PMID- 15191803
OWN - NLM
STAT- MEDLINE
DCOM- 20040810
LR  - 20181130
IS  - 0014-4886 (Print)
IS  - 0014-4886 (Linking)
VI  - 188
IP  - 1
DP  - 2004 Jul
TI  - The ability of grafted human sympathetic neurons to synthesize and store 
      dopamine: a potential mechanism for the clinical effect of sympathetic neuron 
      autografts in patients with Parkinson's disease.
PG  - 65-73
AB  - We have investigated the potential of autologous sympathetic neurons as a donor 
      for cell therapy of Parkinson's disease (PD). Our recent study demonstrated that 
      sympathetic neuron autografts increase the duration of levodopa-induced "on" 
      periods with consequent reduction in the percent time spent in "off" phase. We 
      also found that human sympathetic neurons grown in culture have the ability to 
      convert exogenous levodopa to dopamine and to store the synthesized dopamine. 
      This may explain the clinically observed prolongation in the duration of levodopa 
      effects. To further analyze the mechanism for the graft-mediated effect, the 
      present study investigated the metabolic function of human sympathetic ganglionic 
      neurons xenografted into the dopamine (DA)-denervated striatum of rats by 
      monitoring striatal levels of DA and its primary metabolite, 
      3,4-dihydroxyphenylacetic acid (DOPAC), after systemic administration of 
      levodopa. We also explored whether the graft-mediated effect above may last in 
      four PD patients who had been given the grafts and followed for 12-36 months 
      postgrafting. Clinical evaluations showed that an increase in the duration of 
      levodopa-induced "on" phase is detected during a follow-up period of 12-36 months 
      postgrafting in all the four patients tested. Accordingly, the percent time spent 
      in "off" phase exhibited a 30-40% reduction as compared to the pregrafting 
      values. The animal experiment showed that a significant increase in striatal DA 
      levels is noted after systemic levodopa treatment, and that the DA levels remain 
      high for longer periods of time in the grafted rats than in control animals. When 
      given reserpine pretreatment, the levodopa-induced rise of striatal DA levels was 
      significantly attenuated with concomitant increase in DOPAC levels. Histological 
      examinations demonstrated that the grafts contain some tyrosine hydroxylase 
      (TH)-positive cells. These cells were also found to express aromatic-l-amino acid 
      decarboxylase (AADC) and vesicular monoamine transporter-2 (VMAT), both of which 
      are important molecules for the synthesis and the storage of DA, respectively. 
      These results indicate that grafted sympathetic neurons can provide a site for 
      both the conversion of exogenous levodopa to DA and the storage of the 
      synthesized DA in the DA-denervated striatum, explaining a mechanism by which 
      sympathetic neuron autografts can increase the duration of levodopa-induced "on" 
      phase in PD patients.
FAU - Nakao, Naoyuki
AU  - Nakao N
AD  - Department of Neurological Surgery, Wakayama Medical University, Wakayama 
      641-0012, Japan. nnakao@wakayama-med.ac.jp
FAU - Shintani-Mizushima, Aki
AU  - Shintani-Mizushima A
FAU - Kakishita, Koji
AU  - Kakishita K
FAU - Itakura, Toru
AU  - Itakura T
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (Neuropeptides)
RN  - 0 (Vesicular Biogenic Amine Transport Proteins)
RN  - 0 (Vesicular Monoamine Transport Proteins)
RN  - 102-32-9 (3,4-Dihydroxyphenylacetic Acid)
RN  - 46627O600J (Levodopa)
RN  - 8B1QWR724A (Reserpine)
RN  - 8HW4YBZ748 (Oxidopamine)
RN  - EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
RN  - EC 4.1.1.28 (Aromatic-L-Amino-Acid Decarboxylases)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - 3,4-Dihydroxyphenylacetic Acid/metabolism
MH  - Animals
MH  - Aromatic-L-Amino-Acid Decarboxylases/metabolism
MH  - Brain Tissue Transplantation/*methods
MH  - Corpus Striatum/drug effects/metabolism/surgery
MH  - Denervation
MH  - Disease Models, Animal
MH  - Dopamine/*biosynthesis
MH  - Female
MH  - Ganglia, Sympathetic/cytology/*metabolism/*transplantation
MH  - Graft Survival
MH  - Humans
MH  - Levodopa/metabolism/pharmacology
MH  - Male
MH  - Membrane Glycoproteins/metabolism
MH  - *Membrane Transport Proteins
MH  - Middle Aged
MH  - Neurons/*metabolism/*transplantation
MH  - *Neuropeptides
MH  - Oxidopamine
MH  - Parkinson Disease/metabolism/physiopathology/*therapy
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reserpine/pharmacology
MH  - Transplantation, Heterologous
MH  - Tyrosine 3-Monooxygenase/metabolism
MH  - Up-Regulation/drug effects/physiology
MH  - Vesicular Biogenic Amine Transport Proteins
MH  - Vesicular Monoamine Transport Proteins
EDAT- 2004/06/12 05:00
MHDA- 2004/08/11 05:00
CRDT- 2004/06/12 05:00
PHST- 2003/11/20 00:00 [received]
PHST- 2004/01/19 00:00 [revised]
PHST- 2004/03/03 00:00 [accepted]
PHST- 2004/06/12 05:00 [pubmed]
PHST- 2004/08/11 05:00 [medline]
PHST- 2004/06/12 05:00 [entrez]
AID - S0014488604000937 [pii]
AID - 10.1016/j.expneurol.2004.03.004 [doi]
PST - ppublish
SO  - Exp Neurol. 2004 Jul;188(1):65-73. doi: 10.1016/j.expneurol.2004.03.004.