The blood-brain barrier (BBB) is a major obstacle to delivery of drugs to the central nervous system (CNS). The blood-brain barrier prevents many therapeutics, especially large and/or charged molecules, from reaching the brain and spinal cord to treat disorders of the central nervous system. A non-invasive intranasal method of delivering therapeutic agents to the central nervous system has been developed by William H. Frey II, PhD (Frey, 1991) and subsequently by others (for reviews, see: Frey et al., 2002; Dhanda et al. 2005). This method allows drugs that do not cross the blood-brain barrier to be delivered to the central nervous system. Delivery from the nasal mucosa to the central nervous system occurs within minutes along both the trigeminal and olfactory neural pathways. Intranasal delivery to the central nervous system is non-saturable and does not rely on receptor binding or axonal transport, but rather occurs along extracellular and paracellular pathways. An additional advantage to intranasal administration of therapeutics is the direct targeting of drugs (including those that do cross the blood-brain barrier) to the central nervous system, eliminating the need for systemic delivery, thus decreasing systemic side effects. Furthermore, neither modification of the therapeutic agent nor coupling to a carrier is needed. This method can deliver a wide variety of therapeutic agents to the central nervous system, including both large and small molecules and water-soluble and water-insoluble drugs.
Intranasal administration of therapeutic agents to the brain and spinal cord has been reviewed extensively in the literature over the last few years (Thorne and Frey, 2001; Frey, 2002; Dhanda et al., 2005). Delivery of nerve growth factor (NGF) intranasally has been reported to reverse or prevent both neurodegeneration and memory deficits in the AD11 mouse model of Alzheimer’s disease (Capsoni et al., 2002; De Rosa et al., 2005). Nasal administration of the haemopoietic hormone, erythropoietin, protects against focal cerebral ischemia by reducing infarct volume, brain swelling, and cell damage in the ischemic hemispheres (Yu et al., 2005). Thorne et al. have showed that intranasally delivered Insulin-like growth factor-I (IGF-I) can bypass the BBB via olfactory- and trigeminal-associated extracellular pathways to produce swift biological effects at multiple locations within the CNS (Thorne et al., 2004). Intranasal IGF-I administered within four hours of stroke (middle cerebral artery occlusion) significantly reduces infarct volume and improves neurological function (Liu et al., 2004). Intranasal deferoxamine has been reported by S.S. Panter et al. to provide striking preconditioning and protection of the brain against stroke (the Society for Neuroscience Annual Meeting, 2005).
In addition, NAP (a neuroprotective peptide) has been found to improve performance in the Morris water maze of normal and cognitively impaired rats. Moreover, NAP has been shown to alleviate anxiety and improve cognition after chronic intranasal treatment (Alcalay et al., 2004). Also, intranasal delivery of activity-dependent neurotrophic factor (ADNF) to the brain has been reported to have a neuroprotective effect (Gozes et al., 2000).
Most surprisingly, intranasal neurotrophins (fibroblast growth factor-2 and heparin-binding epidermal growth factor-like growth factor) have been demonstrated to enhance new neuron formation (neurogenesis) in the subventricular zone in adult mice (Jin et al., 2003).
It has been documented that macromolecules such as proteins can be delivered nasally. Interferon beta-1b has been shown to rapidly transport from the nose to the brain, spinal cord, and cervical lymph nodes (Ross et al., 2004). Hypocretin-1 and hypocretin-2 are hypothalamic neuropeptides whose deficiencies are linked to narcolepsy. Hanson et al. have demonstrated direct delivery of hypocretin-1 from the nose to the brain using gamma counting and autoradiography. This presents a significant potential for hypocretin-1 in treating narcolepsy (Hanson et al., 2004). Intranasal exendin has been shown to reach the brain and elicit biological effects including improvement of memory, cognition and neuronal survival (Banks et al., 2004; During et al., 2003).
Interestingly, some studies have indicated that intranasal antineoplastic chemotherapy is achievable (Shingaki et al., 1999; Wang et al., 2004). They have demonstrated that the intranasal route delivers higher concentrations of the chemotherapeutic methotrexate to the cerebrospinal fluid (CSF) than the intravenous route does. In addition, Shingaki et al. have indicated that intranasal methotrexate causes reduction in brain tumor size in animals, suggesting effective chemotherapy with reduced side effects. Intranasal administration of a polynucleotide inhibitor of telomerase, GRN163, resulted in targeting of the drug to human glioblastoma multiformis xenografts in rats and doubling the life span of these animals with brain tumors (Hashizume et al., 2007 submitted). According to Wang et al. (2006), the transportation of the chemotherapeutic raltitrexed from the nose to the brain along the olfactory pathways is about 100-fold greater than with intravenous administration. In another study, da Fonseca et al. (2006) have reported reduction of the size of an enhancing lesion of anaplastic oligodendroglioma in a human after five months of intranasal perillyl alcohol administration.
Studies in cynomolgus monkeys have demonstrated intranasal delivery bypasses the BBB to deliver interferon beta-1b to the CNS (Thorne et al., 2007 in press) and delivers a prostaglandin analog to the brain to induce sleep in these primates (Yamada et al., 2007)
Born et al. (2002) have indicated that intranasally administered neuropeptides such as melanocortin, insulin, and vasopressin gained access to the CSF in humans in as little as 10 minutes. Human studies have demonstrated that intranasal insulin enhances memory and mood in healthy adults (Benedict et al., 2004). Intranasal insulin aspart was shown to be even more effective than regular insulin or placebo in improving memory in normal human adults with no change in the blood levels of insulin or glucose (Benedict et al., 2007). In addition, intranasal insulin improves memory in patients with Alzheimer's disease without affecting insulin or glucose blood levels (Reger et al., 2006). Craft et al. have presented some data at the 10th International Conference on Alzheimer’s disease (ICAD 2006) indicating that administration of intranasal insulin for twenty-one days significantly improved verbal memory in Alzheimer's patients. Moreover, Intranasal insulin has been demonstrated to reduce body fat in men (Hallschmid et al., 2004).
Other studies have shown that intranasal PT-141 (melanocortin analog) enhances erection in humans with erectile dysfunction by acting at the hypothalamic melanocortin receptors implicated in both appetite and sexual response (Diamond et al., 2004). Direct targeting of the neuropeptide oxytocin from the nose to the brain has been found to substantially increase trust in humans (Kosfeld et al., 2005).
Gene therapy of the CNS can be administered through the nasal route. Intranasal delivery of adenoviral vectors and plasmid DNA to the brain has been documented (Draghia et al., 1995; Han et al., 2007). Finally, recent studies have established that intranasal delivery of the recombinant strain of the bacterium Lactococcus lactis secreting leptin has led to significant reduction of food intake and body weight (Bermúdez-Humarán et al., 2007).
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