Intranasal Delivery of Proteins and Peptides in the Treatment of Neurodegenerative Diseases

Meredith, M. Elizabeth; Salameh, Therese S.; Banks, William A.

doi:10.1208/s12248-015-9719-7

Cited by 159 publications

(107 citation statements)

References 72 publications

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“…Intranasal administration is suggested for treatment of neurodegenerative diseases. 23,37 Topical application to skin was used to achieve dermal vasodilation, 38 while buccal delivery for treatment of type 2 diabetes. 39 Topical ocular application of PACAP has already been used to test local, corneal effects of the peptide.…”

Section: Discussionmentioning

confidence: 99%

Ocular Delivery of PACAP1-27 Protects the Retina From Ischemic Damage in Rodents

Werling

Reglődi

Banks

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Werling D, Reglodi D, Banks WA, et al. Ocular delivery of PACAP1-27 protects the retina from ischemic damage in rodents. Invest Ophthalmol Vis Sci. 2016;57:6683-6691. DOI: 10.1167/iovs.16-20630 PURPOSE. Pituitary adenylate cyclase activating polypeptide (PACAP) is neuroprotective in neuronal injuries. Bilateral common carotid artery occlusion (BCCAO) causes chronic hypoperfusion-induced degeneration in the rat retina, where we proved the retinoprotective effect of intravitreal PACAP. Although this route of administration is a common clinical practice in several diseases, easier routes are clinically important. Our aim was to investigate the potential retinoprotective effects of PACAP eye drops in BCCAO-induced ischemic retinopathy.METHODS. After performing BCCAO in rats, the right eyes were treated with PACAP1-27 eye drops (1 lg/drop, 2 3 1 drops/day for 5 days), containing different vehicles: saline, water for injections, thiomersal or benzalkonium solution for ophthalmic use (SOCB). Histology and immunohistochemistry were performed 2 weeks after surgery, while molecular analysis was performed 24 hours after BCCAO. Passage of PACAP1-27 through the ocular layers was tested with radioactive PACAP-SOCB in mice.RESULTS. Bilateral common carotid artery occlusion led to a severe degeneration of all retinal layers. Solution for ophthalmic use was the most effective vehicle for delivering PACAP (PACAP-SOCB), significantly ameliorating BCCAO-induced damage. The massive upregulation of GFAP was not observed in retinas treated with PACAP-SOCB eye drops. PACAP-SOCB treatment also increased activation of the protective Akt and ERK1/2 in hypoperfused retinas. The cytokine profile showing upregulation in different cytokines was attenuated by PACAP-SOCB. Radioactive PACAP reached the retina when delivered in SOCB-containing eye drops.CONCLUSIONS. PACAP1-27, delivered in the SOCB vehicle as eye drops, was retinoprotective in ischemic retinopathy, providing the basis for future therapeutic administration.

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Section: Discussionmentioning

confidence: 99%

Ocular Delivery of PACAP1-27 Protects the Retina From Ischemic Damage in Rodents

Werling

Reglődi

Banks

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…Many viruses and bacteria co-opt this olfactory route for brain infection, and more than 40 substances have been shown to enter the brain by this means (93, 94). Viruses, such as Venezuelan equine encephalitis virus, initially infiltrate the CNS via olfactory axons, then induce BBB permeability throughout the brain to promote a second wave of infection, as virion particles enter the brain from the circulation via the damaged barrier (95).…”

Section: Potential Routes Of Antibody Entry Into the Cnsmentioning

confidence: 99%

Hello from the Other Side: How Autoantibodies Circumvent the Blood–Brain Barrier in Autoimmune Encephalitis

2017

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Antibodies against neuronal receptors and synaptic proteins are associated with autoimmune encephalitides (AE) that produce movement and psychiatric disorders. In order to exert their pathological effects on neural circuits, autoantibodies against central nervous system (CNS) targets must gain access to the brain and spinal cord by crossing the blood–brain barrier (BBB), a tightly regulated gateway formed by endothelial cells lining CNS blood vessels. To date, the pathogenic mechanisms that underlie autoantibody-triggered encephalitic syndromes are poorly understood, and how autoantibodies breach the barrier remains obscure for almost all AE syndromes. The relative importance of cellular versus humoral immune mechanisms for disease pathogenesis also remains largely unexplored. Here, we review the proposed triggers for various autoimmune encephalopathies and their animal models, as well as basic structural features of the BBB and how they differ among various CNS regions, a feature that likely underlies some regional aspects of autoimmune encephalitis pathogenesis. We then discuss the routes that antibodies and immune cells employ to enter the CNS and their implications for AE. Finally, we explore future therapeutic strategies that may either preserve or restore barrier function and thereby limit immune cell and autoantibody infiltration into the CNS. Recent mechanistic insights into CNS autoantibody entry indicate promising future directions for therapeutic intervention beyond current, short-lived therapies that eliminate circulating autoantibodies.

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“…To increase brain targeting, intranasal delivery is an excellent non-invasive form of administration [24]. Banks et al reported that, compared with intravenous administration, intranasal administration of radioactively labeled exendin(9-39), a glucagon-like peptide-1 (GLP-1) receptor antagonist, was four times more effective in delivery to the olfactory bulb, but three times lower in delivery to the rest of the brain [25].…”

Section: Peptide Drug Delivery Is a Key Issuementioning

confidence: 99%

From Nose to Brain: The Promise of Peptide Therapy for Alzheimer’s Disease and Other Neurodegenerative Diseases

Chen¹

2017

J Alzheimers Dis Parkinsonism

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Intranasal Delivery of Proteins and Peptides in the Treatment of Neurodegenerative Diseases

Cited by 159 publications

References 72 publications

Ocular Delivery of PACAP1-27 Protects the Retina From Ischemic Damage in Rodents

Ocular Delivery of PACAP1-27 Protects the Retina From Ischemic Damage in Rodents

Hello from the Other Side: How Autoantibodies Circumvent the Blood–Brain Barrier in Autoimmune Encephalitis

From Nose to Brain: The Promise of Peptide Therapy for Alzheimer’s Disease and Other Neurodegenerative Diseases

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