Delivery of brain-derived neurotrophic factor via nose-to-brain pathway.

PURPOSE: To investigate the plausibility of delivering brain-derived neurotrophic factor (BDNF) to brain via nose-to-brain pathway using chitosan as barrier-modulating agent.

METHODS

Effect of different viscosity grades chitosan at different concentrations on permeation of fluorescein isothio-cyanate dextran (FD 40 K) across bovine olfactory mucosa was studied using Franz diffusion cells. Medium viscosity chitosan was used to carry out permeation studies of BDNF. Pharmacokinetic and pharmacodynamic studies were carried out in Sprague dawley rats upon intranasal/i.v administration of different formulations.

RESULTS

Medium viscosity chitosan more efficiently enhanced permeation of FD 40 K across olfactory mucosa compared to other grades. In case of BDNF, medium viscosity chitosan (0.25% w/v) enhanced permeation ~14-fold over control (18.78 ± 16.69 ng/cm(2)). Brain bioavailability of rats administered intranasally with BDNF solution containing chitosan was significantly enhanced ~13-fold compared to rats administered with same concentration of BDNF solution without chitosan. In rats subjected to immobilization stress, BDNF solution containing chitosan significantly decreased immobility time.

CONCLUSIONS

Intranasal formulations containing chitosan as barrier-modulating agent significantly enhanced brain bioavailability of BDNF. Delivery of BDNF was found to counteract stress-induced depression in rats.