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

Abstract

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.

The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task

“…The role of orexin signaling in response inhibition has not been investigated, but it is known that orexin neurons are interconnected with a variety of modulatory neurotransmitter systems thought to be important for response inhibition, including midbrain dopamine neurons, norepinephrine neurons in the locus coeruleus, and basal forebrain cholinergic neurons (Balcita-Pedicino and Sesack, 2007;Espana et al, 2005;Fadel and Deutch, 2002;Fadel and Burk, 2010;Vittoz and Berridge, 2006). Orexin signaling has also been shown to modulate glutamatergic thalamocortical synapses that ultimately alter acetylcholine and glutamate release in the prefrontal cortex (Calva and Fadel, 2018;Lambe et al, 2005), a part of the brain thought to be crucial for inhibitory control. Finally, substance use disorder is characterized by high levels of impulsivity, including response inhibition deficits (Argyriou et al, 2018;Jentsch et al, 2014;Verdejo-Garcia et al, 2008), perhaps pointing to a common role for the orexin system in mediating these processes.…”

The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task

“…prefrontal cortex) and modulatory neurotransmitter systems (e.g. dopamine, norepinephrine and basal forebrain acetylcholine) thought to be important for arousal, attention and impulsivity (Balcita-Pedicino and Sesack, 2007;Calva and Fadel, 2018;Espana et al, 2005;Fadel and Deutch, 2002;Fadel and Burk, 2010;Lambe et al, 2005;Vittoz and Berridge, 2006). Thirdly, and perhaps most relevant in this case, several recent studies have implicated orexin signaling in other forms of motor impulsivity.…”

“…The role of orexin signaling in response inhibition has not been investigated, but it is known that orexin neurons are interconnected with a variety of modulatory neurotransmitter systems thought to be important for response inhibition, including midbrain dopamine neurons, norepinephrine neurons in the locus coeruleus, and basal forebrain cholinergic neurons (Balcita-Pedicino and Sesack, 2007;Espana et al, 2005;Fadel and Deutch, 2002;Fadel and Burk, 2010;Vittoz and Berridge, 2006). Orexin signaling has also been shown to modulate glutamatergic thalamocortical synapses that ultimately alter acetylcholine and glutamate release in the prefrontal cortex (Calva and Fadel, 2018;Lambe et al, 2005), a part of the brain thought to be crucial for inhibitory control. Finally, substance use disorder is characterized by high levels of impulsivity, including response inhibition (Argyriou et al, 2018;Jentsch et al, 2014;Verdejo-Garcia et al, 2008), perhaps pointing to a common role for the orexin system in mediating these processes.…”

Orexin and Alzheimer’s Disease: A New Perspective

“…59 Intranasal delivery is another option, with a recent review demonstrating intranasal administration of orexin effectively increasing neuronal activation in an animal model. 60…”