Biomedical subjects
Publications and source records attributed to T Furuta.
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Polymer-encapsulated dopamine-secreting cell grafting is one of the most promising approaches for the treatment of Parkinson's disease. We microencapsulated dopamine secreting PC12 cells into agarose/poly(styrene sulfonic acid) complex and grafted them into the xenogeneic brain without immunosuppression. Dopamine secretion from the encapsulated cells was confirmed by high-performance liquid chromatography (HPLC) analysis before grafting. A large number of encapsulated PC12 cells survived in the brain 1 mo after transplantation and these cells were immunoreactive to tyrosine hydroxylase (TH) antibody, suggesting that these cells were secreting dopamine into the brain. There was no apparent immunological rejection or tumor formation. We concluded that microencapsulated PC12 cells survive in the xenogeneic brain without immunosuppression, and this grafting procedure is expected to be applied for the treatment of Parkinson's disease in the near future in combination with stereotaxic thalamotomy or pallidotomy.
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Effects of coenzyme Q10 (CoQ10) on transmembrane action potential, isometric tension, and tissue ATP contents of isolated rabbit ventricular muscles were examined under the hypoxic condition and subsequent reoxygenation. CoQ10 (10 mg/kg/day) was administered intravenously to 15 rabbits for 3 days (CoQ10 group), and 15 other rabbits were treated only with a vehicle for CoQ10 (control group). Membrane action potentials, mechanical contraction, and ATP contents of the preparations under aerobic condition were not affected by the CoQ10 or vehicle pretreatment. Hypoxia for 60 min caused a shortening of action potential duration (APD), a decrease in peak developed tension (DT), and an elevation of resting tension (RT), as well as a decrease in ATP contents of the preparations in both groups. However, these changes were significantly less in the CoQ10 group than those in the control group. A better recovery of APD, DT, and RT of the preparations during reoxygenation period was also observed in the CoQ10 group. These results indicate that the prior and repetitive administration of CoQ10 may protect cardiac muscles from functional deterioration induced by hypoxia, suggesting a beneficial effect of this substance on the metabolism of the energy-depleted myocardium.
The effects of FR34235 (FR) on isolated rabbit cardiac muscle, sinus node, and aortic strips were evaluated and compared with those of nifedipine. FR decreased the developed tension and shortened the action potential duration of ventricular and atrial muscle without affecting the upstroke velocity (Vmax). Nifedipine induced similar but more pronounced electromechanical changes. The ED50 values for FR and nifedipine for producing their negative inotropic effects on ventricular muscle were 1.0 +/- 0.4 X 10(-6) and 2.0 +/- 0.6 X 10(-7), respectively. The slow response and its associated contraction of ventricular muscle were inhibited by FR (5 X 10(-6) M). Both effects of FR were antagonized by increasing [Ca]0. FR, at concentrations higher than 10(-7) M, reduced the amplitude and Vmax of the sinus node action potential. However, these effects were less than those of nifedipine. Spontaneous firing rate was not affected by either drug. The high K+-induced contractile response in rabbit aortic strips was inhibited by both FR and nifedipine at lower concentrations than in cardiac tissue, whereas the potency of FR was greater than nifedipine. The ED50 values for FR and nifedipine were 1.0 +/- 0.3 X 10(-9) and 4.0 +/- 0.4 X 10(-9) M, respectively. The inhibitory action of FR on the contractile response to excess Ca2+ was also greater than that of nifedipine. The inhibitory actions of both FR and nifedipine on the norepinephrine response were less than those on the K+ response. These results indicate that FR has characteristics of slow channel blockade similar to those of nifedipine. However, inhibitory action of FR was more potent in vascular smooth muscle of rabbit aorta and less potent in cardiac tissue than that of nifedipine.
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The PC12 phenochromocytoma tumor cell line is derived from a rat adrenal medullary tumor and secretes dopamine. We have previously reported that grafted microencapsulated PC12 cells using agarose and poly (styrene sulfonic acid) survived in the xenogeneic brain without immunosuppression. To investigate whether unencapsulated PC12 cells form a tumor and how they provoke immunological reaction, PC12 cell suspension was implanted into the striatum of Sprague-Dawley rat (allogeneic graft) or guinea pig (xenogeneic graft) and histological analysis using Nissl stain and immunocytochemical analysis using antityrosine hydroxylase (TH) antibody were performed 1, 2, and 4 wk after transplantation. Host animals were not immunosuppressed. PC12 cells formed a mass 1 and 2 wk after transplantation both in allogeneic and xenogeneic brain. These grafted PC12 cells were immunoreactive to anti-TH antibody. Four weeks after transplantation, however, grafted PC12 cells in the allogeneic brain were only found within the restricted area near the site of implantation. In the xenogeneic brain, only the trace of grafted PC12 cells were found around the site of implantation 4 wk after transplantation. In both allogeneic and xenogeneic animals, a number of lymphocytes were found in and around the grafts at all period investigated. These findings indicate that PC12 cells could survive in the allogeneic or xenogeneic brain for 2 wk and were ultimately rejected by immunological reaction by 4 wk after transplantation. Implantation of encapsulated PC12 cells in the allogeneic or xenogeneic brain is considered a safe and effective method for delivering dopamine into the brain because PC12 cells will not form a tumor in the long-term even if capsules are damaged in some reason.
Intrastriatal implantation of polymer-encapsulated PC12 cells, which constitute a dopaminergic cell line derived from rat pheochromocytoma, has proved useful for ameliorating parkinsonian symptoms in several kinds of animals. In considering the clinical application of this technique, we should make sure that PC12 cells are rejected completely by the host immune system in case the capsule breaks. In the present study, unencapsulated PC12 cells were injected into the brain of Japanese monkeys (Macaca fuscata). Histological [hematoxylin-eosin (H&E), Nissl] and immunocytochemical [tyrosine hydroxylase (TH), and glial fibrillary acidic protein (GFAP)] analyses were performed 1, 2, 4, and 8 weeks after transplantation. Also, encapsulated PC12 cells were transplanted into the brain of another group of Japanese monkeys to investigate the host reaction to the capsule and to confirm that the encapsulated PC12 cells continue to survive in the host brain. H&E and GFAP staining were performed 2, 4, and 8 weeks after transplantation. L-DOPA and dopamine release from the explanted capsules was measured by high performance liquid chromatography. Magnetic resonance imaging was performed in both unencapsulated and encapsulated PC12 cell grafted groups. Although the xenografted unencapsulated cells formed a small cluster at 1 and 2 weeks after implantation, very few and no viable PC12 cells remained at 4 and 8 weeks, respectively. The reaction of the host towards the xenograft gradually decreased. Encapsulated PC12 cells retrieved from the host brain were found to release L-DOPA and dopamine continuously even 8 weeks after implantation. The host reaction to the PC12-loaded capsule was much weaker than that to the unencapsulated PC12 cells, and decreased with time. These results indicate that encapsulated PC12 cell transplantation is an effective and safe strategy for the treatment of Parkinson's disease.
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