Does a therapeutical dose of ivermectin impairs testicular homeostasis of rats via excessive apoptosis?

Ivermectin is a medication used to treat parasite infestations in humans and in veterinary medicine. Previously we showed that therapeutical doses of ivermectin impaired spermatogenesis and spermiogenesis in adult rats. The present study was proposed to understand the pathophysiological mechanism that triggered these impairments induced by ivermectin. It was a particular objective to study if ivermectin induced excessive apoptosis. Adult rats were treated with a therapeutical dose of ivermectin (subcutaneously). Their testis was evaluated for the expression of caspase-3 (a marker of apoptosis), using immunohistochemistry techniques. Results revealed that ivermectin treatment increased the expression of caspase-3 (labeled seminiferous tubules and strongly labeled tubules), as well as increased the number of tubules that presented labeled cells in the tubular lumen, compared to the data of the control group. In conclusion, a therapeutical dose of ivermectin induced expressive apoptosis in cells of the seminiferous tubules of rats, affecting the testicular natural homeostasis process, which resulted in the spermatogenesis and spermiogenesis impairments previously reported.

The dopaminergic D1 receptor modulates the hyperactivity of Bapa mutant mice.

The mutant bate-palmas ("claps"; symbol - bapa) mice induced by the mutagenic chemical ENU present motor incoordination and postural alterations. A previous study showed that bapa mice present increased motor/exploratory behaviors during the prepubertal period due to increased striatal tyrosine hydroxylase expression, suggesting striatal dopaminergic system hyperactivity. This study aimed to evaluate the involvement of striatal dopaminergic receptors in the hyperactivity of bapa mice. Male bapa mice and their wild strain (WT) were used. Spontaneous motor behavior was observed in the open-field test, and stereotypy was evaluated after apomorphine administration. The effects of DR1 and DR2 dopaminergic antagonists (SCH-23,390; sulpiride) and the striatal DR1 and D2 receptor gene expression were evaluated. Relative to WT, bapa mice showed: 1) increased general activity for four days; 2) increased rearing and sniffing behavior and decreased immobility after apomorphine; 3) blockage of rearing behavior after the DR2 antagonist but no effect after DR1 antagonist; 4) blockage of sniffing behavior after the DR1 antagonist in bapa and WT mice but no effect after the DR2 antagonist; 5) increased immobility after the DR1 antagonist but no effect after the DR2 antagonist; 6) increased expression of striatal DR1 receptor gene and reduced the DR2 expression gene after apomorphine administration. Bapa mice showed increased activity in open field behavior. The increased rearing behavior induced by apomorphine of bapa mice resulted from the increased gene expression of the DR1 receptor.

Psychomotor and neurofunctional aspects after COVID-19.

OBJECTIVE: The pandemic caused by the coronavirus disease 2019 (COVID-19, SARS-CoV-2 virus) has infected more than 646 million people and caused more than 6.6 million deaths worldwide (December/2022). It is surprising that a virus that affects airways can trigger neurological manifestations. The aim of this study was to create and apply specific questionnaires/evaluations for post-COVID-19 patients to profile any neurofunctional sequelae. METHODS: Epidemiological and psychomotor aspects as well as the intensity of cognitive, memory, attention, and concentration impairment were assessed. A total of 184 subjects post-COVID-19 and a control group (n = 30) were evaluated. RESULTS: The most prevalent blood types in the COVID-19 group were the same as those from control group and in Brazilian population (no influence). Loss of smell/taste and headache were the most common reported symptoms. Talking about psychomotor and neurofunctional aspects, COVID-19 induced marked impairments in the tests: fine motor development (diadochokinesis, puppets, fan, and knead paper); balance (immobility, static balance, feet in line, and persistence); episodic memory after distractors; verbal fluency; and clock, compared to the control group data. There was also marked increase of synkinesis. Therefore, COVID-19 induced impairments in psychomotor assessments and in different cognitive aspects of the Mini-Mental State Examination. These results are more surprising considering that most participants did not report pre-existing disease and did not require hospitalisation. CONCLUSION: COVID-19 induced psychomotor, neurofunctional, and memory impairments, including in young and healthy subjects. The present study revealed neurological impairments, which should be considered in the development of rehabilitation protocols for patients affected by COVID-19.

Prenatal restraint stress downregulates the hypothalamic kisspeptidergic system transcripts genes, reduces the estrogen plasma levels, delayed the onset of puberty, and reduced the sexual behavior intensity in female rats.

AIMS: This study investigated the possible relationships between the expression of the Kiss1 and Gpr54 gene expressions and the pituitary-gonadal hormones with the female onset of puberty and sexual behavior. The Kiss1 and Gpr54 gene expressions were examined because they are critical to controlling the hypothalamic activation of GnRH neurons and, in turn, the pituitary-gonadal hormones related to the early onset of puberty and sexual behavior. Further, it was evaluated that the pituitary and gonadal hormones involved in the vaginal opening and the expression of sexual behavior. METHODS: Pregnant rats exposed to PRS from gestation days 17 to 20 were evaluated for maternal and open-field behaviors. The maternal behavior was analyzed because it may alter brain sexual organization affecting the pups development. It was observed in female pups the physical and development and, in adult age, the open-field behavior, the anxiety-like behavior, the estrous cycle, the sexual behavior, the serum FSH, LH, estrogen, progesterone, and testosterone levels, and the gene expression of kisspeptin protein (Kiss1) and Gpr54 in the hypothalamus. RESULTS: the maternal and open-field behaviors were unaffected. In the F1 generation, PRS reduced weight at weaning, delayed the day of the vaginal opening and reduced the intensity of lordosis, the estrogen levels, and the Kiss1 and Gpr54 gene expression. These effects were attributed to hypothalamic kisspeptidergic system downregulation of transcripts genes and the reduced estrogen levels affected by the PRS.

Exposure of dams to fluoxetine during lactation disturbs maternal behavior but had no effect on the offspring behavior.

Fluoxetine is one of the most commonly prescribed drugs for treatment of depression during pregnancy as well as postpartum. Nevertheless, fluoxetine can cross the placental barrier and/or be secreted through breastmilk and questions remain unanswered regarding safety of the unborn and/or nursing infant. Passive administration of antidepressants to infants can cause neurological developmental delay and/or dysfunction. To date, there are limited studies on neurobehavioral effects due to passive administration of fluoxetine in nursing animals. Thus, the aim of the present study was to evaluate the effects of fluoxetine exposure on the behavior of lactating dams and their offspring. Dams received either 1, 10 or 20 mg/kg fluoxetine via oral gavage (controls received water alone) from lactating day (LD) 1 to 21. Maternal behavioral studies were conducted from LD5 to LD7 and offspring studies were conducted from LD2 to LD60. Results showed dysfunction in maternal behavior, both in direct and indirect behavior, but there were no differences and/or deficiencies observed in offspring behavior. These data suggest that the impairment of dams maternal behavior combined with the amount of fluoxetine that the offspring received through breast milk during lactation did not alter their social behavior in infancy and/or adulthood, suggesting no neurodevelopmental damage associated with maternal use of fluoxetine. This study contributes to the field of human psychiatric diseases by further elucidating the effects of antidepressant medications on the health of mothers as well as children who were passively exposed to drug treatment.

Chemobrain in rats: Behavioral, morphological, oxidative and inflammatory effects of doxorubicin administration.

Doxorubicin (DOX) is known to cause cognitive impairments in patients submitted to long-term chemotherapy (deficits also known as chemobrain). The present study investigated whether DOX administration could affect behavior and brain morphology, as well as oxidative and inflammatory status in rats. Male Wistar rats were injected with DOX (2.5 mg/kg/week, 4 weeks, i.p.) or saline. Behavioral analyses were performed. Brains were collected and analyzed by hematoxylin-eosin and luxol fast blue staining techniques and by immunohistochemistry (for glial fibrillary acidic protein expression in astrocytes; GFAP). Serum and brain levels of TNF-α, IL-1ß, IL-6, IL-8, IL-10 and CXCL-1 were determined. Oxidative parameters, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), nitric oxide (NO•), brain iron and ferritin levels, as well as reduced and oxidized glutathione (GSH and GSSG, respectively) and thiobarbituric acid reactive substances (TBARS) were also assessed in brain. DOX-injected rats presented cognitive/memory impairments, increased GFAP expression, increased levels of TBARS, NO and GR, but decreased GSSG and ferritin levels in brain homogenate. In addition, increased serum and brain levels of IL-6, IL-8 and CXCL1 were noted in the DOX group, although IL-10 decreased. As DOX has a poor penetration across the blood-brain barrier (BBB), it is proposed that this drug elicits a systemic proinflammatory response with increase of proinflammatory cytokines which cross the BBB and can be involved in the induction of oxidative molecules and proinflammatory cytokines that altogether induce astrogliosis all over the brain. These events may be responsable for chemotherapy-induced cognitive/memory deficits.

Reduced astrocytic expression of GFAP in the offspring of female rats that received hypercaloric diet.

Introduction: Obesity promotes hypothalamic inflammation and local morphological changes in astrocytes, including the increased expression of the astrocytic biomarker glial fibrillary acidic protein (GFAP), which is seen as a sign of neuroinflammation.Objective: This study aimed to observe the astrocytic expression of GFAP in different brain areas from female rats that received a hypercaloric (HD) or a normocaloric (ND) diet during puberty (F0 generation) as well as in their male pups (F1 generation).Methods: Female rats received highly palatable HD (Ensure®) or ND from postnatal day (PND) 23-65. On PND90-95, some were euthanized for the immunohistochemical study and some were mated to obtain the F1 generation. Male pups were immunochallenged on PND50 with lipopolysaccharide (LPS, 100 µg/kg) or 0.9% saline solution (1 mL/kg) intraperitoneal injection. Body weight (BW) and retroperitoneal fat weight (RFW) were recorded on PND95 for F0 generation and on PND50 for F1 generation. GFAP expression for both generations was assessed by morphometry in the parietal/frontal cortex, corpus callosum, nucleus accumbens, arcuate/periventricular nuclei of hypothalamus, pons, molecular/granular layers of cerebellum.Results: Female rats fed with HD presented a significant increase in the GFAP expression in all evaluated areas as well as in the RFW. Male rats born from mothers that received HD showed decreased GFAP expression, BW and RFW when treated with LPS in relation to those from mothers fed with ND.Discussion: HD induced astrogliosis in several brain areas in females from F0 generation and an adaptive phenotypic change of decreased GFAP expression in males from F1 generation after LPS challenge.

Combination of ketamine and xylazine with opioids and acepromazine in rats: Physiological changes and their analgesic effect analysed by ultrasonic vocalization.

In this study, the effect of four anaesthetic protocols that included the combination of xylazine (X) and ketamine (K) with acepromazine (A) and opioids (methadone (Me), morphine (Mo) or tramadol (T)) was evaluated in laboratory rats of both sexes. Ultrasonic vocalization (USV) was used as an indicator of pain during the recovery period. The objective was to evaluate the physiological parameters and the analgesic effect of each protocol to determine which protocol was the safest and fulfil the requirements of a balanced anaesthesia. The better protocols were the XKA protocol for both sexes and the XKMe protocol for females because the combinations achieve surgical plane of anaesthesia in rats. However, pain assessment during the formalin test revealed that rats anaesthetized with XKA produced more numbers of USV, suggesting that it is not a good protocol for the control of immediate postoperative pain. All protocols produced depression in body temperature and respiratory and heart rates, and had important effects, such as micturition and maintenance of open eyes. Only rats anaesthetized with XKA protocol did not present piloerection. These results demonstrated that good monitoring and care during anaesthesia must be included to prevent complications that compromise the life of the animal and to ensure a good recovery. The inclusion of analgesia in anaesthesia protocols must be used routinely, ensuring minimal presence of pain and thus more reliable results in the experimental procedures.

LPS-induced sickness behavior is not affected by selenium but is switched off by psychogenic stress in rats.

Sickness behavior (SB) is considered part of the adaptive behavioral and neuroimmune changes that occur in response to inflammatory processes. However, SB is a motivational state modulated by the environmental context. The objective of this study was to evaluate if selenium could ameliorate symptoms of SB and if stress would affect these responses. We induced SB in rats using lipopolysaccharide (LPS). We choose selenium based on our findings of LPS-exposure decreasing selenium levels in rats. We exposed these rats to a psychogenic stress and studied motivational modulation paradigms, such as cure of the organism, preservation of the species, and fight or flight. We studied ultrasonic vocalizations, open-field behaviors, body weight, and IL-1 beta and IFN-gamma serum levels. LPS-induced SB was evidenced by decreased motor/exploratory activity and increased proinflammatory mediators' levels. Selenium treatment did not exert beneficial effects on SB, revealing that probably the selenium deficiency was not related to SB. When analyzed with the stress paradigm, the behavior of rats was differentially affected. LPS did not affect behavior in the presence of stress. SB was abrogated during stressor events to prioritize survival behaviors, such as fight-or-flight. Contrarily, the association of LPS, selenium, and stress induced SB even during stressor events, revealing that this combination induced a cumulative toxic effect.

Pioglitazone abolishes autistic-like behaviors via the IL-6 pathway.

Autism is characterized by social deficits, communication abnormalities, and repetitive behaviors. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infections by gram-negative bacteria, induces autistic-like behaviors. No effective treatment yet exists for autism. Therefore, we used our rat model to test a possible treatment for autism. We selected pioglitazone to block or ease the impairments induced by LPS because although this drug was designed as an anti-diabetic drug (it has an insulin effect), it also exerts anti-inflammatory effects. Juvenile offspring were treated daily with pioglitazone, and the main behaviors related to autism, namely, socialization (play behavior) and communication (50-kHz ultrasonic vocalizations), were studied. Biomarkers linked to autism and/or pioglitazone were also studied to attempt to understand the mechanisms involved, namely, IL-6, TNF-alpha, MCP-1, insulin, and leptin. Prenatal LPS exposure induced social deficits and communicational abnormalities in juvenile rat offspring as well as elevated plasma IL-6 levels. Daily postnatal pioglitazone treatment blocked the impairments found in terms of the time spent on social interaction, the number of vocalizations (i.e., autistic-like behaviors) and the elevated plasma IL-6 levels. Thus, pioglitazone appears to be a relevant candidate for the treatment of autism. The present findings may contribute to a better understanding and treatment of autism and associated diseases.

Propentofylline decreases hypothalamic astrogliosis induced by hypercaloric diet in the rat.

Obesity is associated with a chronic and low-grade inflammatory response in the hypothalamus, where astrogliosis occurs with the upregulation of the astrocyte structural protein GFAP. As propentofylline (PPF) has inhibitory effects on astrocyte and microglial activation during inflammation, this study aimed to investigate if this xanthine derivative could decrease the astrocyte reaction induced by a hypercaloric diet (HD). Male Wistar rats were divided into four groups: NDS - rats receiving a normocaloric diet (ND) and daily saline solution; NDP - rats receiving ND and daily PPF (12.5 mg/kg/day, intraperitoneal route); HDS - rats receiving HD and saline solution, HDP - rats receiving HD and PPF. On the 21st day, rats were anesthetized, and perfused, and brains were collected for GFAP immunohistochemical study in the hypothalamus. Results showed that HD induced increased weight gain and hypothalamic astrogliosis. Propentofylline decreased the expression of GFAP in the HDP group, although it did not affect the weight gain induced by this diet.

Propentofylline decreases hypothalamic astrogliosis induced by hypercaloric diet in the rat / A propentofilina diminui a astrogliose hipotalâmica induzida pela dieta hipercalórica no rato

ABSTRACT Obesity is associated with a chronic and low-grade inflammatory response in the hypothalamus, where astrogliosis occurs with the upregulation of the astrocyte structural protein GFAP. As propentofylline (PPF) has inhibitory effects on astrocyte and microglial activation during inflammation, this study aimed to investigate if this xanthine derivative could decrease the astrocyte reaction induced by a hypercaloric diet (HD). Male Wistar rats were divided into four groups: NDS - rats receiving a normocaloric diet (ND) and daily saline solution; NDP - rats receiving ND and daily PPF (12.5 mg/kg/day, intraperitoneal route); HDS - rats receiving HD and saline solution, HDP - rats receiving HD and PPF. On the 21st day, rats were anesthetized, and perfused, and brains were collected for GFAP immunohistochemical study in the hypothalamus. Results showed that HD induced increased weight gain and hypothalamic astrogliosis. Propentofylline decreased the expression of GFAP in the HDP group, although it did not affect the weight gain induced by this diet.

RESUMO A obesidade está associada com uma resposta inflamatória crônica e de baixo grau no hipotálamo, onde ocorre astrogliose com a superexpressão da proteína astrocitária GFAP. Como a propentofilina (PPF) possui efeitos inibitórios sobre a ativação astrocitária e microglial durante a inflamação, este estudo visou a investigar se esta xantina podia diminuir a reação astrocitária induzida pela dieta hipercalórica (HD). Ratos Wistar machos foram divididos em 4 grupos: NDS- ratos recebendo dieta normocalórica (ND) e solução salina diária; NDP- ratos recebendo ND e PPF diária (12.5 mg/kg/dia, via intraperitoneal); HDS- ratos recebendo HD e solução salina, HDP- ratos recebendo HD e PPF. No 21° dia, os ratos foram perfundidos e os encéfalos, coletados para estudo imuno-histoquímico para a GFAP no hipotálamo. Os resultados mostram que a HD induziu aumento do ganho de peso e astrogliose no hipotálamo. A PPF diminuiu a expressão de GFAP no grupo HD, embora não tenha afetado o ganho de peso induzido por esta dieta.

Zinc as a therapy in a rat model of autism prenatally induced by valproic acid.

Autism is characterized by numerous behavioral impairments, such as in communication, socialization and cognition. Recent studies have suggested that valproic acid (VPA), an anti-epileptic drug with teratogenic activity, is related to autism. In rodents, VPA exposure during pregnancy induces autistic-like effects. Exposure to VPA may alter zinc metabolism resulting in a transient deficiency of zinc. Therefore, we selected zinc as a prenatal treatment to prevent VPA-induced impairments in a rat model of autism. Wistar female rats received either saline solution or VPA (400 mg/kg, i.p) on gestational day (GD) 12.5. To test the zinc supplementation effect, after 1 h of treatment with saline or VPA, a dose of zinc (2 mg/kg, s.c.) was injected. The offspring were tested for abnormal communication behaviors with an ultrasound vocalization task on postnatal day (PND) 11, repetitive behaviors and cognitive ability with a T-maze task on PND 29, and social interaction with a play behavior task on PND 30. Tyrosine hydroxylase protein (TH) expression was evaluated in the striatum. Prenatal VPA decreased ultrasonic vocalization, induced repetitive/restricted behaviors and cognitive inflexibility, impaired socialization, and reduced striatal TH levels compared with control group. Zinc treatment reduced VPA-induced autistic-like behaviors. However, we found no evidence of an effect of zinc on the VPA-induced reduction in TH expression. The persistence of low TH expression in the VPA-Zn group suggests that Zn-induced behavioral improvement in autistic rats may not depend on TH activity.

Acute Lipopolysaccharide Switches the Selection of Maternal Behavior to Predatory Behavior in Female Rats.

OBJECTIVES: A common problem during the postpartum period and during lactation is being affected by infection due to Gram-negative bacteria. In this situation, a sick mother needs to choose between caring for her pups or the need for survival. This study analyzed the effects of lipopolysaccharide (LPS)-induced sickness behavior on selection between maternal behavior (MB) and predatory behavior (PB) in lactating rats. To assess the LPS-induced sickness behavior, the plasma tumor necrosis factor-α (TNF-α) levels were measured. METHODS: Lactating rats received 100 µg/kg LPS or saline solution on day 5 or 6 of lactation, 2 h before testing. Five pups and 5 cockroaches were introduced to the experimental cage at the same time and maternal and PB were observed for 30 min. The MB was measured by the pup contact, grouping, grooming, and kyphosis and the PB by contacting, eating, and foraging insects. General maternal activity was also observed, including exploration, self-grooming, and immobility. Immediately after the observations, blood was collected to measure the plasma TNF-α levels. RESULTS: LPS administration reduced the time and frequency of pup contact, grouping, grooming, and kyphosis, with an increase in the latency to first pup contact and grouping. With regard to PB, the time of foraging and eating insects increased, and the latencies to first insect contact, eating insects, and foraging decreased. With regard to general maternal activity, immobility time and TNF-α levels increased in the LPS-treated group. CONCLUSIONS: LPS exposure switched MB to PB, prioritizing maternal survival. Thus, in more favorable situations, these rats may have new offspring and therefore her species would survive for long.

Depressive behavior induced by unpredictable chronic mild stress increases dentin hypersensitivity in rats.

OBJECTIVE: The present study evaluated the nociceptive response induced by dentin hypersensitivity after dental erosion in rats that were exhibited to unpredictable chronic mild stress (UCMS)-induced depressive-like behavior. DESIGN: Adult male rats were subjected to UCMS (depression [D] group) or not (no depression [ND] group) for 30days and received either acidic solution to induce dental erosion (E) or water (W), thus forming the WND, END, WD, and ED groups. After the end of treatment, depressive-like parameters (i.e., sucrose preference and immobility in the forced swim test) and dentin hypersensitivity were evaluated. Plasma tumor necrosis factor α (TNF-α) and corticosterone levels were measured, and astrocytic glial fibrillary acidic protein (GFAP) expression was evaluated in the prefrontal cortex, hippocampus, amygdala, and hypothalamus. RESULTS: Administration of the acidic solution potentiated dentin hypersensitivity and increased corticosterone levels in the ED group compared with the WD group. TNF-α levels only increased in the WD group. The ED group exhibited an increase in astrocytic GFAP expression in the hypothalamus and prefrontal cortex but decreases in the hippocampus. CONCLUSIONS: These results suggest that UCMS exacerbated the nociceptive response associated with dentin hypersensitivity, concomitant with an increase in plasma corticosterone levels. Hypothalamic and prefrontal cortex astrogliosis in the ED group may be attributable to the increase in corticosterone associated to UCMS procedure. The reduction of astrocytic GFAP expression in the hippocampus in the ED group supports the association between dentin hypersensitivity and depression.

Propentofylline Prevents Sickness Behavior and Depressive-Like Behavior Induced by Lipopolysaccharide in Rats via Neuroinflammatory Pathway.

Recent studies have demonstrated the intimate relationship between depression and immune disturbances. Aware of the efficacy limits of existing antidepressant drugs and the potential anti-inflammatory properties of propentofylline, we sought to evaluate the use of propentofylline as a depression treatment. We used a rat model of depression induced by repetitive lipopolysaccharide (LPS) administrations. We have studied sickness behavior, by assessing daily body weight, open field behavior, and TNF-α plasmatic levels. Anxiety-like behavior (light-dark test), depressive-like behavior (forced swim test), plasmatic levels of the brain-derived neurotrophic factor (BDNF, depression biomarker), and central glial fibrillary acidic protein (GFAP) expression (an astrocyte biomarker) were also evaluated. LPS induced body weight loss, open field behavior impairments (decreased locomotion and rearing, and increased immobility), and increased TNF-α levels in rats, compared with control group. Thus, LPS induced sickness behavior. LPS also increased the immobility and reduced climbing in the forced swim test, when compared with the control group, i.e., LPS induced depressive-like behavior in rats. Propentofylline prevented sickness behavior after four days of consecutive treatment, as well as prevented the depressive-like behavior after five days of consecutive treatments. Propentofylline also prevented the increase in GFAP expression induced by LPS. Neither LPS nor propentofylline has influenced the anxiety and BDNF levels of rats. In conclusion, repetitive LPS administrations induced sickness behavior and depressive-like behavior in rats. Propentofylline prevented both sickness behavior and depressive-like behavior via neuroinflammatory pathway. The present findings may contribute to a better understanding and treatment of depression and associated diseases.

Maternal periodontitis induces intergenerational injuries on reproductive performance of adult female rat offspring / Periodontite materna induz prejuízos transgeracionais no desempenho reprodutivo da prole feminina na idade adulta

Substantial evidence suggests a direct link between periodontitis in pregnant women and subsequent adverse pregnancy outcomes. However, no studies have evaluated the transgenerational effects of periodontitis on the reproductive performance of subsequent generations. The present study investigated whether maternal periodontal disease exerts deleterious transgenerational effects on reproductive performance in F1 female rats. Rat female offspring from mothers that were subjected to experimentally induced periodontitis or sham operation were mated with sexually experienced male rats. The weight and reproductive performance of these F1 offspring were evaluated on gestation day 21, including maternal weight, litter weight, individual pup weight, number of pups, and number of resorptions. The percentage of dams with resorptions and the litter weight/number of pups were also calculated. Compared with the control group, an increase was observed in the percentage and number of resorptions and litter weight/number of pups, and a decrease was observed in the number of pups born in the experimental group. Maternal weight, litter weight, and individual pup weight were not different between the control and experimental groups. Maternal periodontitis impaired reproductive performance in the F1 generation. We showed that periodontitis may induce reproductive injury in adult offspring even if the offspring do not undergo any inflammatory/infectious process during their postnatal life or during gestation. These findings reinforce the importance of oral care during pregnancy.(AU)

Existem evidências substanciais de uma relação direta entre periodontite em mulheres grávidas com efeitos adversos reprodutivos. No entanto, nenhum estudo avaliou os efeitos intergeracionais da periodontite sobre o desempenho reprodutivo das gerações subsequentes. O presente estudo investigou se a doença periodontal materna exerce efeitos intergeracionais deletérios sobre o desempenho reprodutivo em ratos fêmeas da geração F1. Assim, filhas de ratas cujas mães foram submetidas a periodontite experimental ou falsamente operadas foram acasaladas com ratos machos sexualmente experientes. O peso corporal e desempenho reprodutivo da geração F1 foram avaliados no dia 21 de gestação, incluindo o peso materno, peso da ninhada, peso da individual dos filhotes, número de filhotes e de reabsorções. A percentagem de fêmeas com reabsorção e o peso da ninhada/número de filhotes também foram calculados. Comparados com o grupo controle, observou-se aumento na porcentagem e número de reabsorções e no peso da ninhada/ número de filhotes, e decréscimo no número de filhotes nascidos no grupo experimental. O peso materno, peso da ninhada e individual dos filhotes não foi diferente entre o controle e experimental. Estes resultados mostram que a periodontite experimental materna prejudica o desempenho reprodutivo da geração F1, mesmo que estes animais não tenham sido expostos diretamente a um processo inflamatório.(AU)

Lipopolysaccharide Exposure Induces Maternal Hypozincemia, and Prenatal Zinc Treatment Prevents Autistic-Like Behaviors and Disturbances in the Striatal Dopaminergic and mTOR Systems of Offspring.

Autism is characterized by social deficits, repetitive behaviors, and cognitive inflexibility. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces autistic-like behaviors. To understand the causes of autistic-like behaviors, we evaluated maternal serum metal concentrations, which are involved in intrauterine development and infection/inflammation. We identified reduced maternal levels of zinc, magnesium, selenium and manganese after LPS exposure. Because LPS induced maternal hypozincemia, we treated dams with zinc in an attempt to prevent or ease the impairments in the offspring. We evaluated the social and cognitive autistic-like behaviors and brain tissues of the offspring to identify the central mechanism that triggers the development of autism. Prenatal LPS exposure impaired play behaviors and T-maze spontaneous alternations, i.e., it induced autistic-like behaviors. Prenatal LPS also decreased tyrosine hydroxylase levels and increased the levels of mammalian target of rapamycin (mTOR) in the striatum. Thus, striatal dopaminergic impairments may be related to autism. Moreover, excessive signaling through the mTOR pathway has been considered a biomarker of autism, corroborating our rat model of autism. Prenatal zinc treatment prevented these autistic-like behaviors and striatal dopaminergic and mTOR disturbances in the offspring induced by LPS exposure. The present findings revealed a possible relation between maternal hypozincemia during gestation and the onset of autism. Furthermore, prenatal zinc administration appears to have a beneficial effect on the prevention of autism.

Maternal exposure to Bothrops jararaca snake venom: effects in mice offsprings / Exposição maternal ao veneno de Bothrops jararaca: efeitos na prole de camundongos

Objective - Bothrops jararaca snake is involved in almost 90% of all reports in the State of São Paulo, Brazil. Little is known about the effect of maternal exposure to B. jararaca snake venom [BjV] on fetal development. This study was designed to investigate the effect of a moderate dose of the venom (1.2 mg/kg sc on either gestation day GD5 or GD12), in pregnant mice and their offspring. Methods - In dams, during pregnancy, it was observed the body weight gain, food and water consumptions. In the last day of pregnancy, dams were submitted to a cesarean and the reproductive performance was measured. Thus, the fetuses body weight, the number of live and dead fetuses as wells as the external, visceral or skeletal alterations were assessed. Results - Results showed that the venom injection on GD5 did not change the dams weight and reproductive parameters, the fetuses weight, but it was observed high incidence of skeletal anomalies such as incomplete skull ossification and supernumerary ribs relative to controls. Dams treated in GD11 showed decreased food ingestion in the day after treatment. Their offspring presented a high incidence of skeletal anomalies such as vertebrae anomalies, sternebrae anomalies and incomplete skull ossification, which might be a sign of craniostenosis, than controls. Conclusions - In conclusion, subcutaneous administration of 1.2mg/kg BjV to pregnant mice either at GD4 or GD12 produced subtle maternal toxicity but a clear fetotoxicity. Whether these observations represent a reaction to treatment and, if so, the underlying mechanisms and their toxicological impact remain to be examined further in future studies.

Objetivo - O veneno de Bothrops jararaca está envolvido em quase 90% dos casos de envenenamento do Estado de São Paulo, Brasil. Pouco se sabe sobre o efeito no desenvolvimento fetal quando no caso de envenenamento materno. Este estudo examinou, em camundongas prenhes e sua prole, os efeitos do envenenamento por uma dose moderada do veneno de B. jararaca (1,2 mg/kg sc no 5° (GD5) e 11°(GD11) da gestação. Métodos - Anotou-se durante a gestação o ganho de peso corporal e o consumo de água e comida materno; no último dia de gestação, as mães foram submetidas a uma cesariana e a performance reprodutiva foi avaliada. Para tanto, anotou-se o peso dos fetos, o número de fetos vivos e mortos, assim como examinou-se a presença de alterações externas, esqueléticas, e viscerais. Resultados - Os resultados mostraram que a injeção do veneno no GD5 não alterou o peso materno, o consumo de água e ração, o peso dos fetos e os parâmetros reprodutivos, tendo sido observada alta incidência de anomalias esqueléticas tais como ossificação do crânio incompleta e costelas supranumerárias em relação aos controles. O envenenamento no GD11 promoveu decréscimo na ingestão de alimentos no dia subsequente ao tratamento. Neste caso, a prole apresentou alta incidência de anomalias esqueléticas tais como anomalias vertebrais, do esterno e ossificação incompleta do crânio, ou seja, craniostenose. Conclusões - O envenenamento moderado pelo veneno da B. jararaca em camundongas prenhas tanto no GD5 como no GD11 produziram efeitos sutís ao nível materno, porém nos fetos, apareceram severas alterações. Estudos futuros deverão ser feitos para entender os mecanismos subjacentes a este envenenamento durante a gestação.

Nepeta cataria L. var. citriodora (Becker) increases penile erection in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Nepeta cataria (NC), catnip, induces pleasure in cats and humans. AIM OF THE STUDY: Because sexual behavior is involved in pleasure, the effect of NC on sexual behavior and penile erection was evaluated in male rats that were acutely fed chow enriched with 10% NC leaves. Further, yawning was monitored because we previously demonstrated that NC modifies dopaminergic-related behaviors and that sexual behavior is closely linked with the dopaminergic system. The general activity and the motor coordination were examined to investigate the possible motor and emotional interferences of the sexual performance. MATERIAL AND METHODS: Male rats of the NC group received for a 4h period the chow enriched with 10% NC leaves while the control groups received regular chow. Fifteen min after the end of the 4h period of NC feeding the sexual behavior, apomorphine-induced penile erection and motor coordination were observed; the general activity in the open field was assessed 0, 15, 30 and 60 min after treatment. RESULTS: NC treatment increased male rat's penile erection. A slightly facilitation on male rat sexual behavior and a decreased in general activity of NC treated rats were observed. No effects on motor coordination and yawning episodes were detected by the NC treatment. CONCLUSIONS: It was suggested that NC increases penile erection and slightly improves male rat sexual behavior by an action on dopaminergic systems.