Sex differences in the anticompulsive-like effect of memantine: Involvement of nitric oxide pathway but not AMPA receptors.

Memantine, an N-Methyl-D-Aspartate (NMDA) antagonist, has been examined as a potential treatment for Obsessive-Compulsive Disorder (OCD). Yet, there is limited knowledge regarding how it works to reduce compulsive behaviour and whether it has different effects on individuals based on their sex. Herein, we investigated if there are sex differences in the anticompulsive-like effect of memantine in adult Swiss mice. Additionally, we explored whether the nitric oxide (NO) pathway and α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptors play a role in memantine's effects. To start, we assessed the impact of a single intraperitoneal dose of memantine (at 3, 5, and 10 mg/kg) on behaviours exhibited in the open field test (OFT) and the marble-burying test (MBT), the latter being a predictive test for anticompulsive effects. All doses of memantine reduced marble-burying behaviour in both male and female mice without affecting their locomotor activity in the OFT. This anticompulsive-like effect was also confirmed in another predictive test, the nest-building test, with the highest memantine dose (10 mg/kg) reducing nest-building behaviour without significant differences between male and female mice. We observed that pre-treatment with L-arginine, a NO precursor, mitigated the anticompulsive-like effect of memantine in male mice but had no effect in female mice in the MBT. Finally, NBQX, an AMPA receptor antagonist, did not block the anticompulsive-like effect of memantine. In summary, our study suggests that the anticompulsive-like effect of memantine does not appear to be sex-specific, does not depend on AMPA receptors, and involves the NO pathway primarily in male mice.

S-ketamine exerts sex- and dose-dependent anti-compulsive-like effect as monotherapy or in augmentation to fluoxetine.

Since a significant body of studies supports the involvement of glutamatergic neurotransmission in the neurobiology of obsessive-compulsive disorder (OCD). Ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist with rapid and sustained antidepressant effect, raises as a potential new anti-OCD drug. Evidence from pre-clinical studies indicates that female mice are more sensitive than male mice to ketamine antidepressant effects. Our group previously showed that S-ketamine, one ketamine enantiomer, induces an acute anti-compulsive effect in male mice. Herein, we investigated this S-ketamine effect in female adult Swiss mice as monotherapy or as an adjuvant to fluoxetine, a selective serotonin reuptake inhibitor (SSRI), compared to male mice. For this purpose, we assessed the S-ketamine anti-compulsive-like effect in the marble-burying (MBT) and nest-building (NBT) tests in adult female Swiss mice. S-ketamine reduced the compulsive-like behaviour of female mice in both animal tests in a dose larger (30 mg/kg) than the effective dose in male Swiss mice (10 mg/kg, Tosta et al., 2019). The association of sub-effective doses of S-ketamine and fluoxetine effectively reduced the marble-burying behaviour of both male and female Swiss mice, although male mice present a better response. The variation of female sex hormones (oestrogen and progesterone), inferred by oestrous cycle and ovariectomy, did not influence S-ketamine's response. In conclusion, we found that female mice are less sensitive to S-ketamine's anti-compulsive-like effect than male mice as monotherapy or adjuvant treatment, but oscillations in female sex hormones concentrations do not seem to explain this difference.

Intermittent exposure to chlorpyrifos results in cardiac hypertrophy and oxidative stress in rats.

Forbidden in some countries due to its proven toxicity to humans, chlorpyrifos (CPF) still stands as an organophosphate pesticide (OP) highly used worldwide. Cardiotoxicity assessment is an unmet need in pesticide regulation and should be deeply studied through different approaches to better inform and generate an appropriate regulatory response to OP use. In the present study, we used our 4-week intermittent OP exposure model in rats to address the CPF effects on cardiac morphology allied with cardiovascular functional and biomolecular evaluation. Rats were intermittently treated with CPF at doses of 7 mg/kg and 10 mg/kg or saline (i.p.) and assessed for cardiac morphology (cardiomyocyte diameter and collagen content), cardiopulmonary Bezold-Jarisch reflex (BJR) function, cardiac autonomic tone, left ventricle (LV) contractility, cardiac expression of NADPH oxidase (Nox2), catalase (CAT), superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2) and cardiac levels of advanced oxidation protein products (AOPP) and thiobarbituric acid reactive substances (TBARS). Plasma butyrylcholinesterase (BuChE) and brainstem acetylcholinesterase (AChE) were also measured. Intermittent exposure to CPF induced cardiac hypertrophy, increasing cardiomyocyte diameter and collagen content. An impairment of cardioinhibitory BJR responses and an increase in cardiac vagal tone were also observed in CPF-treated animals without changes in LV contractility. CPF exposure increased cardiac Nox-2, CAT, SOD1, and TBARS levels and inhibited plasma BuChE and brainstem AChE activities. Our data showed that intermittent exposure to CPF induces cardiac hypertrophy together with cardiovascular reflex impairment, imbalance of autonomic tone and oxidative stress, which may bring significant cardiovascular risk to individuals exposed to OP compounds seasonally.

A single dose of the organophosphate triazophos induces fear extinction deficits accompanied by hippocampal acetylcholinesterase inhibition.

Acute organophosphate (OP) poisoning, particularly by suicide attempts, generates high mortality and morbidity. Few studies have systematically addressed the consequences of acute OP intoxication on cognition and memory of survivors. Preclinical evidence suggests that acute OP-induced effects are associated with inhibiting the brain acetylcholinesterase (AChE) enzyme. The OP triazophos has been used worldwide, although its effects on mnemonic processing are yet to be investigated. Based on the above, the present study investigated whether acute triazophos intoxication interferes with the expression and extinction of contextual fear memory in rats. Hippocampal and amygdalar AChE activity and plasma butyrylcholinesterase (BChE) were measured at the end of the experiment to confirm the cholinergic overstimulation. Independent cohorts of animals intoxicated with triazophos were evaluated in the novel object recognition (NOR) test, a less aversive associative memory task. At the dose of 15 mg/kg, triazophos administered immediately after contextual fear conditioning impaired the extinction but not the expression of freezing behavior. Triazophos poisoning induced no changes in the discrimination index in the NOR test. Triazophos inhibited the AChE activity in a time- and brain region-dependent manner. Our findings suggest that fear memory extinction deficits induced by acute triazophos intoxication are accompanied by hippocampal AChE inhibition. The deficient fear extinction associated with acute OP poisoning may represent a behavioral and biochemical phenotype helpful to study mechanisms of neurotoxicity and treatment approach of OP suicide survivors.

Short or moderate-time exposure to the inhalational anesthetics isoflurane and sevoflurane does not alter the marble-burying behavior in mice.

Several studies suggest the involvement of glutamatergic neurotransmission in obsessive-compulsive disorder (OCD). Some NMDA glutamatergic receptor antagonists, such as the general anesthetic ketamine, have shown anti-OCD effects in preclinical and clinical studies. Therefore, we investigated whether the inhalational anesthetics isoflurane and sevoflurane, which are general anesthetics acting as NMDA receptor antagonists, would induce the same effects. To test our hypothesis, adult male Swiss mice were exposed to different concentrations of isoflurane (0.5, 1.5 or 3 %) or sevoflurane (0.8, 2.5 or 4 %) for 20 min (short-time exposure) or 1 h (moderate-time exposure) and submitted to the open field test (OFT) and the marble-burying test (MBT) in the same day (acute effect) or 7 days (long-lasting effect) after anesthetics administration. We found that single short or moderate-time exposure to isoflurane or sevoflurane, at sub-anesthetic or anesthetic concentrations, did not affect marble-burying behavior acutely or even 7 days after their administration. The same treatment schedules with isoflurane or sevoflurane did not impair total distance travelled in the OFT. A single moderate-time exposure to isoflurane (3 %) reduced, acutely, the central exploration of the open field, suggesting an anxiogenic-like effect of isoflurane in mice. Our results suggest that isoflurane and sevoflurane may not be promising anti-compulsive drugs.

Ketamine effects on anxiety and fear-related behaviors: Current literature evidence and new findings.

Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, presents a rapid and sustained antidepressant effect in clinical and preclinical studies. Regarding ketamine effects on anxiety, there is a widespread discordance among pre-clinical studies. To address this issue, the present study reviewed the literature (electronic database MEDLINE) to summarize the profile of ketamine effects in animal tests of anxiety/fear. We found that ketamine anxiety/fear-related effects may depend on the anxiety paradigm, schedule of ketamine administration and tested species. Moreover, there was no report of ketamine effects in animal tests of fear related to panic disorder (PD). Based on that finding, we evaluated if treatment with ketamine and another NMDA antagonist, MK-801, would induce acute and sustained (24 hours later) anxiolytic and/or panicolytic-like effects in animals exposed to the elevated T-maze (ETM). The ETM evaluates, in the same animal, conflict-evoked and fear behaviors, which are related, respectively, to generalized anxiety disorder and PD. Male Wistar rats were systemically treated with racemic ketamine (10, 30 and 80 mg/kg) or MK-801 (0.05 and 0.1 mg/kg) and tested in the ETM in the same day or 24 hours after their administration. Ketamine did not affect the behavioral tasks performed in the ETM acutely or 24 h later. MK-801 impaired inhibitory avoidance in the ETM only at 45 min post-injection, suggesting a rapid but not sustained anxiolytic-like effect. Altogether our results suggest that ketamine might have mixed effects in anxiety tests while it does not affect panic-related behaviors.

The antidotes atropine and pralidoxime distinctively recover cardiorespiratory components impaired by acute poisoning with chlorpyrifos in rats.

In a previous work we showed that the organophosphate pesticide (OP) chlorpyrifos (CPF) reduces the protective chemoreflex and baroreflex responses in rats. However, whether the antidotes atropine (ATR) and pralidoxime (2-PAM) are capable of restoring these reflex functions remains unexplored. Rats were poisoned with CPF (30 mg.kg-1, i.p.) and one hour after the intoxication, ATR (10 mg.kg-1, i.p.) and 2-PAM (40 mg.kg-1, i.p.) were administrated separately or in combination. Cardiorespiratory parameters were recorded in awake rats 24 h after CPF. Systolic blood pressure (SBP) and heart rate (HR) variability and spontaneous baroreflex sensitivity (sBRS) were derived from undisturbed recordings (30 min), while chemoreflex was assessed through potassium cyanide (KCN) i.v. injections (10, 20, 40, 80 µg/rat). CPF poisoning increased SBP variability and low frequency/high frequency (LF/HF) ratio of the HR variability spectrum, indicating autonomic imbalance with increased cardiac sympathetic tone. sBRS was not changed. Treatment with 2-PAM restored SBP variability, whilst both antidotes increased LF/HF ratio. CPF poisoning reduced the hypertensive, bradycardic and tachypneic chemoreflex responses. Chemoreflex-induced hypertensive response was restored by 2-PAM treatment, while ATR recovered the bradycardic response. Both antidotes restored the chemoreflex tachypneic response. Our data show distinct effects of ATR and 2-PAM on cardiorespiratory parameters affected by OP poisoning. While 2-PAM rescued the chemoreflex hypertensive response, ATR reversed chemoreflex bradycardic dysfunction. Although 2-PAM clinical use is questioned in some countries, our data indicate that summation of effects of both antidotes appears beneficial on the cardiorespiratory system and peripheral chemoreflex function.

Intermittent Exposure to Chlorpyrifos Differentially Impacts Neuroreflex Control of Cardiorespiratory Function in Rats.

Previous studies showed that chlorpyrifos (CPF) acute exposure impaired cardiorespiratory reflexes. Evidence also indicates that continuous exposure to organophosphorus compounds impairs cardiovascular function. However, the effect of intermittent exposure to CPF, as may be experienced in the real world, on tonic and reflex cardiorespiratory function remains unexplored. Wistar rats were injected with saline or CPF for 4 weeks (3 times/week) or 12 weeks (once/week) at the doses of 7 mg/kg and 10 mg/kg. After exposure, blood pressure (BP), heart rate (HR), respiratory rate (fR), tidal volume (VT), and minute volume (VE) were recorded. Systolic BP and pulse interval (PI) variability, HR spectrum, spontaneous baroreflex and chemoreflex function were also evaluated. Plasma butyrylcholinesterase and brainstem acetylcholinesterase activities were quantified. Enzymatic activity of the CPF animals was reduced after both treatment periods. Baseline BP, HR, and fR, as well as systolic BP and PI variability indices, did not change, after CPF treatment. VT and VE were elevated in CPF animals. CPF exposure increased the very low-frequency component of the HR spectrum. Baroreflex gain was reduced after CPF 4-week exposure. Chemoreflex bradycardia was reduced in the CPF-treated rats. These data show that intermittent exposure to CPF impairs cardiorespiratory function in rats. These results may have important clinical implications for workers seasonally exposed to these compounds.

Atropine counteracts the depressive-like behaviour elicited by acute exposure to commercial chlorpyrifos in rats.

Acute organophosphate (OP) poisoning induces well-known signs of toxicosis related to acetylcholinesterase (AChE) inhibition. However, the relationship between acute OP poisoning and the onset of psychiatric disorders remains unclear. Thus, we investigated behavioural and biochemical consequences of acute exposure to the OP chlorpyrifos in male rats and also the effectiveness of the antidotes atropine and pralidoxime on reversing these changes. A sub-lethal dose of commercial chlorpyrifos (20 mg/kg, i.p.) elicited signs of acute toxicosis during the first hours after its injection in rats. Twenty-four hours after treatment, this single dose of chlorpyrifos induced a depressive-like behaviour in the rat forced swimming test without impairing locomotor activity. At this time (24 h), chlorpyrifos decreased plasma butyrylcholinesterase (BChE) activity and hippocampal, striatal and prefrontal cortical AChE activity in rats. The behavioural and biochemical consequences of acute chlorpyrifos poisoning do not seem to be long lasting, since 30 days later they were absent. We evaluated whether these behavioural and biochemical consequences of acute chlorpyrifos treatment would be reversed by the antidotes atropine (10 mg/kg i.p.) and/or pralidoxime (40 mg/kg; i.p.) given 1 h after poisoning. Pralidoxime partially reactivated the AChE activity in the prefrontal cortex, but not in the hippocampus and striatum. Atropine attenuated the depressive-like behaviour induced by chlorpyrifos in rats. Our results suggest that acute chlorpyrifos poisoning induces a transient depressive-like behaviour possible related to hippocampal AChE inhibition. They suggest that treatment with atropine and pralidoxime seems to be insufficient to counteract all the effects of OP acute poisoning, at least in rats.

S-ketamine reduces marble burying behaviour: Involvement of ventromedial orbitofrontal cortex and AMPA receptors.

Previous clinical and pre-clinical studies suggest the involvement of ventromedial orbitofrontal cortex (vmOFC) and glutamatergic neurotransmission in obsessive-compulsive disorder (OCD). Ketamine, an NMDA glutamatergic receptor antagonist, has shown a rapid and long-lasting antidepressant effect, but its anti-compulsive effect has been scarcely investigated. The antidepressant effect of ketamine involves NMDA receptor blockade, AMPA receptor activation, increased serotonin (5-HT) release and attenuation of nitric oxide (NO) synthesis. It is not known if these mechanisms are involved in ketamine-induced anti-compulsive effect. Therefore, we firstly investigated the effect of S-ketamine in the marble-burying test (MBT), a model for screening of drugs with potential to treat OCD. Then, we evaluated whether ketamine effects in the MBT would involve the vmOFC, be dependent on AMPA receptors, facilitation of serotonergic neurotransmission and inhibition of nitrergic pathway. Our results showed that single systemic (10 mg/kg) and intra-vmOFC (10 nmol/side) administration of S-ketamine reduces marble burying behaviour (MBB) without affecting spontaneous locomotors activity. Pre-treatment with NBQX (3 mg/kg; AMPA receptor antagonist) blocked the reduction of MBB induced by S-ketamine. However, pre-treatment with p-CPA (150 mg/kg/day; a 5-HT synthesis inhibitor), WAY100635 (3 mg/kg; a 5-HT1A receptor antagonist), or L-arginine (500 mg/kg; a nitric oxide precursor) did not counteract S-ketamine effect in the MBT. In contrast, associating sub-effective doses of L-NAME (10 mg/kg; NOS inhibitor) and S-ketamine (3 mg/kg) decreased MBB. In conclusion, the reduction of MBB by S-ketamine strengthens its possible anti-compulsive effect. The vmOFC is involved in this S-ketamine effect, which is dependent on the activation of AMPA receptors.

The antidepressant-like effect of galanin in the dorsal raphe nucleus of rats involves GAL2 receptors.

Galanin is a neuropeptide distributed in human and rat brain regions that are involved with emotional regulation, such as the dorsal raphe nucleus (DRN). Galanin effects in the DRN are mediated by GAL1 and GAL2 receptors. Intracerebral infusion of a GAL2 (AR-M1896) or a GAL1 (M617) agonist induced either antidepressant or depressive-like effect, respectively, in rats exposed to the forced swimming test (FST). However, it is not clear if GAL1 and/or GAL2 receptors present in the DRN would be involved in such effects. Therefore, we investigated the effects induced by intra-DRN infusion of galanin (0.3 nmol), AR-M1896 (1 nmol, GAL2 agonist), or M617 (GAL1 agonist) in rats exposed to the FST. Galanin and AR-M1896 intra-DRN administration induced antidepressant-like effect in the FST. However, M617 did not induce any change in the FST. Neither M617 nor AR-M1896 changed the locomotor activity of rats in the open field test. Intra-DRN pre-treatment with M871 (1 nmol), a selective GAL2 antagonist, counteracted the antidepressant-like effect induced by galanin. These results suggest that galanin signaling through GAL2 receptors in the DRN produces triggers antidepressant-like effect.

Neuroreflex control of cardiovascular function is impaired after acute poisoning with chlorpyrifos, an organophosphorus insecticide: Possible short and long term clinical implications.

Although it is well-established that severe poisoning by organophosphorus (OP) compounds strongly affects the cardiorespiratory system, the effects of sub-lethal exposure to these compounds on the neural control of cardiovascular function are poorly explored. The aim of this study was to evaluate the effects of acute sub-lethal exposure to chlorpyrifos (CPF), a commonly used OP insecticide, on three basic reflex mechanisms involved in blood pressure regulation, the peripheral chemoreflex, the baroreflex and the Bezold-Jarisch reflex. Adult male Wistar rats were injected intraperitoneally with a single dose of CPF (30 mg/kg) or saline (0.9%). 24 h after injections, cardiovascular reflexes were tested in awake rats. Potassium cyanide (KCN) and phenylbiguanide (PBG) were injected intravenously to activate the chemoreflex and the Bezold-Jarisch reflex, respectively. The baroreflex was activated by phenylephrine and sodium nitroprusside infusions. Blood samples were taken for measurements of butyrylcholinesterase (BChE) activity while acetylcholinesterase (AChE) activity was measured in brainstem samples. Animals treated with CPF presented signs of intoxication such as ataxia, tremor, lacrimation, salivation, tetany, urination and defecation. The hypertensive and the bradycardic responses of the chemoreflex as well as the hypotensive and bradycardic responses of the Bezold-Jarisch reflex were attenuated in CPF treated animals (P < 0.05). Concerning the baroreflex responses, CPF treatment reduced the bradycardia plateau, the range and the gain of the reflex (P < 0.05). Plasma BChE and brainstem AChE were both reduced significantly after CPF treatment (P < 0.05). Our results showed that acute sub-lethal exposure to CPF impairs the cardiovascular responses of homeostatic and defensive cardiovascular reflexes. These effects are associated with a marked inhibition of plasma BChE and brainstem AChE.

Methamidophos, an Organophosphorus Insecticide, Induces Pro-aggressive Behaviour in Mice.

Although evidence indicates that exposure to organophosphorus (OP) pesticides induces neurobehavioral disorders, little is known about the effects of OP on aggressive behaviour. Our study investigated the effects of repeated exposure to an OP pesticide, methamidophos, on the isolation-induced aggressive behaviour in mice. Forty seven male mice were individually housed for a month. Socially isolated animals were then confronted with a standard non-isolated opponent for 15 min (pre-treatment trial), and the latency and frequency of aggressive and general exploratory behaviours were recorded. Based on the presence of attack behaviour in the pre-treatment trial, mice were classified as isolation-induced aggressive and non-aggressive. All mice were then treated for 7 days with methamidophos (3.5 mg/kg/day, n = 22, intraperitoneal (i.p.)) or saline (1 mL/kg/day, control group, n = 25, i.p.), and a second trial was performed. Repeated exposure to methamidophos induced attack behaviour in non-aggressive mice. The treatment with methamidophos also decreased plasma butyrylcholinesterase and brain acetylcholinesterase activity. These results suggest that methamidophos has a pro-aggressive effect on socially isolated mice.

On the verge of a respiratory-type panic attack: Selective activations of rostrolateral and caudoventrolateral periaqueductal gray matter following short-lasting escape to a low dose of potassium cyanide.

Intravenous injections of potassium cyanide (KCN) both elicit escape by its own and facilitate escape to electrical stimulation of the periaqueductal gray matter (PAG). Moreover, whereas the KCN-evoked escape is potentiated by CO2, it is suppressed by both lesions of PAG and clinically effective treatments with panicolytics. These and other data suggest that the PAG harbors a hypoxia-sensitive alarm system the activation of which could both precipitate panic and render the subject hypersensitive to CO2. Although prior c-Fos immunohistochemistry studies reported widespread activations of PAG following KCN injections, the employment of repeated injections of high doses of KCN (>60µg) in anesthetized rats compromised both the localization of KCN-responsive areas and their correlation with escape behavior. Accordingly, here we compared the brainstem activations of saline-injected controls (air/saline) with those produced by a single intravenous injection of 40-µg KCN (air/KCN), a 2-min exposure to 13% CO2 (CO2/saline), or a combined stimulus (CO2/KCN). Behavioral effects of KCN microinjections into the PAG were assessed as well. Data showed that whereas the KCN microinjections were ineffective, KCN intravenous injections elicited escape in all tested rats. Moreover, whereas the CO2 alone was ineffective, it potentiated the KCN-evoked escape. Compared to controls, the nucleus tractus solitarius was significantly activated in both CO2/saline and CO2/KCN groups. Additionally, whereas the laterodorsal tegmental nucleus was activated by all treatments, the rostrolateral and caudoventrolateral PAG were activated by air/KCN only. Data suggest that the latter structures are key components of a hypoxia-sensitive suffocation alarm which activation may trigger a panic attack.

Infusion of galanin into the mid-caudal portion of the dorsal raphe nucleus has an anxiolytic effect on rats in the elevated T-maze.

Galanin and 5-HT coexist in dorsal raphe nucleus (DRN) neurons. Microinjection of galanin into the DRN reduces the firing rate of serotonin neurons. Serotonergic neurons projecting from the DRN to the amygdala facilitate learned anxiety producing an anxiogenic effect, while those projecting from the periaqueductal grey affect innate anxiety producing a panicolytic effect. We tested the hypothesis that injection of galanin into rat DRN would induce anxiolytic/panicogenic effects in the elevated T-maze (ETM), a model that allows for the evaluation of both of these effects. Galanin infusion into the mid-caudal DRN, but not into the rostral DRN, impaired inhibitory avoidance, suggesting an anxiolytic effect. The effective dose of galanin (0.3 nmol) did not modify locomotor activity in the open field. Contrary to expectations, microinjection of galanin into the DRN did not facilitate the latency of one-way escape in the ETM. Pretreatment with a galanin antagonist, M40, attenuated galanin-induced impairment of inhibitory avoidance. The results show that microinjection of a low dose of galanin only into the mid-caudal DRN has an anxiolytic effect. This effect seems to be mediated, at least in part, by galanin receptors. Further investigation is necessary to identify the receptor subtypes and the DRN subregion involved in the anxiolytic effect of galanin.

The effect of isotretinoin on triglycerides and liver aminotransferases.

BACKGROUND: Isotretinoin has been used to treat the most severe cases of acne; however, it may provoke adverse events in mucocutaneous and hepatic tissues, lead to alterations in lipid levels and cause teratogenicity. OBJECTIVE: The objective of this study was to evaluate the profile of changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride levels in patients who had been treated with oral isotretinoin dispensed by the São Mateus/ES pharmacy for special drugs. METHODS: A retrospective, observational, longitudinal study was conducted by carrying out a secondary analysis of each patient's data. RESULTS: Of the 130 patients who received isotretinoin between January and December 2009, only 70 were actually treated for 3 months or more and handed in the results of their laboratory tests. Of these 70 patients, 39 (55.7%) were female. The mean age of the women (23.9 years) was higher than the mean age of the men (20.1 years). There was a statistically significant increase in the levels of triglycerides (87.01 ± 48.25 versus 105.32 ± 48.76 mg/dL), AST (20.44 ± 6.26 versus 24.38 ± 11.92 U/L) and ALT (18.24 ± 8.31 versus 23.34 ± 20.03 U/L) performed prior to and 3 months or more after oral isotretinoin treatment. After treatment with oral isotretinoin, triglyceride levels had increased beyond the normal range in 11% of the patients, while 8.6% had elevated AST levels and 7.3% had increased ALT levels. CONCLUSION: The results in this population show that the use of oral isotretinoin for the treatment of acne may result in altered triglyceride, AST and ALT levels. These findings are in accordance with data published previously in the scientific literature, confirming the need to monitor these patients.

The effect of isotretinoin on triglycerides and liver aminotransferases / Influência da isotretinoína nas transaminases hepáticas e triglicerídeos

BACKGROUND: Isotretinoin has been used to treat the most severe cases of acne; however, it may provoke adverse events in mucocutaneous and hepatic tissues, lead to alterations in lipid levels and cause teratogenicity. OBJECTIVE: The objective of this study was to evaluate the profile of changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride levels in patients who had been treated with oral isotretinoin dispensed by the São Mateus/ES pharmacy for special drugs. METHODS: A retrospective, observational, longitudinal study was conducted by carrying out a secondary analysis of each patient's data. RESULTS: Of the 130 patients who received isotretinoin between January and December 2009, only 70 were actually treated for 3 months or more and handed in the results of their laboratory tests. Of these 70 patients, 39 (55.7%) were female. The mean age of the women (23.9 years) was higher than the mean age of the men (20.1 years). There was a statistically significant increase in the levels of triglycerides (87.01 ± 48.25 versus 105.32 ± 48.76 mg/dL), AST (20.44 ± 6.26 versus 24.38 ± 11.92 U/L) and ALT (18.24 ± 8.31 versus 23.34 ± 20.03 U/L) performed prior to and 3 months or more after oral isotretinoin treatment. After treatment with oral isotretinoin, triglyceride levels had increased beyond the normal range in 11% of the patients, while 8.6% had elevated AST levels and 7.3% had increased ALT levels. CONCLUSION: The results in this population show that the use of oral isotretinoin for the treatment of acne may result in altered triglyceride, AST and ALT levels. These findings are in accordance with data published previously in the scientific literature, confirming the need to monitor these patients.

FUNDAMENTOS: A isotretinoína tem sido usada no tratamento dos casos mais graves de acne, embora possa induzir reações adversas nos tecidos mucocutâneos e hepáticos, alterações nos níveis lipídicos e teratogenicidade. OBJETIVOS: Este estudo avaliou o perfil de alterações nas concentrações de Alanina Aminotransferrase, Aspartato Aminotransferrase e triglicerídeos em pacientes que fizeram uso de isotretinoína oral fornecida pelo serviço Farmácia de Medicamentos Excepcionais de São Mateus/ES. MÉTODOS: Foi realizado estudo observacional longitudinal exploratório retrospectivo, utilizando coleta de dados secundários de cada paciente. RESULTADOS: Dos 130 pacientes que receberam isotretinoína no período de janeiro a dezembro de 2009, somente 70 realizaram o tratamento por 3 meses ou mais e apresentaram os resultados dos exames. Desses 70 pacientes, 39 (55,7%) eram do sexo feminino. A média de idade das mulheres (23,9 anos) foi maior do que a média de idade dos homens (20,1 anos). Houve aumento estatisticamente significante nas dosagens de triglicerídeos (87,01±48,25 versus 105,32 ± 48,76), Aspartato Aminotransferrase (20,44 ± 6,26 versus 24,38 ± 11,92) e Alanina Aminotransferrase (18,24 ± 8,31 versus 23,34 ± 20,03), realizadas antes e após 3 meses ou mais de tratamento com isotretinoína oral. Após o tratamento com isotretinoína oral, 11% dos pacientes apresentaram elevação de triglicerídeos acima dos valores normais, 8,6% apresentaram elevação da Aspartato Aminotransferrase e 7,3% tiveram elevação da Alanina Aminotransferrase. CONCLUSÃO: Os resultados mostraram que o uso de isotretinoína oral para o tratamento da acne, na população estudada, pode levar a alterações nas dosagens de triglicerídeos, Alanina Aminotransferrase e Aspartato Aminotransferrase, como mostrado pela literatura científica, confirmando a necessidade de monitoramento.

Activation of neurons containing the enzyme nitric oxide synthase following exposure to an elevated plus maze.

The elevated plus-maze (EPM) is one of the most used animal models of anxiety. Exposure to the EPM activates brain regions related to anxiety/fear. Systemic or intra-dorsolateral periaqueductal gray (dlPAG) inhibition of nitric oxide synthase (NOS) induces anxiolytic effect in animals submitted to an EPM. Additionally, exposure to an innate fear stimulus, such as a live predator, activates neurons containing NOS in regions related to defensive behavior. Considering these pieces of evidence, the present study investigated if neurons containing NOS localized in regions related to anxiety/fear are also activated after exposure to an EPM. Male Wistar rats were exposed to the EPM for 15 min and 2 h later their brains were removed and processed for c-Fos immunohistochemistry (a marker of neuronal functional activation) and NADPH-diaphorase histochemistry (NADPH-d; used to detect the presence of NOS neurons). Exposure to the EPM significantly increased double-stained cells (c-Fos + NADPHd positive neurons) in the parvocellular paraventricular (pPVN) and lateral (LH) hypothalamic nuclei, dlPAG and dorsal raphe nucleus (DRN), but not in the amygdaloid complex, bed nucleus of stria terminallis, dorsal premammillary nucleus of hypothalamus and inferior colicullus. These results suggest that exposure to an EPM activates NOS containing neurons in brain areas related to fear/anxiety.

c-Fos expression increase in NADPH-diaphorase positive neurons after exposure to a live cat.

The present study investigated if NOS positive neurons localized in regions related to defensive reactions are activated after exposure to an innate fear stimulus (a live cat). Male Wistar rats were exposed to a live or a toy cat for 10 min and 2h later had their brains removed and processed for c-Fos immunohistochemistry (a marker of neuronal functional activation) and NADPH-diaphorase (NADPH-d; used to detect the presence of NOS neurons) histochemistry. Cat exposure induced a small (11%) to moderate (50%) significant increase in the percentage of double-stained cells (c-Fos+NADPH-d positive neurons) in the anteromedial bed nucleus of stria terminalis (BSTMA), medial amygdala (MeA), parvocellular paraventricular (pPVN), lateral (LH) and dorsal premammillary (PMd) hypothalamic nuclei, dorsolateral periaqueductal grey (dlPAG) and dorsal raphe nucleus (DRN). This increase was attenuated in the PMd, DRN and dlPAG by i.c.v. injection of AP7 (5 nmol/2 microl), an NMDA receptor antagonist. The drug increased the percentage of time the rats remained close to the cat in the observation box. The results suggest that exposure to a live predator activates neurons containing NOS in brain areas related to defensive reactions. They also indicate that this effect probably involves activation of NMDA glutamate receptors.

Effects of Hypericum perforatum and paroxetine in the mouse defense test battery.

Since (a) Hypericum perforatum shows anxiolytic-like effect in some animal models, (b) antidepressant drugs (AD) have been used as the main drug treatment for panic disorder (PD), (c) AD are also effective in generalized anxiety disorder (GAD), and (d) H. perforatum exhibits antidepressant activity, it was hypothesized that H. perforatum might possess an antipanic-like and/or anxiolytic-like effect. Previous studies with the mouse defense test battery (MDTB) have suggested that this model may be useful for the investigation of anxiolytic-like and antipanic-like compounds. Thus, the aim of the present study was to evaluate the effect of H. perforatum extract in the MDTB. The effect of acute, subchronic (7 days), and chronic (21 days) H. perforatum (150 and 300 mg/kg) extract administration was evaluated in mice submitted to the MDTB. Paroxetine (5 mg/kg), a selective serotonin re-uptake inhibitor with anxiolytic and antipanic effect, was used as a positive control. The results showed that 21 days of repeated administration of H. perforatum 300 mg/kg and paroxetine 5 mg/kg reduced flight reactions (number of avoidances, avoidance distance, and overall flight speed) to the presence of the predator. While the effect of paroxetine confirms that MDTB is useful for the detection of antipanic-like drugs, the effect of H. perforatum suggests a putative antipanic-like effect for this extract. Moreover, after 21 days of repeated administration, paroxetine increased the number of approaches/withdrawals and reduced the number of upright postures, suggesting a partial anxiolytic-like effect, while H. perforatum only reduced the number of upright postures. The present results suggest anxiolytic-like and antipanic-like effects of H. perforatum extract. However, it should be emphasized that the risk assessment (the main index of anxiety) was not affected by the extract, while the attack reactions were only weakly modified.