Dose-response comparison of recombinant human nerve growth factor and recombinant human basic fibroblast growth factor in the fimbria fornix model of acute cholinergic degeneration.
Both nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) have been proposed for the treatment of Alzheimer's disease. This study describes a comparative, dose-response analysis of recombinant human (rh)NGF and rhbFGF in a rat unilateral fimbria-fornix model of acute cholinergic neuronal degeneration. Doses for rhNGF were 0.6, 6, 60, 600 and 1,800 ng/rat/day and for rhbFGF were 600, 1,800, 3,000 and 6,000 ng/rat/day, delivered for 4 weeks. The number of surviving septal cholinergic neurons was evaluated using ChAT immunohistochemistry. In control animals, the number of ChAT-positive neurons remaining on the lesioned side was between 22 and 18% compared to the non-lesioned side. Infusion with either neurotrophic factor increased the number of ChAT-positive neurons on the lesioned side in a dose-dependent manner. The maximal response to rhbFGF peaked at 3,000 ng/rat/day with a cell savings of 47%. However, there was evidence of neuropathological changes associated with rhbFGF. In contrast, rhNGF produced a maximal response with an infusion of 600 ng rhNGF/rat/day and a cell savings of 70% and no evidence of neuropathology, indicating that rhNGF was better tolerated and more efficacious than rhbFGF.
Emmett
C J
CJ
Department of Neurosciences, Syntex Discovery Research, Palo Alto, CA 94303, USA.
Aswani
S P
SP
Stewart
G R
GR
Fairchild
D
D
Johnson
R M
RM
D000110:Acetylcholinesterase; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009410:Nerve Degeneration; D009414:Nerve Growth Factors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012686:Septal Nuclei
D009414:Nerve Growth Factors; D016222:Fibroblast Growth Factor 2; D000110:Acetylcholinesterase