Orexin-A

Orexin A, also known as Hypocretin-1, is a naturally occurring, highly excitatory, neuropeptide released by the hypothalamus. As a pharmaceutical drug, Orexin A is most commonly administered as a nasal spray. This drug counteracts intellectual deficiencies and altered brain metabolism, which is found in sleep-deprived subjects.

Side Effects
To date, taking Orexin A has shown no negative side effects. Positive side effects of this drug include an improvement in cognitive ability and functionality in a sleep-deprived state. Taking Orexin A also increases arousal, alertness, attention, and muscle tone. Orexin A has no effect on subjects who are well rested. It is important to note that the study and testing of this drug is fairly new and it has not yet been administered to humans. The most important side effect Orexin A is thought to have is counteracting the effects of narcolepsy.

Ongoing Research
The subjects of one particular study, rhesus monkeys, were deprived of sleep in durations of 30 to 36 hours, and were immediately assessed in short term memory tasks. The rhesus monkeys were split into a test group and into a control group. The test group was administered Orexin A intravenously, or nasally. The control group was given a placebo. The sleep-deprived monkeys, which were given the nasal form of Orexin A, performed far better than the ones treated with injections. Orexin A not only restored the monkey’s cognitive abilities but made their brains appear awake in PET scans. The same was not true for the control group, which did not exhibit any changes. The findings of these studies strongly favor an effective way to alleviate cognitive limitations due to sleep loss.

Structure
Orexin-A is a peptide composed of 33 amino acids including an N-terminal pyroglutamyl residue and two intramolecular disulfide bridges between cysteine residues in 6 and 12 and 7 and 14 positions.

Mechanism
Orexins are highly excitatory neuropeptide hormones that were first discovered in the brains of rats. It is a peptide that is produced by a very small population of cells in the lateral and posterior hypothalamus. Orexins strongly excite various brain nuclei (neurons) to affect an organism’s wakefulness by affecting their dopamine, norepinephrine, histamine and acetylcholine systems. These systems work together to stabilize the organism’s sleep cycles. Once made, the Orexin peptides can bind to the orexin receptor; which is a G protein coupled receptor. This G protein linked receptor, senses molecules outside the cell and activate inside signal transduction pathways to elicit cellular responses.

Research shows that an absence of Orexin A appears to cause narcolepsy. Deficit amounts of Orexin A will make people sleepy and research suggests that by adding it back into the brain, narcoleptic effects will be reduced. The research determined how glucose inhibited a particular class of glucose-sensing neurons; which produce tiny proteins called Orexins. However, it is unknown how glucose suppresses the electrical activity of Orexin cells.

A study from the University of Manchester discovered how glucose inhibited neurons which affected regulating sleep cycles. Tests show a class of potassium ion channels that are porelike proteins in the cell membrane and they affect the cellular responses by controlling the flow of potassium into the cell. The exact mechanism of the potassium ion channels is unknown, but the experiments show that the absence of glucose inhibited the Orexin neurons by acting on this class of potassium ion channels known as "tandem pore" channels.

Summary
Orexin A is a recently studied drug most commonly used to improve sleep cycles in subjects who are sleep-deprived. Much of the mechanism of Orexin A and how it is utilized in the treatment of narcolepsy is still unknown. Researchers know what pathways are used to counteract narcolepsy, but they do not fully understand the procedure of how it is achieved.