EFFECTS OF INTRAVENTRICULAR ENCAPSULATED HNGF-SECRETING FIBROBLASTS IN AGED RATS

Exogenous NGF administered into the central nervous system (CNS) has b een reported to improve cognitive function in aged rats, However, conc erns have been expressed about the risks involved with supplying NGF t o the CNS, In this study, baby hamster kidney cells (BHK) genetically modified to secrete human NGF (hNGF) were encapsulated in semipermeabl e membranes and implanted intraventricularly. ChAT/LNGFR-positive basa l forebrain neurons were shown to atrophy and degenerate with age, esp ecially in cognitively impaired rats. The encapsulated BHK-NGF cells p roduced less than 10% of doses previously reported to be effective, bu t this was sufficient to increase the size of ChAT/LNGFR-positive basa l forebrain neurons in the aged and learning-impaired rats to the size of the neurons in young healthy rats, The hNGF from these encapsulate d 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, somatos ensory thresholds, potential hyperalgesia, and activity levels, sugges ted that these levels of exogenous hNGF are not toxic or harmful to ag ed rats, These results suggest that CNS-implanted semipermeable membra nes, containing genetically modified xenogeneic cells continuously pro ducing these levels of hNGF, attenuate age-related cognitive deficits in nonimmunosuppressed aged rats, and that both the surgical implantat ion procedure and long-term exposure to low doses of hNGF appear safe in aged rats.