Intranasal administration of orexin peptides: Mechanisms and therapeutic potential for age-related cognitive dysfunction

• Published in: Brain research Vol. 1731; p. 145921
• Main Authors: Calva, Coleman B., Fadel, Jim R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.03.2020
• Subjects: Administration, Intranasal; Aging - physiology; Aging - psychology; Animals; Basal Forebrain - drug effects; Basal Forebrain - physiology; Brain - drug effects; Brain - physiology; Cholinergic Neurons - drug effects; Cholinergic Neurons - physiology; Cognitive Dysfunction - physiopathology; Cognitive Dysfunction - prevention & control; Humans; Neurons - drug effects; Neurons - physiology; Orexins - administration & dosage; Orexins - physiology
• ISSN: 0006-8993; 1872-6240; 1872-6240
• DOI: 10.1016/j.brainres.2018.08.024

•Impaired orexin signaling is implicated in several neuropsychiatric conditions.•Intranasal orexin targets brain regions and neurotransmitters implicated in cognition.•The orexin-1 receptor mediates most, but not all, of these responses.•Intranasal orexin may be an effective, non-invasive means of cognitive enhancement. Cognitive impairment is a core feature of several neuropsychiatric and neurological disorders, including narcolepsy and age-related dementias. Current pharmacotherapeutic approaches to cognitive enhancement are few in number and limited in efficacy. Thus, novel treatment strategies are needed. The hypothalamic orexin (hypocretin) system, a central integrator of physiological function, plays an important role in modulating cognition. Several single- and dual-orexin receptor antagonists are available for various clinical and preclinical applications, but the paucity of orexin agonists has limited the ability to research their therapeutic potential. To circumvent this hurdle, direct intranasal administration of orexin peptides is being investigated as a prospective treatment for cognitive dysfunction, narcolepsy or other disorders in which deficient orexin signaling has been implicated. Here, we describe the possible mechanisms and therapeutic potential of intranasal orexin delivery. Combined with the behavioral evidence that intranasal orexin-A administration improves cognitive function in narcoleptic and sleep-deprived subjects, our neurochemical studies in young and aged animals highlights the capacity for intranasal orexin administration to improve age-related deficits in neurotransmission. In summary, we highlight prior and original work from our lab and from others that provides a framework for the use of intranasal orexin peptides in treating cognitive dysfunction, especially as it relates to age-related cognitive disorders.