Assessment of patients' knowledge and preferences for the use of orthodontic aligners.

OBJECTIVE: To evaluate the knowledge and preference of patients treated at a Dental School in Jaraguá do Sul, Brazil, about using aligners and the reasons for choosing this device as a treatment option. DESIGN: A cross-sectional study. PARTICIPANTS: A total of 82 participants aged 18-45 years recruited at a screening clinic. METHODS: A questionnaire was completed in person using a tablet with digital forms. RESULTS: Almost half of the participants (49%) knew about aligners; 40% were aged 18-24 years, and 77% were female. When observing the images of the types of orthodontic appliances, the aligners had an acceptance rate of 80%. Among the reasons that led to the preference for choosing aligners, 68% cited aesthetics and 42% comfort. CONCLUSION: Recently, clear aligners have become a popular choice for orthodontic treatment, particularly among adults. Despite their popularity and effectiveness, many patients still need more information about aligner treatment. Over half of the respondents did not know what orthodontic aligners were. Younger participants had more knowledge about aligners than older participants. Patients still need more knowledge about the types of appliances available for orthodontic treatment. When presented with images of the kinds of devices available, almost 80% of participants showed greater satisfaction with aligners.

Glibenclamide treatment prevents depressive-like behavior and memory impairment induced by chronic unpredictable stress in female mice.

Glibenclamide is a second-generation sulfonylurea used in the treatment of Type 2 Diabetes Mellitus. The primary target of glibenclamide is ATP-sensitive potassium channels inhibition; however, other possible targets include the control of inflammation and blood-brain barrier permeability, which makes this compound potentially interesting for the management of brain-related disorders. Here, we showed that systemic treatment with glibenclamide (5 mg/kg, p.o., for 21 days) could prevent the behavioral despair and the cognitive dysfunction induced by chronic unpredictable stress (CUS) in mice. In nonhypoglycemic doses, glibenclamide attenuated the stress-induced weight loss, decreased adrenal weight, and prevented the increase in glucocorticoid receptors in the prefrontal cortex, suggesting an impact in hypothalamic-pituitary-adrenal (HPA) axis function. Additionally, we did not observe changes in Iba-1, NLRP3 and caspase-1 levels in the prefrontal cortex or hippocampus after CUS or glibenclamide treatment. Thus, this study suggests that chronic treatment with glibenclamide prevents the emotional and cognitive effects of chronic stress in female mice. On the other hand, the control of neuroinflammation and NLRP3 inflammasome pathway is not the major mechanism mediating these effects. The behavioral effects might be mediated, in part, by the normalization of glucocorticoid receptors and HPA axis.

Glutamatergic system and mTOR-signaling pathway participate in the antidepressant-like effect of inosine in the tail suspension test.

Glutamatergic system and mTOR signaling pathway have been proposed to be important targets for pharmacological treatment of major depressive disorder. Previous studies have shown that inosine, an endogenous purine, is able to exert a remarkable antidepressant-like effect in mice. Nevertheless, the role of glutamatergic system and mTOR in this effect was not previously determined. This study was designed to investigate the possible modulation of NMDA receptors (NMDAR), AMPA receptors (AMPAR) and mTOR complex 1 (mTORC1) signaling pathway in the inosine anti-immobility effect in the tail suspension test (TST) in mice. Pre-treatment of mice with NMDA (0.1 pmol/mouse, NMDAR agonist, i.c.v.) and D-serine (30 µg/mouse, NMDAR co-agonist, i.c.v.) prevented inosine (10 mg/kg, i.p.) anti-immobility effect in the TST. In addition, a synergistic antidepressant-like effect was observed when a sub-effective dose of inosine (0.1 mg/kg, i.p.) was combined with sub-effective doses of NMDAR antagonists MK-801 (0.001 mg/kg, p.o.) or ketamine (0.1 mg/kg, i.p.). Conversely, the antidepressant-like effect elicited by inosine was not altered by pre-treatment with AMPAR antagonist, DNQX (2.5 µg/mouse, i.c.v.). The mTORC1 inhibitor rapamycin (0.2 nmol/mouse, i.c.v.) prevented the inosine anti-immobility effect in the TST. Noteworthy, inosine treatment did not change the immunocontent of the synaptic proteins PSD95, GluA1 and synapsin I. Mice locomotor activity assessed by open-field test, was not altered by treatments. Taken together, this study shows a pivotal role of NMDAR inhibition and mTORC1 activation for inosine antidepressant-like effect and extends the knowledge concerning the molecular mechanism and potential of inosine for antidepressant strategies.

Signaling pathways underlying the antidepressant-like effect of inosine in mice.

Inosine is a purine nucleoside formed by the breakdown of adenosine that elicits an antidepressant-like effect in mice through activation of adenosine A1 and A2A receptors. However, the signaling pathways underlying this effect are largely unknown. To address this issue, the present study investigated the influence of extracellular-regulated protein kinase (ERK)1/2, Ca2+/calmoduline-dependent protein kinase (CaMKII), protein kinase A (PKA), phosphoinositide 3-kinase (PI3K)/Akt, and glycogen synthase kinase 3beta (GSK-3ß) modulation in the antiimmobility effect of inosine in the tail suspension test (TST) in mice. In addition, we attempted to verify if inosine treatment was capable of altering the immunocontent and phosphorylation of the transcription factor cyclic adenosine monophosphatate (cAMP) response-binding element protein (CREB) in mouse prefrontal cortex and hippocampus. Intracerebroventricular administration of U0126 (5 µg/mouse, MEK1/2 inhibitor), KN-62 (1 µg/mouse, CaMKII inhibitor), H-89 (1 µg/mouse, PKA inhibitor), and wortmannin (0.1 µg/mouse, PI3K inhibitor) prevented the antiimmobility effect of inosine (10 mg/kg, intraperitoneal (i.p.)) in the TST. Also, administration of a sub-effective dose of inosine (0.1 mg/kg, i.p.) in combination with a sub-effective dose of AR-A014418 (0.001 µg/mouse, GSK-3ß inhibitor) induced a synergic antidepressant-like effect. None of the treatments altered locomotor activity of mice. Moreover, 24 h after a single administration of inosine (10 mg/kg, i.p.), CREB phosphorylation was increased in the hippocampus. Our findings provided new evidence that the antidepressant-like effect of inosine in the TST involves the activation of PKA, PI3K/Akt, ERK1/2, and CaMKII and the inhibition of GSK-3ß. These results contribute to the comprehension of the mechanisms underlying the purinergic system modulation and indicate the intracellular signaling pathways involved in the antidepressant-like effect of inosine in a preclinical test of depression.

Effects of cholecalciferol on behavior and production of reactive oxygen species in female mice subjected to corticosterone-induced model of depression.

Major depressive disorder (or depression) is one of the most frequent psychiatric illnesses in the population, with chronic stress being one of the main etiological factors. Studies have shown that cholecalciferol supplementation can lead to attenuation of the depressive state; however, the biochemical mechanisms involved in the relationship between cholecalciferol and depression are not very well known. The objective of this study was to investigate the effects of the administration of cholecalciferol on behavioral parameters (tail suspension test (TST), open field test (OFT), splash test (ST)) and redox state (dichlorofluorescein (DCF)) in adult female Swiss mice subjected to a model of depression induced by chronic corticosterone treatment. Corticosterone (20 mg/kg, p.o.) was administered once a day for 21 days. For investigation of the antidepressant-like effect, cholecalciferol (100 IU/kg) or fluoxetine (10 mg/kg, positive control) was administered p.o. within the last 7 days of corticosterone administration. After the treatments, the behavioral tests and biochemical analyses in the hippocampus and prefrontal cortex of the rodent samples were performed. Animals submitted to repeated corticosterone administration showed a depressive-like behavior, evidenced by a significant increase in the immobility time in the TST, which was significantly reduced by the administration of cholecalciferol or fluoxetine. In addition, the groups treated with cholecalciferol and fluoxetine showed a significant decrease in the production of reactive oxygen species (ROS) in the hippocampus. These results show that cholecalciferol, similar to fluoxetine, has a potential antidepressant-like effect, which may be related to the lower ROS production.

The involvement of GABAergic system in the antidepressant-like effect of agmatine.

Considering the involvement of GABAergic system in the action of the fast-acting antidepressant ketamine, and that agmatine may exert an antidepressant-like effect through mechanisms similar to ketamine, the purpose of the present study was to evaluate the involvement of GABAA and GABAB receptors in the antidepressant-like effect of agmatine. The administration of muscimol (0.1 mg/kg, i.p., GABAA receptor agonist) or diazepam (0.05 mg/kg, p.o., GABAA receptor positive allosteric modulator) at doses that caused no effect in the tail suspension test (TST) combined with a subeffective dose of agmatine (0.0001 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST. In another set of experiments, the administration of baclofen (1 mg/kg, i.p., GABAB receptor agonist) abolished the reduction of immobility time in the TST elicited by agmatine (0.1 mg/kg, p.o., active dose). In another cohort of animals, treatment with NMDA (0.1 pmol/site, i.c.v.) prevented the antidepressant-like effect of the combined administration of agmatine and muscimol as well as ketamine and muscimol in the TST. Results suggest that the effect of agmatine in the TST may involve an activation of GABAA receptors dependent on NMDA receptor inhibition, similar to ketamine, as well as modulation of GABAB receptors.

A single coadministration of subeffective doses of ascorbic acid and ketamine reverses the depressive-like behavior induced by chronic unpredictable stress in mice.

In this study, we investigated the ability of a single coadministration of subeffective doses of ascorbic acid and ketamine to reverse the depressive-like behavior induced by chronic unpredictable stress (CUS) in mice. Moreover, we examined the effect of combined administration of ascorbic acid and ketamine on hippocampal phosphorylation of p70S6K and immunocontents of GLUA1 and PSD-95 in mice submitted to the CUS procedure. CUS procedure was applied for 21 days. Animals received a single coadministration of subeffective doses of ascorbic acid (0.1 mg/kg) and ketamine (0.1 mg/kg) and were subjected to behavioral evaluation 24 h after the treatments. Immediately after the behavioral observations the hippocampi were dissected for Western blotting analyses. Our results revealed that a single administration of subeffective doses of ascorbic acid and ketamine completely reversed the depressive-like behavior induced by CUS, however, this effect was not accompanied by changes in the phosphorylation of p70S6K and immunocontent of GLUA1 or PSD95 in the hippocampus. These findings point to a synergistic antidepressant-like effect of ascorbic acid and ketamine, paving the way for additional studies on the combined use of these compounds for the management of major depressive disorder (MDD).

Agmatine produces antidepressant-like effects by activating AMPA receptors and mTOR signaling.

The activation of AMPA receptors and mTOR signaling has been reported as mechanisms underlying the antidepressant effects of fast-acting agents, specially the NMDA receptor antagonist ketamine. In the present study, oral administration of agmatine (0.1mg/kg), a neuromodulator that has been reported to modulate NMDA receptors, caused a significant reduction in the immobility time of mice submitted to the tail suspension test (TST), an effect prevented by the administration of DNQX (AMPA receptor antagonist, 2.5µg/site, i.c.v.), BDNF antibody (1µg/site, i.c.v.), K-252a (TrkB receptor antagonist, 1µg/site, i.c.v.), LY294002 (PI3K inhibitor, 10nmol/site, i.c.v.) or rapamycin (selective mTOR inhibitor, 0.2nmol/site, i.c.v.). Moreover, the administration of lithium chloride (non-selective GSK-3ß inhibitor, 10mg/kg, p.o.) or AR-A014418 (selective GSK-3ß inhibitor, 0.01µg/site, i.c.v.) in combination with a sub-effective dose of agmatine (0.0001mg/kg, p.o.) reduced the immobility time in the TST when compared with either drug alone. Furthermore, increased immunocontents of BDNF, PSD-95 and GluA1 were found in the prefrontal cortex of mice just 1h after agmatine administration. These results indicate that the antidepressant-like effect of agmatine in the TST may be dependent on the activation of AMPA and TrkB receptors, PI3K and mTOR signaling as well as inhibition of GSK-3ß, and increase in synaptic proteins. The results contribute to elucidate the complex signaling pathways involved in the antidepressant effect of agmatine and reinforce the pivotal role of these molecular targets for antidepressant responses.

Agmatine enhances antidepressant potency of MK-801 and conventional antidepressants in mice.

Agmatine, an endogenous guanidine amine, has been shown to produce antidepressant-like effects in animal studies. This study investigated the effects of the combined administration of agmatine with either conventional monoaminergic antidepressants or the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 in the tail suspension test (TST) in mice. The aim was to evaluate the extent of the antidepressant synergism by examining the ability of a fixed dose of agmatine to shift the antidepressant potency of fluoxetine, imipramine, bupropion and MK-801. A sub-effective dose of agmatine (0.0001 mg/kg, p.o.) significantly increased the potency by which fluoxetine, imipramine, bupropion and MK-801 decreased immobility time in the TST by 2-fold (fluoxetine), 10-fold (imipramine and bupropion) and 100-fold (MK-801). Combined with previous evidence indicating a role of monoaminergic systems in the effect of agmatine, the current data suggest that agmatine may modulate monoaminergic neurotransmission and augment the activity of conventional antidepressants. Moreover, this study found that agmatine substantially augmented the antidepressant-like effect of MK-801, reinforcing the notion that this compound modulates NMDA receptor activation. These preclinical data may stimulate future clinical studies testing the effects of augmentation therapy with agmatine for the management of depressive disorders.

Effects of Agmatine on Depressive-Like Behavior Induced by Intracerebroventricular Administration of 1-Methyl-4-phenylpyridinium (MPP(+)).

Considering that depression is a common non-motor comorbidity of Parkinson's disease and that agmatine is an endogenous neuromodulator that emerges as a potential agent to manage diverse central nervous system disorders, this study investigated the antidepressant-like effect of agmatine in mice intracerebroventricularly (i.c.v.) injected with the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)). Male C57BL6 mice were treated with agmatine (0.0001, 0.1 or 1 mg/kg) and 60 min later the animals received an i.c.v. injection of MPP(+) (1.8 µg/site). Twenty-four hours after MPP(+) administration, immobility time, anhedonic behavior, and locomotor activity were evaluated in the tail suspension test (TST), splash test, and open field test, respectively. Using Western blot analysis, we investigated the putative modulation of MPP(+) and agmatine on striatal and frontal cortex levels of tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF). MPP(+) increased the immobility time of mice in the TST, as well as induced an anhedonic-like behavior in the splash test, effects which were prevented by pre-treatment with agmatine at the three tested doses. Neither drug, alone or in combination, altered the locomotor activity of mice. I.c.v. administration of MPP(+) increased the striatal immunocontent of TH, an effect prevented by the three tested doses of agmatine. MPP(+) and agmatine did not alter the immunocontent of BDNF in striatum and frontal cortex. These results demonstrate for the first time the antidepressant-like effects of agmatine in an animal model of depressive-like behavior induced by the dopaminergic neurotoxin MPP(+).

TNF-α-induced depressive-like phenotype and p38(MAPK) activation are abolished by ascorbic acid treatment.

We investigated the effects of ascorbic acid on depressive-like behavior induced by tumor necrosis factor (TNF-α) in mice. Additionally, we examined the effects of combined administration of ascorbic acid and antidepressants, MK-801 and 7-nitroindazole in mice exposed or not to TNF-α and the capacity of TNF-α and ascorbic acid to modulate hippocampal and cerebrocortical phosphorylation of extracellular signal-regulated kinase (ERK), p38(MAPK) and c-Jun N-terminal kinase (JNK). In control animals, ascorbic acid reduced the immobility time in the tail suspension test (TST). Unilateral intracerebroventricular administration of TNF-α produced a depressive-like behavior in the TST, and the treatment with ascorbic acid prevented this effect. Sub-effective dose of ascorbic acid combined with sub-effective doses of fluoxetine, imipramine, bupropion, MK-801 or 7-nitroindazole produced a synergistic antidepressant-like effect in mice exposed or not to TNF-α. No treatment caused significant alterations in the locomotor activity of mice. Administration of TNF-α increased the phosphorylation of p38(MAPK) in hippocampus and cerebral cortex, and the treatment with ascorbic acid prevented this effect. Ascorbic acid increased phosphorylation of ERK1 in the hippocampus of saline- and TNF-α-treated animals, however it did not produce alterations in the cerebral cortex. No effects on phosphorylation of ERK2 or JNK were found. The observed effect of ascorbic acid seems to be associated, at least partially, with a reduced p38(MAPK) phosphorylation, activation of the monoaminergic systems as well as inhibition of N-methyl-D-aspartate (NMDA) receptors and nitric oxide (NO) synthesis.

Depressive-like behavior induced by tumor necrosis factor-α is abolished by agmatine administration.

Agmatine, an endogenous cationic amine, has been shown to exert antidepressant-like effects. This study investigated the ability of agmatine administered orally to abolish the depressive-like behavior induced by the administration of the pro-inflammatory cytokine, tumor necrosis factor (TNF-α) in mice. In control animals, agmatine (0.001, 0.01, 0.1, and 1 mg/kg) reduced the immobility time in the tail suspension test (TST). Acute administration of TNF-α (0.001 fg/mouse, i.c.v.) increased immobility time in the TST, indicative of a depressive-like behavior, and agmatine (0.0001, 0.1, and 1 mg/kg) prevented this effect. Additionally, we examined the effects of the combined administration of sub-effective doses of agmatine with antidepressants, the NMDA receptor antagonist MK-801 and the neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) in mice exposed to either TNF-α or saline. In control mice, administration of a sub-effective dose of agmatine (0.0001 mg/kg) combined with sub-effective doses of either fluoxetine (5 mg/kg, p.o.), imipramine (0.1 mg/kg, p.o.), bupropion (1 mg/kg, p.o.), MK-801 (0.001 mg/kg, p.o.) or 7-NI (25 mg/kg, i.p.) produced a synergistic antidepressant-like effect in the TST. All these administrations prevented the increased immobility time induced by TNF-α. The effect of agmatine in the TNF-α model of depression appears to be associated, at least partially, with an activation of the monoaminergic systems and inhibition of NMDA receptors and nitric oxide synthesis, although converging signal transduction pathways that may underlie the effect of agmatine should be further investigated. This set of results indicates that agmatine may constitute a new therapeutic alternative for the treatment of depression associated with inflammation.