RESUMO
BACKGROUND: Plasmodium vivax malaria is characterized by the presence of dormant liver-stage parasites, called hypnozoites, which can cause malaria relapses after an initial attack. Primaquine, which targets liver hypnozoites, must be used in combination with a schizonticidal agent to get the radical cure. However, relapses can sometimes occur in spite of correct treatment, due to different factors such as a diminished metabolization of primaquine. CASE PRESENTATION: In January 2019, a 21 years old woman with residence in Madrid, returning from a trip to Venezuela with clinical symptoms compatible with malaria infection, was diagnosed with vivax malaria. Chloroquine for 3 days plus primaquine for 14 days was the elected treatment. Two months later and after a second trip to Venezuela, the patient presented a second P. vivax infection, which was treated as the previous one. A third P. vivax malaria episode was diagnosed 2 months later, after returning from a trip to Morocco, receiving chloroquine for 3 days but increasing to 28 days the primaquine regimen, and with no more relapses after 6 months of follow up. The genotyping of P. vivax in the three malaria episodes revealed that the same strain was present in the different relapses. Upon confirmation of correct adherence to the treatment, non-description of resistance in the infection area and the highly unlikely re-infection on subsequent trips or stays in Spain, a possible metabolic failure was considered. CYP2D6 encodes the human cytochrome P450 isoenzyme 2D6 (CYP2D6), responsible for primaquine activation. The patient was found to have a CYP2D6*4/*1 genotype, which turns out in an intermediate metabolizer phenotype, which has been related to P. vivax relapses. CONCLUSIONS: The impairment in CYP2D6 enzyme could be the most likely cause of P. vivax relapses in this patient. This highlights the importance of considering the analysis of CYP2D6 gene polymorphisms in cases of P. vivax relapses after a correct treatment and, especially, it should be considered in any study of dosage and duration of primaquine treatment.
Assuntos
Antimaláricos/uso terapêutico , Citocromo P-450 CYP2D6/metabolismo , Malária Vivax/tratamento farmacológico , Primaquina/uso terapêutico , Antimaláricos/metabolismo , Feminino , Humanos , Malária Vivax/parasitologia , Fenótipo , Plasmodium vivax/fisiologia , Primaquina/metabolismo , Recidiva , Espanha , Venezuela , Adulto JovemRESUMO
Reproductive experience in mammals produces significant neuroendocrine and behavioral changes that are necessary to ensure the survival of the mother and the young. Exposure to stress during postpartum may affect the proper development of maternal behaviors. The present study examined whether previous reproductive experience affects neurobehavioral responses in females exposed to mother-infant separation stress during the postpartum period (4.5â¯h/day for 3â¯weeks). Anxiety-like behavior and spatial learning were evaluated in nulliparous (NP), primiparous (PRI) and multiparous (MULT). In maternal animals (PRI and MULT), maternal behavior was also assessed. Cell survival and proliferation in the dentate gyrus, as well as BDNF expression in the hippocampus, were evaluated by immunohistochemistry as possible candidates for mediating brain plasticity in response to reproductive experience and stress. Anxiety-like behavior as measured on the open field test showed an increase in NP and PRI-stressed, while neither stressed nor unstressed MULT expressed this behavior. Maternal unstressed animals both PRI and MULT exhibited enhanced memory task performance in the Barnes maze. Multiparity increased cell proliferation and cell survival in female rats and these changes occurred independently of pup exposure. The expression of BDNF was higher in the CA1 area in MULT rats. Although multiparity protects the mother against some of the effects of maternal separation stress, promoting behaviors directed to the pups during the early postpartum, preventing anxiety-like behaviors and mitigating memory deterioration after weaning, the data showed that disrupting natural dam-pup interaction produced neurobiological consequences on the mother even with multiple reproductive experience.
Assuntos
Comportamento Animal/fisiologia , Comportamento Materno/fisiologia , Privação Materna , Memória/fisiologia , Estresse Psicológico/metabolismo , Animais , Feminino , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Aprendizagem em Labirinto/fisiologia , Mães/psicologia , Plasticidade Neuronal/fisiologia , Período Pós-Parto/psicologia , Ratos Wistar , DesmameRESUMO
PURPOSE: The aim of this study was to analyze whether early maternal separation would result in long-term, persistent alterations in stress response in adulthood, altering mineralocorticoid receptor immunoreactivity (MR-ir) in the dorsal hippocampal areas [CA1, CA2, CA3 and dentate gyrus (DG)], paraventricular nucleus of the hypothalamus and medial and central nucleus of the amygdala, key structures involved in stress response regulation. We also analyzed whether chronic treatment with the antidepressant tianeptine reverses these possible changes. MATERIAL AND METHODS: Male Wistar rats were subjected to daily maternal separation for 4.5 h during 3 weeks or left undisturbed. As adults, they were exposed to chronic stress during 24 days or left undisturbed, and they were also daily treated with tianeptine (10 mg/kg i.p.) or isotonic solution. RESULTS: In the CA2 and DG areas of the dorsal hippocampus, there was an increase in MR-ir in non-maternally separated and chronic stressed groups. Tianeptine raised MR-ir in the CA3. In the DG, control and maternally separated + chronic stress groups treated with tianeptine showed more MR-ir than their respective vehicle groups. In the paraventricular nucleus, tianeptine decreased MR-ir in non-separated groups, but not in maternally separated rats. CONCLUSIONS: Our results support findings that early-life events induce long-term changes in stress response regulation, persistent into adulthood, which are manifested during challenges in later life, and that treatment with tianeptine, which tends to attenuate the hypothalamus-pituitary-adrenal axis dysregulation, depends on the individual experience of each rat.
Assuntos
Privação Materna , Receptores de Mineralocorticoides/metabolismo , Estresse Psicológico/metabolismo , Tiazepinas/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Estresse Psicológico/tratamento farmacológico , Tiazepinas/uso terapêuticoRESUMO
Vulnerability to emotional disorders like depression derives from interactions between early and late environments, including stressful conditions. The serotonin (5HT) system is strongly affected by stress and chronic unpredictable stress can alter the 5HT system. We evaluated the distribution of active serotonergic neurons in the dorsal raphe nucleus (DR) through immunohistochemistry in maternally separated and chronically stressed rats treated with an antidepressant, tianeptine, whose mechanism of action is still under review. Male Wistar rats were subjected to daily maternal separation (MS) for 4.5 h between postnatal days (PND) 1-21, or to animal facility rearing (AFR). Between (PND) days 50-74, rats were exposed to chronic unpredictable stress and were treated daily with tianeptine (10 mg/kg) or vehicle. We found an interaction between the effects of MS and chronic unpredictable stress on Fos-5HT immunoreactive cells at mid-caudal level of the DR. MS-chronically stressed rats showed an increase of Fos-5HT immunoreactive cells compared with AFR-chronically stressed rats. The ventrolateral (DRL/VLPAG) and dorsal (DRD) subdivisions of the DR were significantly more active than the ventral part (DRV). At the rostral level of the DR, tianeptine decreased the number of Fos-5HT cells in DR in the AFR groups, both unstressed and stressed. Overall, our results support the idea of a match in phenotype exhibited when the early and the adult environment correspond.
Assuntos
Núcleo Dorsal da Rafe/citologia , Privação Materna , Neurônios Serotoninérgicos/citologia , Estresse Psicológico , Animais , Antidepressivos Tricíclicos/farmacologia , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/metabolismo , Imuno-Histoquímica , Masculino , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Tiazepinas/farmacologiaRESUMO
Early maternal separation (MS) may produce lasting effects in the dorsal hippocampus (DH) that can change its response to chronic stress in adulthood. Chronic stress affects DH morphology and function, but tianeptine (an anti-depressant) can reverse the stress-induced morphological impairments. Morphologic alterations of hippocampus can affect contextual memory. Therefore, we evaluated the effect of tianeptine in MS and chronically stressed rats on: 1) volume of the DH and its areas using stereology and 2) hippocampal-dependent memory using a fear conditioning test. Male Wistar rats were subjected to daily MS for 4.5 h between postnatal days (PND) 1-21, or to animal facility rearing (AFR). Between (PND) days 50 and 74, rats were exposed to chronic unpredictable stress and were treated daily with tianeptine (10 mg/kg) or vehicle, providing eight groups: AFR-unstressed/vehicle (n = 5 for stereology, n = 18 for fear conditioning test); AFR unstressed/tianeptine (n = 6 and n = 10); AFR-chronic stress/vehicle (n = 6 and n = 14); AFR-chronic stress/tianeptine (n = 6 and n = 10), MS-unstressed/vehicle (n = 5 and n = 19), MS-unstressed/tianeptine (n = 6 and n = 10), MS-chronic stress/vehicle (n = 6 and n = 18), and MS-chronic stress/tianeptine (n = 6 and n = 10). MS-chronic stress/tianeptine rats showed a diminished CA1 area than the corresponding MS-unstressed/tianeptine rats. The combination of stressors produced a freezing response similar to those of the control group during postconditioning. During retrieval, MS led to a diminished freezing response compared to the AFR-unstressed groups. Tianeptine had no effect on freezing behavior. Our results show that tianeptine can affect the CA1 area volume differently depending on the nature and quantity of stressors but cannot alter freezing to context.
Assuntos
Antidepressivos Tricíclicos/uso terapêutico , Ansiedade de Separação/patologia , Hipocampo/patologia , Privação Materna , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/patologia , Tiazepinas/uso terapêutico , Animais , Ansiedade de Separação/psicologia , Região CA1 Hipocampal/patologia , Doença Crônica , Medo/psicologia , Masculino , Ratos , Ratos Wistar , Estresse Psicológico/psicologiaRESUMO
Metformin displays antileukemic effects partly due to activation of AMPK and subsequent inhibition of mTOR signaling. Nevertheless, Metformin also inhibits mitochondrial electron transport at complex I in an AMPK-independent manner, Here we report that Metformin and rotenone inhibit mitochondrial electron transport and increase triglyceride levels in leukemia cell lines, suggesting impairment of fatty acid oxidation (FAO). We also report that, like other FAO inhibitors, both agents and the related biguanide, Phenformin, increase sensitivity to apoptosis induction by the bcl-2 inhibitor ABT-737 supporting the notion that electron transport antagonizes activation of the intrinsic apoptosis pathway in leukemia cells. Both biguanides and rotenone induce superoxide generation in leukemia cells, indicating that oxidative damage may sensitize toABT-737 induced apoptosis. In addition, we demonstrate that Metformin sensitizes leukemia cells to the oligomerization of Bak, suggesting that the observed synergy with ABT-737 is mediated, at least in part, by enhanced outer mitochondrial membrane permeabilization. Notably, Phenformin was at least 10-fold more potent than Metformin in abrogating electron transport and increasing sensitivity to ABT-737, suggesting that this agent may be better suited for targeting hematological malignancies. Taken together, our results suggest that inhibition of mitochondrial metabolism by Metformin or Phenformin is associated with increased leukemia cell susceptibility to induction of intrinsic apoptosis, and provide a rationale for clinical studies exploring the efficacy of combining biguanides with the orally bioavailable derivative of ABT-737, Venetoclax.
Assuntos
Apoptose/efeitos dos fármacos , Biguanidas/farmacologia , Compostos de Bifenilo/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transporte de Elétrons/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Nitrofenóis/farmacologia , Sulfonamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Metformina/farmacologia , Mitocôndrias/metabolismo , Fenformin/farmacologia , Piperazinas/farmacologia , Rotenona/farmacologia , Células U937RESUMO
Early-life adversity can lead to long-term consequence persisting into adulthood. Here, we assess the implications of an adverse early environment on vulnerability to stress during adulthood. We hypothesized that the interplay between early and late stress would result in a differential phenotype regarding the number of neurons immunoreactive for glucocorticoid receptor (GR-ir) and neuronal activity as assessed by Fos immunoreactivity (Fos-ir) in brain areas related to stress responses and anxiety-like behavior. We also expected that the antidepressant tianeptine could correct some of the alterations induced in our model. Male Wistar rats were subjected to daily maternal separation (MS) for 4.5 h during the first 3 weeks of life. As adults, the rats were exposed to chronic stress for 24 d and they were treated daily with tianeptine (10 mg/kg intraperitoneal) or vehicle (isotonic saline). Fos-ir was increased by MS in all structures analyzed. Chronic stress reduced Fos-ir in the hippocampus, but increased it in the paraventricular nucleus. Furthermore, chronic stress increased GR-ir in hippocampus (CA1) and amygdala in control non-MS rats. By contrast, when MS and chronic stress were combined, GR-ir was decreased in these structures. Additionally, whereas tianeptine did not affect Fos-ir, it regulated GR-ir in a region-dependent manner, in hippocampus and amygdala opposing in some cases the stress or MS effects. Furthermore, tianeptine reversed the MS- or stress-induced anxious behavior. The interplay between MS and chronic stress observed indicates that MS rats have a modified phenotype, which is expressed when they are challenged by stress in later life.