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Drugs for Treatment of Neurological and Psychological Conditions
Published in Richard J. Sundberg, The Chemical Century, 2017
The amphetamines and analogs act by releasing noradrenaline and dopamine in the hypothalamus and have a powerful effect of inhibiting appetite (anorexigens). The hypothalamus has receptors for neuropeptides that either enhance (orexigenic) or suppress (anorexigenic) appetite. Norephedrine was available over-the-counter in the United States and Europe as its hydrochloride salt under brand names such as Monydrin, Proin, and Propalin. It was withdrawn in 2000 as a result of studies that indicated an increased risk of hemorrhagic stroke. An amphetamine analog, aminorex, was introduced as an anorexigen in Europe in the 1960s. It was subsequently linked to an increased incidence of primary pulmonary hypertension and was withdrawn from the market in the 1970s. Phentermine was granted FDA approval in the United States in 1959. Fenfluramine was approved in 1973. They were approved only for treatment of obesity and for short-term use. These drugs act by stimulating release of serotonin and activating serotonin receptors. These effects suppress appetite through the effect of serotonin on cerebral centers. During the 1990s, the use of amphetamine weight-loss drugs grew rapidly. The pure active enantiomer of fenfluramine, called dexfenfluramine and sold as Redux, was approved for use in 1995, on a close split vote of the FDA advisory panel. The approved use was for short-term treatment of obesity. Approval was withdrawn in 1997. The combination of fenfluramine and phentermine, known as fen-phen, was introduced in 1992, although the combination was never approved by FDA. It is believed that more than 8 million people, mostly women, received prescriptions. The structures of these drugs are shown in Scheme 17.9.
Implications of estrogen receptor alpha (ERa) with the intersection of organophosphate flame retardants and diet-induced obesity in adult mice
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Gwyndolin M. Vail, Sabrina N. Walley, Ali Yasrebi, Angela Maeng, Thomas J. Degroat, Kristie M. Conde, Troy A. Roepke
While control ERαKO males fed a HFD exhibited the WT pattern of increased meal frequency compared to LFD, OPFR treatment eliminated this difference. Potentially, this may be resulting from elevated levels of ghrelin in OPFR-treated LFD males. Ghrelin is a potent orexigenic hormone and higher signal in LFD animals may confer an enhanced stimulus to feed specific to LFD animals exposed to OPFRs. This may account for how the diet effect was eliminated in OPFR-exposed males. Interestingly, Vail et al. (2020; Table 3) previously found that WT males exhibited lower ghrelin levels on a LFD. This is indicative of interaction between OPFR endocrine disruption and ERα, which is known to stimulate ghrelin signaling (Kellokoski et al. 2005; Sakata et al. 2006). Further, OPFR induced an enhanced expression of Npy in the ARC from male mice (Table 2). Npy is the transcript for neuropeptide Y, a neuropeptide that stimulates food intake, and might be contributing to the noted effects on LFD meal frequency and circulating ghrelin.
Evaluation of sucrose-enriched diet consumption in the development of risk factors associated to type 2 diabetes, atherosclerosis and non-alcoholic fatty liver disease in a murine model
Published in International Journal of Environmental Health Research, 2021
Carolina Gabriela Plazas Guerrero, Selene De Jesús Acosta Cota, Francisco Humberto Castro Sánchez, Marcela De Jesús Vergara Jiménez, Efrén Rafael Ríos Burgueño, Juan Ignacio Sarmiento Sánchez, Lorenzo Antonio Picos Corrales, Ulises Osuna Martínez
Otherwise, high-sucrose consumption promotes higher insulinemic responses which triggers signals that are important in the control of food intake (Petykó et al. 2009). Insulin has an anorexigenic effect by decreasing the expression of orexigenic peptide Neuropeptide Y (NPY) and stimulating other satiety signals such as CCK and corticotropin-releasing hormone (CRH) (Hita et al. 2006). Insulin also stimulates leptin synthesis by adipocytes which increases satiety and decreases food intake since leptin acts on the hypothalamus by inhibiting the synthesis of NPY and increases the expression of anorexigenic peptides such as CRH (Sánchez 2005; Hita et al. 2006). This possible increase in blood leptin levels has already been observed in previous studies with mice fed with a high-sucrose diet (Oliveira et al. 2014; Castellanos Jankiewicz et al. 2015; Harris 2018).
Implications of peroxisome proliferator-activated receptor gamma (PPARY) with the intersection of organophosphate flame retardants and diet-induced obesity in adult mice
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Gwyndolin M. Vail, Sabrina N. Walley, Ali Yasrebi, Angela Maeng, Thomas J. Degroat, Kristie M. Conde, Troy A. Roepke
Terminal plasma hormone levels were analyzed for leptin, insulin, and ghrelin. PPARγKO male mice demonstrated no marked effect due to OPFR exposure (Figure 8A–8C). The only significant effect reported in males was that HFD induced an overall effect to elevate circulating leptin levels (Figure 8B). Female PPARγKO mice, however, displayed more interesting results. Leptin levels were increased by HFD (Figure 8E), but post-hoc testing only revealed a significant effect of diet in control mice (Figure 8E); there was no significant difference between LFD and HFD leptin levels in OPFR-exposed females. This may be attributed to a significant repression of circulating leptin by OPFRs in HFD-fed animals (Figure 8E) and highlights the interaction of OPFR exposure and diet-induced alterations to leptin signaling (Figure 8E). Furthermore, this effect is in agreement with the insulin results (Figure 8D). Whereas the significant effect of diet (Figure 8D) is represented in post-hoc significance between LFD- and HFD-fed controls, there was no significant difference found in the OPFR-treated group. Finally, the inverse was found for the orexigenic hormone ghrelin (Figure 8F). An overall diet effect was also noted with HFD reducing circulating ghrelin (Figure 8F), but this period of OPFR exposure was shown to exacerbate the effect of diet by significantly increasing the levels of ghrelin in LFD-fed females (Figure 8F). This led to a significant difference between diets (Figure 8F) only within the OPFR-treated mice. Taken together, it appears that female PPARγKO mice may be more susceptible to OPFR disruption of plasma hormones than their male counterparts. Further, OPFR exposure was found to interact with diet by reducing the typical rise of anorexigenic insulin and leptin in the blood in response to a HFD, while also increasing plasma levels of orexigenic ghrelin when fed LFD.