RESUMO
Treatment options for alcohol use disorders (AUDs) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a bioinformatics approach. We prioritized a newer PDE4 inhibitor, apremilast, as ideal for repurposing (i.e., FDA approved for psoriasis, low incidence of adverse events, excellent safety profile) and tested it using multiple animal strains and models, as well as in a human phase IIa study. We found that apremilast reduced binge-like alcohol intake and behavioral measures of alcohol motivation in mouse models of genetic risk for drinking to intoxication. Apremilast also reduced excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. Using site-directed drug infusions and electrophysiology, we uncovered that apremilast may act to lessen drinking in mice by increasing neural activity in the nucleus accumbens, a key brain region in the regulation of alcohol intake. Importantly, apremilast (90 mg/d) reduced excessive drinking in non-treatment-seeking individuals with AUD in a double-blind, placebo-controlled study. These results demonstrate that apremilast suppresses excessive alcohol drinking across the spectrum of AUD severity.
Assuntos
Alcoolismo , Inibidores da Fosfodiesterase 4 , Psoríase , Humanos , Camundongos , Animais , Talidomida/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Psoríase/tratamento farmacológico , Etanol , Consumo de Bebidas Alcoólicas/genéticaRESUMO
High-fat feeding (HFF) is a well-accepted model for nutritionally-induced insulin resistance. The purpose of this investigation was to assess the metabolic responses of female lean Zucker rats provided regular chow (4% fat) or a high-fat chow (50% fat) for 15 wk. HFF rats spontaneously adjusted food intake so that daily caloric intake matched that of chow-fed (CF) controls. HFF animals consumed more (P < 0.05) calories from fat (31.9 +/- 1.2 vs. 2.4 +/- 0.2 kcal/day) and had significantly greater final body weights (280 +/- 10 vs. 250 +/- 5 g) and total visceral fat (24 +/- 3 vs. 10 +/- 1 g). Fasting plasma insulin was 2.3-fold elevated in HFF rats. Glucose tolerance (58%) and whole body insulin sensitivity (75%) were markedly impaired in HFF animals. In HFF plantaris muscle, in vivo insulin receptor beta-subunit (IR-beta) and insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and phosphorylation of Akt Ser473 and glycogen synthase kinase-3beta (GSK-3beta) Ser9, relative to circulating insulin levels, were decreased by 40-59%. In vitro insulin-stimulated glucose transport in HFF soleus was decreased by 54%, as were IRS-1 tyrosine phosphorylation (26%) and phosphorylation of Akt Ser473 (38%) and GSK-3beta Ser9 (25%), the latter indicative of GSK-3 overactivity. GSK-3 inhibition in HFF soleus using CT98014 increased insulin-stimulated glucose transport (28%), IRS-1 tyrosine phosphorylation (28%) and phosphorylation of Akt Ser473 (38%) and GSK-3beta Ser9 (48%). In summary, the female lean Zucker rat fed a high-fat diet represents an isocaloric model of nutritionally-induced insulin resistance associated with moderate visceral fat gain, hyperinsulinemia, and impairments of skeletal muscle insulin-signaling functionality, including GSK-3beta overactivity.
Assuntos
Gorduras na Dieta/farmacologia , Quinase 3 da Glicogênio Sintase/metabolismo , Resistência à Insulina/fisiologia , Músculo Esquelético/enzimologia , Animais , Glicemia/metabolismo , Modelos Animais de Doenças , Feminino , Insulina/sangue , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Ratos , Ratos Zucker , Transdução de Sinais/fisiologiaRESUMO
We have demonstrated previously in insulin-sensitive skeletal muscle that lithium, an alkali metal and non-selective inhibitor of glycogen synthase kinase-3 (GSK-3), activates glucose transport by engaging the stress-activated p38 mitogen-activated protein kinase (p38 MAPK). However, it is presently unknown whether this same mechanism underlies lithium action on the glucose transport system in insulin-resistant skeletal muscle. We therefore assessed the effects of lithium on basal and insulin-stimulated glucose transport, glycogen synthesis, insulin signalling (insulin receptor (IR), Akt, and GSK-3), and p38 MAPK in soleus muscle from female obese Zucker rats. Lithium (10 mM LiCl) increased basal glucose transport by 49% (p < 0.05) and net glycogen synthesis by 2.4-fold (p < 0.05). In the absence of insulin, lithium did not induce IR tyrosine phosphorylation, but did enhance (p < 0.05) Akt ser(473) phosphorylation (40%) and GSK-3beta ser(9) phosphorylation (88%). Lithium potentiated (p < 0.05) the stimulatory effects of insulin on glucose transport (74%), glycogen synthesis (2.4-fold), Akt ser(473) phosphorylation (39%), and GSK-3beta ser(9) phosphorylation (36%), and elicited robust increases (p < 0.05) in p38 MAPK phosphorylation both in the absence (100%) or presence (88%) of insulin. The selective p38 MAPK inhibitor A304000 (10 muM) completely blocked basal activation of glucose transport by lithium, and significantly reduced (42%, p < 0.05) the lithium-induced enhancement of insulin-stimulated glucose transport in insulin-resistant muscle. These results indicate that lithium enhances both basal and insulin-stimulated glucose transport and glycogen synthesis in insulin-resistant skeletal muscle of female obese Zucker rats, and that these lithium-dependent effects are associated with enhanced Akt and GSK-3beta serine phosphorylation. As in insulin-sensitive muscle, the lithium-induced activation of glucose transport in insulin-resistant skeletal muscle is dependent on the engagement of p38 MAPK.