Other possible routes across the BBB include: transcellular uptake through at least two lipid bilayers via endocytosis, carrier-mediated transport through the use of specific receptors, or peptide-mediated transport. Attempts have been made to increase BBB penetration by increasing the systemic dose; however, the concentrations necessary to penetrate this barrier and exert an effect in the central nervous system can have deleterious systemic side effects. Therefore, there is interest in identifying more direct access routes into the CNS other than systemic administration. Currently available direct modalities include intraventricular and intraparenchymal administration; cost, time, inconvenience, invasiveness and lack of efficacy make these options of poor clinical utility. A more novel route is intranasal administration, which allows agents to be rapidly delivered to the CNS and avoids the negative IWP-3 aspects of systemic administration. Agents are thought to traverse the nasal mucosa into the CNS via the olfactory and trigeminal nerves ; however, details of intranasal uptake remain elusive. Many drugs administered intranasally have been able to reach the CNS and exert a therapeutic effect in humans. Melanocortin delivered intranasally rapidly enters the CNS without systemic spread, resulting in weight reduction after treatment for 6 weeks. Intranasal insulin has been studied for the treatment of diabetes, and more successfully so, in SHP-099 Alzheimer disease with patients showing improvements in attention, memory and cognitive function. Losartan administered intranasally in a mouse model of Alzheimer disease resulted in a decrease in plaque surface area and inflammatory mediators. Intranasal versus intravenous naloxone was compared in a human randomized controlled trial that showed both administration routes produced equivalent responses in patients. Our lab and others have shown that both erythropoietin and Insulin-Like Growth Factor I, when given intranasally, can enter the CNS in high concentrations in rodent models.Tau protein hyperphosphorylation has been found in brains of both humans with HAND, and the murine model, to be associated with neuronal damage and loss.