S3–04–03: Bypassing the blood–brain barrier with intranasal delivery to treat Alzheimer's disease and related disorders

Intranasal delivery provides a practical, noninvasive, method of bypassing the blood–brain barrier to deliver therapeutic agents to the brain and spinal cord. [See Dhanda (2005) Drug Delivery Technology 5(4):64–72 for a review.] Intranasal delivery allows drugs that do not cross the blood–brain barrier to be delivered to the central nervous system (CNS) within minutes. It also directly targets drugs that do cross the blood–brain barrier to the CNS, eliminating the need for systemic delivery and thereby reducing unwanted systemic side effects. Intranasal delivery does not require any modification of the therapeutic agent. A wide variety of therapeutics, including both small molecules and macromolecules are rapidly delivered intranasally to the brain and can target the olfactory and connected memory areas affected by Alzheimer's disease (AD). This is possible because of the unique connection that the olfactory and trigeminal nerves provide between the brain and external environment [Thorne (2004) Neuroscience 127:481–496]. Using the intranasal delivery method, which I first introduced in 1989, researchers in Italy have reversed neurodegeneration and rescued memory in a transgenic mouse model of AD [Capsoni (2002) PNAS 99(19):12432–12437 and De Rosa (2005) PNAS 102(10): 3811–3816]. We and others have demonstrated both treatment of and protection against stroke in animals with intranasal IGF–I [Liu (2004) Journal of Stroke and Cerebrovascular Diseases 13(1): 16–23], deferoxamine [Panter (2005) Society for Neuroscience Abstracts #669.5] and EPO [Yu (2005) Neurosci Lett 387:5]. Researchers in Israel have used intranasal delivery to target NAP and ADNF to the brain to treat anxiety and neurodegeneration [Alcalay (2004) Neuroscience Letters 361:128–131; Gozes (2000) JPET 293(3):1091–1098.] Intranasal NGF and EGF have been shown to stimulate neurogenesis in adult animals [Jin (2003) Ann Neurol 53:405–409]. Our collaborators [Reger (2006) Neurobiology of Aging: in press] have demonstrated that intranasal insulin acutely improves memory in patients with AD and those with mild cognitive impairment while researchers in Germany [Benedict (2004) Psychoneuroimmunol. 29:1326–1334] have shown that eight weeks of intranasal insulin treatment improves both memory and mood in normal adult humans. This new method of delivery can revolutionize the treatment of Alzheimer's disease, stroke, and other brain disorders.