Intraparenchymal nerve growth factor improves behavioral deficits while minimizing the adverse effects of intracerebroventricular delivery.
Nerve growth factor (NGF) delivered via intracerebroventricular (ICV) infusion restores behavioral and biochemical deficits in animal models of cholinergic hypofunction. However, ICV infusion of NGF induces an array of adverse events including weight loss, thermal hyperalgesia, and Schwann cell hyperplasia. We compared ICV administration with three different doses of intraparenchymally delivered NGF with cytochrome C infusion serving as a control. The goal of the study was to determine whether direct infusion of NGF would result in a more restricted topographical distribution of NGF leading to a reduction or elimination of the adverse events while still augmenting cholinergic functioning sufficiently to restore spatial mnemonic processing. Subsequent to bilateral ibotenic acid lesions of the nucleus basalis magnocellularis (NBM), NGF was delivered into the lateral ventricle or adjacent to the NBM for 11 weeks. Ibotenic acid lesions resulted in reductions in choline acetyltransferase (ChAT) activity in the cortex. The highest and medium dose of NGF led to significant restoration in ChAT activity on par with ICV infusion. The lowest dose was ineffective in altering ChAT activity in any region assayed. Similarly, the two highest doses did not alter weight gain, but ICV-NGF led to a significant weight loss. Intraparenchymal infusion resulted in a dose-dependent attenuation of the development of thermal hyperalgesia. However, the highest dose of intraparenchymal NGF induced Schwann cell hyperplasia at the level of the medulla and upper cervical spinal cord. ICV-NGF was able to completely restore spatial learning and memory as predicted while only the highest intraparenchymal dose was able to able to restore the mnemonic deficits. These data suggest that intraparenchymal infusion of growth factors may provide a viable delivery method in clinical trials using this mode of drug delivery once an optimal dose has been established.
Pizzo
D P
DP
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Thal
L J
LJ
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D020532:Basal Nucleus of Meynert / Q000187:drug effects / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D006930:Hyperalgesia / Q000503:physiopathology; D006965:Hyperplasia; D007051:Ibotenic Acid / Q000494:pharmacology; D007267:Injections; D007276:Injections, Intraventricular / Q000009:adverse effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008526:Medulla Oblongata / Q000187:drug effects / Q000473:pathology; D020932:Nerve Growth Factor / Q000008:administration & dosage*; D051381:Rats; D011916:Rats, Inbred F344; D012583:Schwann Cells / Q000187:drug effects / Q000473:pathology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D015430:Weight Gain / Q000187:drug effects; D015431:Weight Loss / Q000187:drug effects
D007051:Ibotenic Acid; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase