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.
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.
Nakao
Naoyuki
N
Department of Neurological Surgery, Wakayama Medical University, Wakayama 641-0012, Japan. nnakao@wakayama-med.ac.jp
Shintani-Mizushima
Aki
A
Kakishita
Koji
K
Itakura
Toru
T
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism; D016380:Brain Tissue Transplantation / Q000379:methods*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000601:surgery; D003714:Denervation; D004195:Disease Models, Animal; D004298:Dopamine / Q000096:biosynthesis*; D005260:Female; D005728:Ganglia, Sympathetic / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation*; D006085:Graft Survival; D006801:Humans; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism* / Q000637:transplantation*; D009479:Neuropeptides; D016627:Oxidopamine; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D012110:Reserpine; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D001142:Aromatic-L-Amino-Acid Decarboxylases; D004298:Dopamine