The nose may help the brain: intranasal drug delivery for treating neurological diseases

While enormous progress has been made regarding our understanding of the pathogenic mechanisms of neurological diseases, there are only a small number of effective drugs for treating these illnesses. A key obstacle for developing effective drugs for treating neurological diseases is the blockage of drug entrance into the CNS by the BBB [1]. Less than 2% of all small-molecule drugs, and virtually no large-molecule drugs, can cross the BBB. Therefore, it is of critical significance to search for drug-delivery strategies that can effectively deliver drugs into the CNS. An increasing number of studies on both animals and human subjects have suggested that intranasal drug delivery could be used to deliver both smalland largesized drugs into the CNS by bypassing the BBB. It appears increasingly reasonable to conduct clinical trials to determine if intranasal drug delivery may be used to treat neurological diseases. In the 1970s and 1980s there were multiple studies suggesting that intranasal administration may enable substances to directly enter into the brain by pathways involving the olfactory epithelium and olfactory bulb [2]. In 1995 Thorne et al. reported the first quantitative study indicating that intranasal administration could deliver large-sized molecules into the brain by bypassing the BBB [3]. Intranasal administration of wheatgerm agglutinin-horseradish peroxidase (WGA-HRP) led to a significant presence of WGA-HRP in the olfactory bulb of rats, while there was no detectable amount of WGA-HRP in the olfactory bulb after intravenous injection of the same concentration of WGA-HRP. Since 1997, many studies have indicated that intranasal administration can enable large-sized molecules, such as IGF-1, FGF-2, TGF-β1, erythropoietin, IFN-β, HIV-1 Tat, insulin and leptin, to be transported into the CNS at least partially through direct nose-to-brain routes [2,4–9]. A number of studies using animal models of neurological diseases have demonstrated that intranasal delivery of large-sized molecules can produce beneficial effects. For example, intranasal nerve growth factor (NGF) administration can attenuate memory deficits and neurodegeneration in transgenic models of Alzheimer’s disease (AD) [10]; administration of erythropoietin [8] or IGF-I [11] by the intranasal approach can significantly decrease ischemic brain damage; and intranasal delivery of growth factors can also increase neurogenesis in rat brains [9]. We have conducted studies to directly compare the efficacy of intranasal drug delivery with that of intravenous drug delivery in treating brain ischemia. Based on the cell-culture studies showing the protective effects of gallotannin (GT) and nobotanin B – two inhibitors of poly(ADP-ribose) glycohydrolase – against oxidative cell injury [12], we found that intranasal delivery of GT is much more effective than intravenous injection of GT in decreasing ischemic brain injury [13]. On the basis of the in vitro findings that nicotinamide adenine dinucleotide (NAD+) treatment can prevent oxidative stress-induced cell death [14], we also found that intranasal NAD+ administration can produce up to 90% decreases in infarct formation when given 2 h after ischemia, which is the most profound protection ever reported from drugs that have been administered hours after ischemic onset [15,16].