Alleviation of behavioral deficits in aged rodents following implantation of encapsulated GDNF-producing fibroblasts.
The present study examined the effects of encapsulated cells which were genetically modified to secrete human glail-derived neurotrophic factor (hGDNF) on the motor deficits in aged rodents. Prior to implantation, animals were tested on a battery of motor tasks. Spontaneous locomotion and motor coordination was evaluated in young (5 month) and aged (20 months) rats. Aged animals tested for spontaneous locomotor activity were found to be hypoactive relative to young animals. Compared to the young animals the aged animals also: (1) were impaired on a bar pressing task, (2) were unable to descend a wooden pole covered with wire mesh in a coordinated manner, (3) fell more rapidly from a rotating rod and (4) were unable to maintain their balance on a series of wooden beams of varying widths. Following baseline testing, aged animals received either no implant, encapsulated baby hamster kidney fibroblast cells that were modified to produce hGDNF (BHK-hGDNF) or encapsulated BHK cells which were not modified to produce hGDNF (BHK-Control) implanted bilaterally into the striatum. Following surgery, a significant increase in locomotor activity and bar pressing was observed in those aged animals receiving BHK-hGDNF implants. Bar pressing in aged animals receiving BHK-Control cells was improved to a lesser extent and reached the level of performance seen in young rats. No recovery was observed in the animals receiving BHK-Control cell-loaded capsules on any of the other motor tasks. Histological analysis revealed that implants of hGDNF-producing cells produced a marked increase in the density of tyrosine hydroxylase staining in the striatum adjacent to the implant site. This increased staining was not seen in animals receiving BHK-Control cells. Histological analysis also revealed the presence of viable BHK-hGDNF cells within the capsules that continued to produce hGDNF as measured by ELISA. These results indicate that polymer-encapsulated hGDNF-secreting cells survive following implantation into aged rats and may be useful for treating some of the behavioral consequences of aging or disorders characterized by dopaminergic hypofunction.
Emerich
D F
DF
Cyto Therapeutics, Inc., Providence, RI 02906, USA.
Plone
M
M
Francis
J
J
Frydel
B R
BR
Winn
S R
SR
Lindner
M D
MD
D000375:Aging; D000818:Animals; D001835:Body Weight; D002460:Cell Line; D017690:Cell Transplantation; D003216:Conditioning, Operant; D006224:Cricetinae; D005347:Fibroblasts / Q000637:transplantation; D015316:Genetic Therapy; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D007668:Kidney; D008297:Male; D009043:Motor Activity; D009414:Nerve Growth Factors / Q000096:biosynthesis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D011597:Psychomotor Performance; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection
C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins