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In order to determine the contribution of intranasal (i.n.) administration to the uptake of large molecular weight (MW) substances into central nervous system (CNS), concentration in brain of the centrally acting polypeptide cobrotoxin (NT-I) versus time profiles were studied using dual-probe microdialysis in awake free-moving rats. NT-I, radiolabeled with sodium 125I-Iodide (125I-NT-I), was administered at the dose of 105 μg/kg intravenously and intranasally in the same set of rat (n = 15). The 125I-NT-Inasal preparations were formulated with borneol/menthol eutectic mixture (+BMEM) as an absorption enhancer and without (−BMEM). After application, the dialysates sampled simultaneously from olfactory bulb and cerebellar nuclei were measured in a gamma-counter for radioactivity. The real concentrations of NT-I were recalculated by in vivo recoveries of microdialysis probes. The results showed that the area under the curve (AUC) value in cerebellar nuclei (2283.51 ± 34.54 min ng/ml) following i.n. administration (+BMEM) was significantly larger than those (AUColfactory = 1141.92 ± 26.42 min ng/ml; AUCcerebellar = 1364.62 ± 19.35 min ng/ml) after intravenous (i.v.) bolus, respectively. A prolonged time values to peak concentrations after i.n. application (+BMEM) were observed compared with those following i.v. administration. Also, following i.n. application (+BMEM) the measured time value to peak concentration in cerebellar nuclei (85 min) was statistically longer than that in olfactory bulb (75 min), which could be plausibly an indication for NT-I delivery into brain via nose–brain pathway in the presence of absorption enhancer. i.n. administration (−BMEM) had little or no ability of NT-I delivering into brain. In conclusion, i.n. administration (+BMEM) significantly enhanced brain transport of NT-I with uneven distribution in discrete regions of brain compared with i.v. administration. Additionally, multi-probe microdialysis technique should be considerably valuable in brain delivery studies.