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Endocrine Disease
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
ACTH is generated by enzymatic cleavage of pro-opiomelanocortin (POMC; Figures 12.10 and 12.11) and inhibited through direct negative feedback control by cortisol.
Cushing's Syndrome
Published in K. Gupta, P. Carmichael, A. Zumla, 100 Short Cases for the MRCP, 2020
K. Gupta, P. Carmichael, A. Zumla
Nelson's syndrome formerly occurred as a complication of bilateral adrenalectomy for Cushing's disease. Over a 10-year period 10% to 20% of patients treated in this way will develop the syndrome. This is now less common due to the treatment of choice now being surgical resection of the pituitary adenoma by the trans-sphenoidal approach. The mechanism is very straightforward: in the absence of the negative feedback effect of cortisol, the ACTH secreting pituitary adenoma expands, causing headaches, visual problems and, if not treated, hypopituitarism. The characteristic increased pigmentation is secondary to a melanocyte stimulating component of the ACTH precursor molecule, pro-opiomelanocortin. In cases where an adenoma is not radiologically demonstrable, exploration of the pituitary fossa with or without venous sampling is carried out in those patients with a positive high dose dexamethasone suppression test. If no adenoma is found, a hypophysectomy is often performed. In those centres where bilateral adrenalectomy is performed in the absence of pituitary irradiation, then over a period of time a proportion may develop Nelson's syndrome.
Other Sleep Modulators
Published in Shojiro Inoué, Biology of Sleep Substances, 2020
It is well known that proopiomelanocortin (POMC) is the prohormone of β-lipotropic hormone (β-LPH), which is cleaved into γ-LPH and (β-endorphin, and ACTH, a 39-amino acid residue peptide, which is cleaved into a-melanophore-stimulating hormone (α-MSH; = ACTH1 13) and corticotropin-like intermediate lobe peptide (CLIP; = ACTH 18 39). ACTH primarily stimulates the release of corticosteroids from the adrenal gland, but it exerts a wide spectrum of behavioral effects. α-MSH and CLIP may undergo some modifications, such as acetylation and phosphorylation. Desacetyl-α-MSH (des-α-MSH) is known to exist in a natural form of a-MSH. These POMC-derived peptides have been regarded to be closely related to various kinds of mental activities, such as motivation, vigilance, fear, stress, learning, and memory retrieval. Circadian variations of these hormones are well known, a-MSH can enhance EEG delta waves.75 Recently, it has been reported that the a-MSH content exhibits a definite circadian rhythm in the medial basal hypothalamus and the POA in rats, being high during the dark period, i.e., the active phase of the animal species.76 a-MSH seems to play a role in temperature regulation as an antipyretic neuropeptide.77
Is there a therapeutic potential in combining bupropion and naltrexone in schizophrenia?
Published in Expert Review of Neurotherapeutics, 2022
Samer A. El Hayek, Malek A. Shatila, Jana A. Adnan, Luna E. Geagea, Firas Kobeissy, Farid R. Talih
BUPNAT is an oral extended-release tablet composed of a combination of the dopamine (DA) and norepinephrine (NE) reuptake inhibitor bupropion (BUP) and the µ-opioid receptor antagonist naltrexone (NAT) [18]. The BUP 90 mg/NAT 8 mg formulation (marketed under the brand name Contrave by Orexigen Therapeutics), is typically titrated to 4 tablets per day (BUP 360 mg/NAT 32 mg) by the fourth week of treatment [19]. The development of the drug started in the late 2000s. It gained FDA approval for the treatment of obesity in 2014 [20]. It is hypothesized to work via the stimulation of the hypothalamic pro-opiomelanocortin (POMC) neurons that release alpha-melanocyte-stimulating hormone (α-MSH). α-MSH, in turn, targets specific receptors that serve to reduce caloric intake and increase energy expenditure. When α-MSH is released, POMC neurons also simultaneously secrete µ-opioid receptor agonists. This activates a negative feedback loop on the system. BUPNAT works on both pathways by stimulating POMC neurons (via its BUP component) and inhibiting the negative feedback loop (through the NAT component) [21] (Figure 1).
COVID-19 and alcohol use disorder: putative differential gene expression patterns that might be associated with neurological complications
Published in Hospital Practice, 2022
Jibran Sualeh Muhammad, Ruqaiyyah Siddiqui, Naveed Ahmed Khan
Using the RNAseq expression databases previously mentioned, we co-plotted the expression profile of these genes in alcoholic versus normal and COVID-19 versus normal brain tissue. We observed that all the seven genes were upregulated significantly (p < 0.01) in both disease groups. Of note, three of these genes (VGF, NPTX2, and PDYN) depicted a twofold increase, and three genes (GHRL, IL1RL1, and RPRML) were overexpressed more than threefold in COVID-19 patients’ brain tissues compared to alcoholics’ brain tissues (Figure 2C). Next, protein–protein interaction analysis showed that the transcripts of three of these genes (GHRL, VGF, and PDYN) have several known or predicted interactions with Neuropeptide Y (NPY), Prepronociceptin protein (PNOC), Proopiomelanocortin (POMC), and several subtypes of Opioid Receptors (OPRM1, OPRL1, OPRK1, and OPRD1), suggesting a role in modulation of perception of pain. NPTX2 is shown to interact with PDYN, IL1RL1 has a predicted interaction with IL33, and VGF has known interactions with SCG3 (Figure 2D). Relevant functions of the seven candidate genes and eight genes of the closely interacting proteins are described (Table 1). Lastly, we elucidated the expression profile of these 15 genes in normal brain tissue. We found that VGF and SCG3 were upregulated in almost all types of human brain tissues, whereas the GHRL, IL1RL1, GHSR, and OPRM1 expression was very low (Figure 2E).
Olanzapine-samidorphan combination tablets for the treatment of schizophrenia and bipolar I disorder - what is it, and will it be used?
Published in Expert Review of Neurotherapeutics, 2022
Justin Faden, Ryan Serdenes, Leslie Citrome
Overall, several mechanisms explaining opioid mediated weight modulation have been proposed. Inhibition of hypothalamic proopiomelanocortin neuron-negative feedback via opioid receptor antagonists increase alpha-melanocyte-stimulating hormone and subsequent melanocortin-4 receptor mediated appetite suppression. Opioid receptor antagonism can also disinhibit GABAergic interneurons and inhibit glutamatergic input into ventral tegmental dopaminergic neurons projecting to the nucleus accumbens [44,45]. Finally, opioid receptor antagonism within the nucleus accumbens shell has been shown to reduce caloric intake [46]. Additional physiological relationships of cerebral opioids with orexin, ghrelin, leptin, and insulin have been identified and remain under investigation [47–50]. The mu-opioid receptor appears to be the most associated with obesity risk, via complex interplay via insulin, opioid and endocannabinoid messaging systems in the brain [51].