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1.
Geroscience ; 46(1): 795-816, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38041783

ABSTRACT

In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% (p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% (p = 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± SE (n) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang-Allison test. Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging.


Subject(s)
Flavonols , Hydrogen Sulfide , Longevity , Phenylbutyrates , Female , Mice , Male , Animals , Meclizine/pharmacology , Hydrogen Sulfide/pharmacology , Dimethyl Fumarate/pharmacology , Mycophenolic Acid/pharmacology , Xanthophylls
2.
Article in English | MEDLINE | ID: mdl-37273836

ABSTRACT

Cannabidiol (CBD) is a non-intoxicating phytochemical from Cannabis sativa that is increasingly used to manage pain. The potential for CBD to ameliorate dimensional behavior symptoms occurring in multiple psychiatric disorders was suggested, including social interaction impairments. To test this hypothesis, adult male BTBRT+Itpr3tf/J (BTBR) mice, a model of idiopathic autism exhibiting social preference deficits and restrictive repetitive behaviors, were acutely treated with vehicle or 0.1, 1, or 10 mg/kg CBD. Social interaction preference was assessed 50 min after treatment, followed by social novelty preference at 60 min, marble burying at 75 min and social dominance at 120 min. CBD (10 mg/kg) enhanced BTBR social interaction but not social novelty preference, marble burying or dominance, with serum levels = 29 ± 11 ng/mg at 3 h post-injection. Next, acute 10 mg/kg CBD was compared to vehicle treatment in male serotonin transporter (SERT) knock-out mice, since SERT deficiency is an autism risk factor, and in their wildtype background strain controls C57BL/6J mice. CBD treatment generally enhanced social interaction preference and attenuated social novelty preference, yet neither marble burying nor dominance was affected. These findings show acute treatment with as little as 10 mg/kg purified CBD can enhance social interaction preference in male mice that are otherwise socially deficient.

3.
J Physiol ; 601(11): 2189-2216, 2023 06.
Article in English | MEDLINE | ID: mdl-35924591

ABSTRACT

Impaired mitochondrial function and disrupted proteostasis contribute to musculoskeletal dysfunction. However, few interventions simultaneously target these two drivers to prevent musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) activates a transcriptional programme promoting cytoprotection, metabolism, and proteostasis. We hypothesized daily treatment with a purported Nrf2 activator, PB125, in Hartley guinea pigs, a model of musculoskeletal decline, would attenuate the progression of skeletal muscle mitochondrial dysfunction and impaired proteostasis and preserve musculoskeletal function. We treated 2- and 5-month-old male and female Hartley guinea pigs for 3 and 10 months, respectively, with the phytochemical compound PB125. Longitudinal assessments of voluntary mobility were measured using Any-MazeTM open-field enclosure monitoring. Cumulative skeletal muscle protein synthesis rates were measured using deuterium oxide over the final 30 days of treatment. Mitochondrial oxygen consumption in soleus muscles was measured using high resolution respirometry. In both sexes, PB125 (1) increased electron transfer system capacity; (2) attenuated the disease/age-related decline in coupled and uncoupled mitochondrial respiration; and (3) attenuated declines in protein synthesis in the myofibrillar, mitochondrial and cytosolic subfractions of the soleus. These effects were not associated with statistically significant prolonged maintenance of voluntary mobility in guinea pigs. Collectively, treatment with PB125 contributed to maintenance of skeletal muscle mitochondrial respiration and proteostasis in a pre-clinical model of musculoskeletal decline. Further investigation is necessary to determine if these documented effects of PB125 are also accompanied by slowed progression of other aspects of musculoskeletal dysfunction. KEY POINTS: Aside from exercise, there are no effective interventions for musculoskeletal decline, which begins in the fifth decade of life and contributes to disability and cardiometabolic diseases. Targeting both mitochondrial dysfunction and impaired protein homeostasis (proteostasis), which contribute to the age and disease process, may mitigate the progressive decline in overall musculoskeletal function (e.g. gait, strength). A potential intervention to target disease drivers is to stimulate nuclear factor erythroid 2-related factor 2 (Nrf2) activation, which leads to the transcription of genes responsible for redox homeostasis, proteome maintenance and mitochondrial energetics. Here, we tested a purported phytochemical Nrf2 activator, PB125, to improve mitochondrial function and proteostasis in male and female Hartley guinea pigs, which are a model for musculoskeletal ageing. PB125 improved mitochondrial respiration and attenuated disease- and age-related declines in skeletal muscle protein synthesis, a component of proteostasis, in both male and female Hartley guinea pigs.


Subject(s)
NF-E2-Related Factor 2 , Proteostasis , Male , Female , Animals , Guinea Pigs , NF-E2-Related Factor 2/metabolism , Muscle, Skeletal/physiology , Mitochondria/metabolism , Aging/physiology
4.
J Forensic Sci ; 59(3): 683-9, 2014 May.
Article in English | MEDLINE | ID: mdl-24502274

ABSTRACT

Venlafaxine (VEN) and its metabolite O-desmethylvenlafaxine (ODV) inhibit reuptake of serotonin and norepinephrine. This study examines whether VEN is differentially distributed in postmortem brain and examines relationships between brain and femoral blood concentrations from donors prescribed VEN for treatment of depression. Using high-pressure liquid chromatography-ultraviolet detection, VEN and ODV concentrations were measured in temporal, occipital, and cerebellar cortex of six postmortem brains. The ODV/VEN ratio was calculated as a relative measure of drug metabolism within each region where higher ratios indicated a greater conversion of VEN to ODV. Compared to the other regions examined, the cerebellum showed decreased VEN (p = 0.056), ODV (p = 0.006), and ODV/VEN (p = 0.027) ratios. In parts per million, VEN was higher in temporal and occipital cortex, but not cerebellum, as compared to femoral blood concentration. These observations suggest that VEN and ODV are differentially distributed in the brain, and metabolism of VEN to ODV may vary across brain regions.


Subject(s)
Brain Chemistry , Cyclohexanols/pharmacokinetics , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Adult , Chromatography, Liquid , Cyclohexanols/analysis , Desvenlafaxine Succinate , Female , Humans , Male , Middle Aged , Postmortem Changes , Selective Serotonin Reuptake Inhibitors/analysis , Venlafaxine Hydrochloride
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