ABSTRACT
Epidemiological investigations have indicated that insufficient sleep is prevalent among adolescents, posing a globally underestimated health risk. Sleep fragmentation and sleep loss during adolescence have been linked to concurrent emotional dysregulation and an increase in impulsive, risk-taking behaviors, including a higher likelihood of substance abuse. Among the most widely used substances, alcohol stands as the primary risk factor for deaths and disability among individuals aged 15-49 worldwide. While the association between sleep loss and alcohol consumption during adolescence is well documented, the extent to which prior exposure to sleep loss in adolescence contributes to heightened alcohol use later in adulthood remains less clearly delineated. Here, we analyzed longitudinal epidemiological data spanning 9 years, from adolescence to adulthood, including 5497 participants of the Avon Longitudinal Study of Parents And Children cohort. Sleep and alcohol measures collected from interviews and questionnaires at 15 and 24 years of age were analyzed with multivariable linear regression and a cross-lagged autoregressive path model. Additionally, we employed a controlled preclinical experimental setting to investigate the causal relationship underlying the associations found in the human study and to assess comorbid behavioral alterations. Preclinical data were collected by sleep restricting Marchigian Sardinian alcohol preferring rats (msP, n=40) during adolescence and measuring voluntary alcohol drinking concurrently and in adulthood. Polysomnography was used to validate the efficacy of the sleep restriction procedure. Behavioral tests were used to assess anxiety, risky behavior, and despair. In humans, after adjusting for covariates, we found a cross-sectional association between all sleep parameters and alcohol consumption at 15 years of age but not at 24 years. Notably, alcohol consumption (Alcohol Use Disorder Identification Test for Consumption) at 24 years was predicted by insufficient sleep at 15 years whilst alcohol drinking at 15 years could not predict sleep problems at 24. In msP rats, adolescent chronic sleep restriction escalated alcohol consumption and led to increased propensity for risk-taking behavior in adolescence and adulthood. Our findings demonstrate that adolescent insufficient sleep causally contributes to higher adult alcohol consumption, potentially by promoting risky behavior.
ABSTRACT
Insulin resistance (IR) is a risk factor for metabolic disorders and neurodegeneration. Peroxisome proliferator-activated receptor (PPAR) agonists have been proven to mitigate the neuronal pathology associated with IR. However, the synergetic efficacy of these agonists is yet to be fully described. Hence, we aimed to investigate the efficacy of PPARα/γ agonists (fenofibrate and pioglitazone) on a high-fat diet (HFD) and streptozotocin (STZ)-induced hippocampal neurodegeneration. Male Wistar rats (200 ± 25 mg/body weight [BW]) were divided into five groups. The experimental groups were fed on an HFD for 12 weeks coupled with 5 days of an STZ injection (30 mg/kg/BW, i.p) to induce IR. Fenofibrate (FEN; 100 mg/kg/BW, orally), pioglitazone (PIO; 20 mg/kg/BW, orally), and their combination were administered for 2 weeks postinduction. Behavioral tests were conducted, and blood was collected to determine insulin sensitivity after treatment. Animals were killed for assessment of oxidative stress, cellular morphology characterization, and astrocytic evaluation. HFD/STZ-induced IR increased malondialdehyde (MDA) levels and decreased glutathione (GSH) levels. Evidence of cellular alterations and overexpression of astrocytic protein was observed in the hippocampus. By contrast, monotherapy of FEN and PIO increased the GSH level (p < 0.05), decreased the MDA level (p < 0.05), and improved cellular morphology and astrocytic expression. Furthermore, the combined treatment led to improved therapeutic activities compared to monotherapies. In conclusion, FEN and PIO exerted a therapeutic synergistic effect on HFD/STZ-induced IR in the hippocampus.
ABSTRACT
Parkinson's disease (PD) and dementia with Lewy bodies have several commonalities including neurochemical, morphological and clinical features as well as widespread of cortical and limbic α-synuclein and amyloid-ß pathologies. Thus, we evaluated the action of hesperidin on α-synuclein and amyloid-ß-induced neurodegeneration in Drosophila melanogaster. The disease causing human Aß peptide or α- synuclein was expressed respectively, in Elav-GAL4 (pan-neuronally) and dopaminergic neurons (ddc-GAL4) using the UAS-GAL4 system. Flies were either grown on food media supplemented with or without hesperidin (HSD) (1, 5, or 10mM). Behavioral assays were carried to investigate the effect of treatment on fecundity, larval motility, climbing ability and lifespan. Aß>Elav or α-syn>DDC caused significant decrease in fecundity, larva contraction, motility, survival rate, and climbing activities in flies indicative of neurodegeneration. However, supplementation of flies' media with hesperidin (1mM, 5mM and 10mM) showed a dose-dependent increase in the number of line crosses in the egg laying, larva motility, climbing activity in comparison with flies grown on food media only. Conversely, supplementation of fly feed with HSD caused no significant change in lifespan. Findings from this experiment showed that hesperidin could be a potential neuroprotective agent in the amelioration of PD and AD pathogenesis.
Subject(s)
Dementia , Hesperidin , Parkinson Disease , Amyloid beta-Peptides , Animals , Drosophila melanogaster , Hesperidin/pharmacology , Parkinson Disease/drug therapy , alpha-SynucleinABSTRACT
Combination antiretroviral therapy (cART), which is a lifelong therapy for people living with human immunodeficiency virus, has been associated with nephrotoxicity and hepatotoxicity leading to its discontinuation. This study aimed at investigating the ameliorative potential of naringenin and quercetin on cART-induced hepatotoxicity and nephrotoxicity. Seventy male Wistar rats (225-260 g) were divided into seven groups as control, cART, naringenin, quercetin, dimethyl sulfoxide (DMSO), naringenin/cART (CN) and quercetin/cART (CQ). cART (24 mg/kg), naringenin (50 mg/kg) and quercetin (50 mg/kg) were dissolved in 1% v/v DMSO and administered orally for 56 days. Combination of cART and bioflavonoids had significant increase in superoxide dismutase (P < 0.05), catalase (P < 0.01), reduced glutathione (P < 0.001) and decreased malondialdehyde (P < 0.001) compared to cART only. Tumor necrosis factor Alpha (TNFα) level increased significantly in cART and CQ (P < 0.01) groups, while others showed no significant changes compared to control. TNFα also significantly decreased in CQ level compared to cART (P < 0.001). In addition, significant increase in creatinine level in cART only indicated progressive renal toxicity. Also, progressive pathological changes including congested blood vessels and hepatocellular necrosis were found in the liver, while the kidney had glomerular atrophy, and tubular distortion in cART-only group. Control, naringenin- and quercetin-treated groups showed normal renal and hepatic cytoarchitecture. These findings elucidate that progressive renal and hepatic toxicity is associated with the continuous use of cART; however, a combination of quercetin and naringenin with cART showed possible potential of ameliorating the damages posed by cART.
