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Hypocretin-1 (HC, orexin-A) is a neuropeptide involved in regulating physiological functions of sleep, appetite and arousal, and it has been shown that intranasal (IN) administration can target HC to the brain. Recent clinical studies have shown that IN HC has functional effects in human clinical trials. In this study, we use rats to determine whether IN HC has an immediate effect on food consumption and locomotor activity, whether distribution in the brain after IN delivery is dose-dependent, and whether MAPK and PDK1 are affected after IN delivery. Food intake and wheel-running activity were quantified for 24h after IN delivery. Biodistribution was determined 30min after IN delivery of both a high and low dose of 125I-radiolabelled HC throughout the brain and other bodily tissues, while Western blots were used to quantify changes in cell signaling pathways (MAPK and PDK1) in the brain. Intranasal HC significantly increased food intake and wheel activity within 4h after delivery, but balanced out over the course of 24h. The distribution studies showed dose-dependent delivery in the CNS and peripheral tissues, while PDK1 was significantly increased in the brain 30min after IN delivery of HC. This study adds to the growing body of evidence that IN administration of HC is a promising strategy for treatment of HC related behaviors., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

In addition to the hallmark accumulation of amyloid and hyper-phosphorylation of tau, brain changes in Alzheimer's disease are multifactorial including inflammation, oxidative stress, and metal dysregulation. Metal chelators have been explored as a less well known approach to treatment. One chelator currently being developed is deferoxamine (DFO), administered via the intranasal (IN) route. In the current study, APP/PS1 amyloid mice were treated with a chronic, low dose of IN DFO, subjected to a rigorous battery of behavior tests, and the mechanism of action was examined. Mice were treated 3x/week with 0.24 C IN DFO for 18 weeks from 36 to 54 weeks of age, 4 weeks of behavior tests were performed that included both working and reference memory, anxiolytic and motor behaviors, and finally brain tissues were analyzed for amyloid, protein oxidation, and other proteins affected by DFO. We found that IN DFO treatment significantly decreased loss of both reference and working memory in the Morris and radial arm water mazes (p < 0.05), and also decreased soluble Aβ40 and Aβ42 in cortex and hippocampus (p < 0.05). Further, IN DFO decreased activity of GSK3β, and led to decreases in oxidative stress (p < 0.05). These data demonstrate that low doses of IN DFO can modify several targets along the multiple pathways implicated in the neuropathology of Alzheimer's, making it an attractive candidate for the treatment of this heterogeneous disease., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Adopting RNAi technology for targeted manipulation of gene expression in the central nervous system (CNS) will require delivery of RNAi constructs to the CNS followed by cellular transfection and induction of the RNAi machinery. Significant strides have been made in enhancing RNAi transfection and tailoring knockdown toward specific gene targets, however, delivery of the RNAi constructs to the CNS remains a significant challenge. One possible solution for targeting siRNA to the CNS is intranasal administration, which noninvasively delivers a variety of compounds to the CNS. The current study examined delivery of fluorescently labeled siRNA from the nasal cavity to the olfactory bulbs via the olfactory nerve pathway. siRNA was observed along the length of the olfactory nerve bundles, from the olfactory mucosa of the nasal cavity to the anterior regions of the olfactory bulbs. In the olfactory mucosa, labeled siRNA was found within the olfactory epithelium, Bowman's glands, and associated with blood vessels and bundles of olfactory nerves. In the olfactory bulbs, siRNA was observed in the olfactory nerve, glomerular and mitral cell layers. These results demonstrate a role of the olfactory nerve pathway in targeting siRNA to the olfactory bulbs. Additional investigations will be required to assess the distribution of intranasal siRNA to additional regions of the brain and explore the capacity of the delivered siRNA to silence gene expression in the CNS., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Intranasal administration of therapeutic agents offers a noninvasive method of drug delivery that bypasses the blood-brain barrier and directly targets the central nervous system (CNS) and lymph nodes. We examined whether intranasal peptoid CHIR5585, an antagonist of the urokinase plasminogen activator receptor (uPAR), is delivered to the CNS. Peptoids are a novel class of peptide isomers that are oligomeric N-substituted glycine peptides. Anesthetized male rats were administered peptoid CHIR5585 intranasally, and tissue distribution was evaluated quantitatively by gamma counting and qualitatively by autoradiography. Intranasal administration resulted in significant delivery throughout the CNS (olfactory bulbs, 3.9microM; cortex, 0.3microM; trigeminal nerve, 1.7microM) and deep cervical lymph nodes (4.5microM). Autoradiography demonstrated a similar delivery pattern to the CNS.

Insulin-like growth factor-I (IGF-I) has been proposed as a treatment for stroke. However, it does not efficiently cross the blood-brain barrier (BBB). Intracerebroventricular injection of IGF-I has been shown to offer protection against cerebral ischemic damage in rats although this invasive method of administration may not be practical in humans. Non-invasive intranasal (IN) delivery of IGF-I to the brain is a promising alternative. We have assessed the therapeutic effect of IN IGF-I in rats following middle cerebral artery occlusion (MCAO). Treatment was initiated 10 min after the onset of MCAO and then again 24 and 48 h later. Intranasal dosing of 75 microg IGF-1 (225 microg total IGF-I over 48 h) significantly reduced corrected infarct volumes by 60% vs. control (P<0.01) and hemispheric swelling by 45.6% vs. control (P<0.05). Neurologic function, assessed by the postural reflex, flexor response and adhesive tape tests, was also improved by IN IGF-I as compared to control. Our study indicates IN delivery of IGF-1 holds significant promise as a non-invasive and efficacious method of bypassing the BBB for the treatment of stroke.