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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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Isao Date, Takashi Imaoka, Yasuyuki Miyoshi, Takeshi Ono, Shoji Asari, and Takashi Ohmoto

✓ A 55-year-old woman with severe Parkinson's disease was treated by cografting adrenal medulla with pretransected peripheral nerve into the bilateral caudate nuclei. The patient showed modest improvement of her akinesia; this effect persisted for 1 year after transplantation, when she suddenly died from upper gastrointestinal bleeding unrelated to the grafting procedure. At autopsy, a large number of tyrosine hydroxylase—immunoreactive chromaffin cells were observed within the caudate graft sites and a dense network of host dopaminergic fibers was visualized. This autopsy finding is very important for the field of experimental and clinical chromaffin cell grafting because it is the first evidence that cografts using pretransected peripheral nerve might enhance the survival of chromaffin cells and the recovery of host dopaminergic fibers in humans suffering from Parkinson's disease.

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Kenichiro Muraoka, Tetsuro Shingo, Takao Yasuhara, Masahiro Kameda, Wen Ji Yuen, Takashi Uozumi, Toshihiro Matsui, Yasuyuki Miyoshi, and Isao Date

Object

The therapeutic effects of adult and embryonic neural precursor cells (NPCs) were evaluated and their therapeutic potential compared in a rat model of Parkinson disease.

Methods

Adult NPCs were obtained from the subventricular zone and embryonic NPCs were taken from the ganglionic eminence of 14-day-old embryos. Each NPC type was cultured with epidermal growth factor. The in vitro neuronal differentiation rate of adult NPCs was approximately equivalent to that of embryonic NPCs after two passages. Next, the NPCs were transfected with either green fluorescent protein or glial cell line–derived neurotrophic factor (GDNF) by adenoviral infection and transplanted into the striata in a rat model of Parkinson disease (PD) induced by unilateral intrastriatal injection of 6-hydroxydopamine. An amphetamine-induced rotation test was used to evaluate rat behavioral improvement, and immunohistochemical analysis was performed to compare grafted cell survival, differentiation, and host tissue changes.

Results

The rats with GDNF-transfected NPCs had significantly fewer amphetamine-induced rotations and less histological damage. Except for the proportion of surviving grafted cells, there were no significant differences between adult and embryonic NPCs.

Conclusions

Adult and embryonic NPCs have a comparable therapeutic potential in a rat model of PD.

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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

Object

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.

Methods

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.

Conclusions

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.