Abstract: AimThe feasibility of intranasal brain targeting drug delivery system via the olfactory pathway from nose to brain was explored. MethodsUsing gellan gum, a cation-sensitive gel forming excipient, huperzine A (Hup A) nasal in situ gel was prepared by pH gradient precipitation method. The pharmacokinetics of Hup A in blood and cerebrospinal fluid (CSF) after intranasal, intravenous and intragastric adminstration to rats was studied using cisternal cannulation for serial CSF sampling and femoral artery cannulation for serial blood sampling. The distributions of Hup A into rat brain tissues following intranasal dosing were compared with those after intravenous and intragastric dosing by tissue homogeneization. The therapeutics effects of Hup A nasal in situ gel on cognitive function were tested in mice and rats with Morris water maze, step down test and step through test. ResultsThe AUC_{0→6 h} value in plasma obtained after nasal administration was 0.94 of that after intravenous administration, but the AUC_{0→6 h} of CSF after nasal administration was 1.3 and 2.3 times of that after intravenous and intragastric administration. The AUC_{0→6 h} of cerebrum, hippocampus, cerebellum, left olfactory bulb and right olfactory bulb after nasal administration were 1.5, 1.3, 1.0, 1.2 and 1.0 of that after intravenous administration, 2.7, 2.2, 1.9, 3.1 and 2.6 times of that after intragastric administration, respectively. Intranasal adminintration of 17.5-35 μg·kg^-1 showed equal effects after oral adminintration of 70 μg·kg^-1 commercial tablets, which was in good agreement with the results of pharmacokinetics. ConclusionIntranasal administration of huperzine A nasal in situ gel significantly increased the distributions of Hup A into rat brain tissues, especially into cerebrum and hippocampus which should be the target areas of Hup A, and enhanced the brain targeting of Hup A.