Anticonvulsant activity of Tetrahydrolinalool: behavioral, electrophysiological, and molecular docking approaches.

Tetrahydrolinalool (THL) is an acyclic monoterpene alcohol, produced during linalol metabolism and also a constituent of essential oils. As described in the literature, many monoterpenes present anticonvulsant properties, and thus we became interested in evaluating the anticonvulsant activity of Tetrahydrolinalool using in mice model as well as in silico approaches. Our results demonstrated that THL increased latency to seizure onset and also reduced the mortality, in picrotoxin induced seizure tests. The results may be related to GABAergic regulation, which was also suggested in seizure testing induced by 3-mercapto-propionic acid. In the strychnine-induced seizure testing, none of the groups pretreated with THL modulated the parameters indicative of anticonvulsant effect. The electrophysiological results revealed that THL treatment reduces seizures induced by pentylenetetrazole. The in silico molecular docking studies showed that the interaction between THL and a GABAA receptor model formed a stable complex, in comparison to the crystaligraphic structure of diazepam, a structurally related ligand. In conclusion, all the evidences showed that THL presents effective anticonvulsant activity related to the GABAergic pathway, being a candidate for treatment of epileptic syndromes.

Barriers in Access to Dental Services Hindering the Treatment of People with Disabilities: A Systematic Review.

BACKGROUND: People with disabilities tend to have greater oral health problems compared to those without disabilities. This may be due to barriers they come across in accessing dental services. OBJECTIVES: The objective of this systematic review was to provide a critical digest of the scientific literature concerning barriers and facilitators of access to oral health services for people with disabilities. METHODS: The electronic databases PubMed, Scopus, Web of Science, Latin American and Caribbean Health Sciences Literature (LILACS), and Brazilian Library of Dentistry (BBO) were searched using keywords relevant to the subject. The search was not restricted to specific languages or years of publication; all relevant studies were translated and reviewed. RESULTS: Sixteen studies including 14 articles, a doctoral thesis, and a monograph were selected, and their quality was analysed using the Downs and Black assessment tool. Barriers to dental services were divided into physical or nonphysical based on the dentist's perspective, as per the perception of parents/guardians or by the persons with disabilities. The barriers that emerged included the dentist's lack of preparation to assist people with disabilities, structural problems of access to dental offices, communication difficulties, and lack of awareness regarding the need for dental treatment for the disabled person. CONCLUSION: It is concluded that people with disabilities continue to run into complex physical, behavioural, or multidimensional barriers in accessing dental services. Improved training of dentists for the care of this population is hereby emphasized. The legal framework enabling access to dental care for people with disabilities must also be respected in each country.

Age-related alterations in pituitary and testicular functions in long-lived growth hormone receptor gene-disrupted mice.

The somatotropic axis, GH, and IGF-I interact with the hypothalamic-pituitary-gonadal axis in health and disease. GH-resistant GH receptor-disrupted knockout (GHRKO) male mice are fertile but exhibit delayed puberty and decreases in plasma FSH levels, testicular content of LH, and prolactin (PRL) receptors, whereas PRL levels are elevated. Because the lifespan of GHRKO mice is much greater than the lifespan of their normal siblings, it was of interest to compare age-related changes in the hypothalamic-pituitary-gonadal axis in GHRKO and normal animals. Plasma IGF-I, insulin, PRL, LH, FSH, androstenedione and testosterone levels, and acute responses to GnRH and LH were measured in young (2-4 and 5-6 months of age) and old (18-19 and 23-26 months of age) male GHRKO mice and their normal siblings. Plasma IGF-I was not detectable in GHRKO mice. Plasma PRL levels increased with age in normal mice but declined in GHRKO males, and did not differ in old GHRKO and normal animals. Plasma LH responses to acute GnRH stimulation were attenuated in GHRKO mice but increased with age only in normal mice. Plasma FSH levels were decreased in GHRKO mice regardless of age. Plasma testosterone responses to LH stimulation were attenuated in old mice regardless of genotype, whereas plasma androstenedione responses were reduced with age only in GHRKO mice. Testicular IGF-I mRNA levels were normal in young and increased in old GHRKO mice, whereas testicular concentrations and total IGF-I levels were decreased in these animals. These findings indicate that GH resistance due to targeted disruption of the GH receptor gene in mice leads to suppression of testicular IGF-I levels, and modifies the effects of aging on plasma PRL levels and responses of the pituitary and testes to GnRH and LH stimulation. Plasma testosterone levels declined during aging in normal but not in GHRKO mice, and the age-related increase in the LH responses to exogenous GnRH was absent in GHRKO mice, perhaps reflecting a delay of aging in these remarkably long-lived animals.

Effects of mild calorie restriction on reproduction, plasma parameters and hepatic gene expression in mice with altered GH/IGF-I axis.

The somatotropic axis, the hypothalamic-pituitary-gonadal axis and the nutritional status are deeply interrelated in mammals. Calorie restriction (CR) prolongs lifespan, but usually at some cost to reproduction. Interestingly, many of the physiological characteristics of animals with interruption in the somatotropic axis are shared by CR animals. The level of CR in most studies is 30-60%. We tested if a milder (20%) CR would promote health benefits without inhibiting reproduction in four types of mice with altered somatotropic axis: Ames dwarfs, GHR-KO, and PEPCK-bGH and MT-bGH transgenics. Fertility was not altered by CR in any of the examined groups. Mild CR did not affect final body weights or relative reproductive organ weights; did not alter plasma levels of glucose, insulin, IGF-I, testosterone, progesterone or estradiol; and did not influence hepatic expression of genes related to longevity. Altered activity of the GH/IGF-I axis in the different mice models studied had a major impact on the parameters analyzed. This preliminary study encourages speculation that mild regimens of CR can produce health and longevity benefits without the "costs" of impaired reproductive potential.

Mild calorie restriction does not affect testosterone levels and testicular gene expression in mutant mice.

The hypothalamic-pituitary-gonadal (HPG) axis and the somatotropic axis are influenced by nutritional factors. Calorie restriction (CR) extends lifespan but suppresses both the HPG and the somatotropic axes. Since most CR studies use a fairly severe (40%-60%) reduction of calorie intake, we hypothesized that a milder CR (20%) might not be deleterious to reproduction in male mice. To test this hypothesis, we evaluated the effects of 20% CR on testicular testosterone content and on testicular expression of genes that are relevant to testicular function and reproductive competence, including insulin-like growth factor-I, cytochrome P450 aromatase (Cyp19a1), androgen receptor, luteinizing hormone receptor, follicle-stimulating hormone receptor, cytochrome P450c17 and 3-beta-hydroxysteroid dehydrogenase/isomerase. To relate CR effects to the activity of the somatotropic axis, we have used growth hormone-resistant GHR knockout mice as well as transgenic mice overexpressing GH. Mild CR did not affect testosterone levels in testis homogenates and had little effect on expression of the examined genes in the reproductive organs. Altered activity of the GH/insulin-like growth factor-1 axis had a major impact on the parameters analyzed. The results also suggest that expression of several key genes involved in the control of testicular function is preserved under conditions of mild CR and encourage speculation that mild regimens of CR can produce longevity benefits without impairing reproduction.

Long-lived growth hormone receptor knockout mice show a delay in age-related changes of body composition and bone characteristics.

There is conflicting information on the physiological role of growth hormone (GH) in the control of aging. This study reports dual-energy x-ray absorptiometry (DXA) measurements of body composition and bone characteristics in young, adult, and aged long-lived GH receptor knockout (GHR-KO) and normal mice to determine the effects of GH resistance during aging. Compared to controls, GHR-KO mice showed an increased percentage of body fat. GHR-KO mice have reduced total-body bone mineral density (BMD), bone mineral content, and bone area, but these parameters increased with age. In addition, GHR-KO mice have decreased femur length, femur BMD, and lower lumbar BMD compared to controls in all age groups. These parameters also continued to increase with age. Our results indicate that GH resistance alters body composition, bone growth, and bone maintenance during aging in GHR-KO mice.

The growth hormone receptor gene-disrupted mouse fails to respond to an intermittent fasting diet.

The interaction of longevity-conferring genes with longevity-conferring diets is poorly understood. The growth hormone receptor gene-disrupted (GHR-KO) mouse is long lived; and this longevity is not responsive to 30% caloric restriction, in contrast to wild-type animals from the same strain. To determine whether this may have been limited to a particular level of dietary restriction, we subjected GHR-KO mice to a different dietary restriction regimen, an intermittent fasting diet. The intermittent fasting diet increased the survivorship and improved insulin sensitivity of normal males, but failed to affect either parameter in GHR-KO mice. From the results of two paradigms of dietary restriction, we postulate that GHR-KO mice would be resistant to any manner of dietary restriction; potentially due to their inability to further enhance insulin sensitivity. Insulin sensitivity may be a mechanism and/or a marker of the lifespan extending potential of an intervention.

Disruption of growth hormone receptor prevents calorie restriction from improving insulin action and longevity.

Most mutations that delay aging and prolong lifespan in the mouse are related to somatotropic and/or insulin signaling. Calorie restriction (CR) is the only intervention that reliably increases mouse longevity. There is considerable phenotypic overlap between long-lived mutant mice and normal mice on chronic CR. Therefore, we investigated the interactive effects of CR and targeted disruption or knock out of the growth hormone receptor (GHRKO) in mice on longevity and the insulin signaling cascade. Every other day feeding corresponds to a mild (i.e. 15%) CR which increased median lifespan in normal mice but not in GHRKO mice corroborating our previous findings on the effects of moderate (30%) CR on the longevity of these animals. To determine why insulin sensitivity improves in normal but not GHRKO mice in response to 30% CR, we conducted insulin stimulation experiments after one year of CR. In normal mice, CR increased the insulin stimulated activation of the insulin signaling cascade (IR/IRS/PI3K/AKT) in liver and muscle. Livers of GHRKO mice responded to insulin by increased activation of the early steps of insulin signaling, which was dissipated by altered PI3K subunit abundance which putatively inhibited AKT activation. In the muscle of GHRKO mice, there was elevated downstream activation of the insulin signaling cascade (IRS/PI3K/AKT) in the absence of elevated IR activation. Further, we found a major reduction of inhibitory Ser phosphorylation of IRS-1 seen exclusively in GHRKO muscle which may underpin their elevated insulin sensitivity. Chronic CR failed to further modify the alterations in insulin signaling in GHRKO mice as compared to normal mice, likely explaining or contributing to the absence of CR effects on insulin sensitivity and longevity in these long-lived mice.

Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction.

Reduced intake of nutrients [calorie restriction (CR)] extends longevity in organisms ranging from yeast to mammals. Mutations affecting somatotropic, insulin, or homologous signaling pathways can increase life span in worms, flies, and mice, and there is considerable evidence that reduced secretion of insulin-like growth factor I and insulin are among the mechanisms that mediate the effects of CR on aging and longevity in mammals. In the present study, mice with targeted disruption of the growth hormone (GH) receptor [GH receptor/GH-binding protein knockout (GHRKO) mice] and their normal siblings were fed ad libitum (AL) or subjected to 30% CR starting at 2 months of age. In normal females and males, CR produced the expected increases in overall, average, median, and maximal life span. Longevity of normal mice subjected to CR resembles that of GHRKO animals fed AL. In sharp contrast to its effects in normal mice, CR failed to increase overall, median, or average life span in GHRKO mice and increased maximal life span only in females. In a separate group of animals, CR for 1 year improved insulin sensitivity in normal mice but failed to further enhance the remarkable insulin sensitivity in GHRKO mutants. These data imply that somatotropic signaling is critically important not only in the control of aging and longevity under conditions of unlimited food supply but also in mediating the effects of CR on life span. The present findings also support the notion that enhanced sensitivity to insulin plays a prominent role in the actions of CR and GH resistance on longevity.