Neuropeptides
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Orexins A and B (hypocretins 1 and 2) and their two receptors (OX1R and OX2R) were discovered in 1998 by two different groups. Orexin A and B are derived from the differential processing of a common precursor, the prepro-orexin peptide. The neuropeptides are expressed in a few thousand cells located in the lateral hypothalamus (LH), but their projections and receptor distribution are widespread throughout the brain. ⋯ However, despite early findings in feeding and appetite control, orexin receptor antagonists have not produced the anticipated effects in models of increased food intake or obesity in rodents, nor have they shown marked effects on weight in the existing clinical trials. The role of orexin in a number of other domains such as pain, mood, anxiety, migraine and neurodegenerative diseases is an active area of research. The progress of the orexin field is thus extraordinary, and the community awaits the clinical testing of more receptor selective antagonists in sleep and other disorders, as well as that of orexin agonists, with the latter expected to produce positive outcomes in narcolepsy/cataplexy and other conditions.
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Migraine is a debilitating neurological disorder that affects about 12% of the population. In the past decade, the role of the neuropeptide calcitonin gene-related peptide (CGRP) in migraine has been firmly established by clinical studies. CGRP administration can trigger migraines, and CGRP receptor antagonists ameliorate migraine. ⋯ One candidate is pituitary adenylate cyclase-activating peptide (PACAP), which shares some of the same actions as CGRP, including the ability to induce migraine in migraineurs and light aversive behavior in rodents. Interestingly, both CGRP and PACAP act on receptors that share an accessory subunit called receptor activity modifying protein-1 (RAMP1). Thus, comparisons between the actions of these two migraine-inducing neuropeptides, CGRP and PACAP, may provide new insights into migraine pathophysiology.
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Although detailed disease mechanisms of migraine remain poorly understood, migraine is known to have a complex pathophysiology with both vascular and neuronal mechanisms. The neuronal mechanisms of migraine may be attributed to cortical spreading depression (CSD); consequently, CSD has been widely studied for understanding the pathophysiology of migraine. Well validated CSD models have been developed for evaluating anti-migraine drugs. ⋯ This review briefly summarizes our current understanding of CSD and CGRP involvement in CSD. Although CSD can also worsen strokes, this brief paper has excluded the possible connection between the neuropeptide and CSD associated with them. Instead it has focused solely on CGRP in CSD associated with migraine.
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Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) act through three class B G-protein coupled receptors, PAC1, VPAC1 and VPAC2, initiating multiple signaling pathways. In addition to natural peptides ligands, a number of synthetic peptides and a small molecular antagonist have been generated. Genetically modified animals have been produced for the neuropeptides and receptors. ⋯ Whereas knockout animals are appropriate to address loss-of-function of human genetics, transgenic mice overexpressing human transgenes in native environment using artificial chromosomes are particularly valuable and essential to address the consequences of gain-of-function. This review focuses on role of PACAP and PAC1 receptor in brain development, behavior of animals and potential implication in human neurodevelopmental disorders. It also encourages keeping an open mind that alterations of VIP/PACAP signaling may associate with psychiatric illness without overt neuroanatomic changes, and that tuning of VIP/PACAP signaling may represent a novel avenue for the treatment of the psychiatric illness.
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There is now unequivocal evidence that the angiotensin-converting enzyme 2(ACE2)-Ang-(1-7)-Mas axis is a key component of the renin-angiotensin system (RAS) cascade, which is closely correlated with ischemic insult occurrence. Our previous studies demonstrated that the Ang-(1-7), was an active member of the brain RAS. However, the ACE2-Ang-(1-7)-Mas axis expression after cerebral ischemic injury are currently unclear. ⋯ Both ACE2 and Mas expression were markedly enhanced compared to the control in the ischemic tissues (P<0.05). Mas immunopositive neurons were also seen stronger expression in the ischemic cortex (19.167±2.858 vs. 7.833±2.483) (P<0.05). The evidence collected in our present study will indicate that, ACE2-Ang-(1-7)-Mas axis are upregulated after acute ischemic stroke and would play a pivotal role in the regulation of acute neuron injury in ischemic cerebrovascular diseases.