Effects of intraventricular encapsulated hNGF-secreting fibroblasts in aged rats.
Exogenous NGF administered into the central nervous system (CNS) has been reported to improve cognitive function in aged rats. However, concerns have been expressed about the risks involved with supplying NGF to the CNS. In this study, baby hamster kidney cells (BHK) genetically modified to secrete human NGF (hNGF) were encapsulated in semipermeable membranes and implanted intraventricularly. ChAT/LNGFR-positive basal forebrain neurons were shown to atrophy and degenerate with age, especially in cognitively impaired rats. The encapsulated BHK-NGF cells produced less than 10% of doses previously reported to be effective, but this was sufficient to increase the size of ChAT/LNGFR-positive basal forebrain neurons in the aged and learning-impaired rats to the size of the neurons in young healthy rats. The hNGF from these encapsulated cells also improved performance in a repeated-acquisition version of the Morris water maze spatial learning task in learning-impaired 20.6- and 26.7-mo-old rats. Furthermore, there was no evidence that these doses of hNGF impaired Morris water maze performance in the youngest 3.3-5.4 mo rats, and analyses of mortality rates, body weights, somatosensory thresholds, potential hyperalgesia, and activity levels, suggested that these levels of exogenous hNGF are not toxic or harmful to aged rats. These results suggest that CNS-implanted semipermeable membranes, containing genetically modified xenogeneic cells continuously producing these levels of hNGF, attenuate age-related cognitive deficits in nonimmunosuppressed aged rats, and that both the surgical implantation procedure and long-term exposure to low doses of hNGF appear safe in aged rats.
Lindner
M D
MD
Cyto Therapeutics Inc., Providence, RI 02906, USA. MLINDNER@CYTO.COM
Kearns
C E
CE
Winn
S R
SR
Frydel
B
B
Emerich
D F
DF
D000375:Aging / Q000502:physiology*; D000818:Animals; D001284:Atrophy; D001522:Behavior, Animal / Q000502:physiology; D001835:Body Weight; D002214:Capsules; D002452:Cell Count; D017690:Cell Transplantation / Q000009:adverse effects; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation*; D006801:Humans; D006930:Hyperalgesia / Q000503:physiopathology; D007668:Kidney / Q000166:cytology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008567:Membranes, Artificial; D008568:Memory / Q000502:physiology; D009026:Mortality; D009046:Motor Neurons / Q000166:cytology / Q000502:physiology; D009410:Nerve Degeneration / Q000502:physiology; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000633:toxicity; D009475:Neurons, Afferent / Q000166:cytology / Q000502:physiology; D011108:Polymers; D016548:Prosencephalon / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000378:metabolism / Q000633:toxicity; D012684:Sensory Thresholds / Q000502:physiology
D002214:Capsules; D008567:Membranes, Artificial; D009414:Nerve Growth Factors; D011108:Polymers; D011994:Recombinant Proteins; D002795:Choline O-Acetyltransferase