenesis and gliogenesis significantly increased in the region around the capsule in animals that received BHK-VEGF cell capsules without an increase in focal cerebral blood flow; this did not occur in animals that received the BHK-control cell capsule. In behavioral studies rats that received the BHK-VEGF cell capsule displayed significant recovery while participating in the accelerating rotarod test after stroke.


Continuous intracerebral administration of low-dose VEGF165 through encapsulated grafts of VEGF-producing cells produces neuroprotective and angiogenic effects. These effects improve subsequent motor function.

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Takao Yasuhara, Tetsuro Shingo, Kenichiro Muraoka, Kazuki Kobayashi, Akira Takeuchi, Akimasa Yano, Yuan WenJi, Masahiro Kameda, Toshihiro Matsui, Yasuyuki Miyoshi, and Isao Date

Object. Glial cell line—derived neurotrophic factor (GDNF) has been shown to confer neuroprotective effects on dopaminergic neurons. The authors investigated the effects of GDNF on 6-hydroxydopamine (6-OHDA)—treated dopaminergic neurons in vitro and in vivo.

Methods. First, the authors examined how 1, 10, or 100 ng/ml of GDNF, administered to cells 24 hours before, simultaneously with, or 2 or 4 hours after 6-OHDA was added, affected dopaminergic neurons. In a primary culture of E14 murine ventral mesencephalic neurons, earlier treatment with the higher dosage of GDNF suppressed 6-OHDA—induced loss of dopaminergic neurons better than later treatment. Next, the authors examined whether continuous infusion of GDNF at earlier time points would demonstrate a greater neuroprotective effect in a rat model of Parkinson disease (PD). They established a human GDNF-secreting cell line, called BHK-GDNF, and encapsulated the cells into hollow fibers. The encapsulated cells were unilaterally implanted into the striatum of adult rats 1 week before; simultaneously with; or 1, 2, or 4 weeks after 6-OHDA was given to induce lesions of the same striatum. With the earlier transplantation of a BHK-GDNF capsule, there was a significant reduction in the number of amphetamine-induced rotations displayed by the animals. Rats that had received earlier implantation of BHK-GDNF capsules displayed more tyrosine hydroxylase—positive neurons in the substantia nigra pars compacta and a tendency for glial proliferation in the striatum.

Conclusions. These neuroprotective effects may be related to glial proliferation and signaling via the GDNF receptor α1. The results of this study support a role for this grafting technique in the treatment of PD.