RESUMEN
Neurological impairments are frequently detected in children surviving cerebral malaria (CM), the most severe neurological complication of infection with Plasmodium falciparum. The pathophysiology and therapy of long lasting cognitive deficits in malaria patients after treatment of the parasitic disease is a critical area of investigation. In the present study we used several models of experimental malaria with differential features to investigate persistent cognitive damage after rescue treatment. Infection of C57BL/6 and Swiss (SW) mice with Plasmodium berghei ANKA (PbA) or a lethal strain of Plasmodium yoelii XL (PyXL), respectively, resulted in documented CM and sustained persistent cognitive damage detected by a battery of behavioral tests after cure of the acute parasitic disease with chloroquine therapy. Strikingly, cognitive impairment was still present 30 days after the initial infection. In contrast, BALB/c mice infected with PbA, C57BL6 infected with Plasmodium chabaudi chabaudi and SW infected with non lethal Plasmodium yoelii NXL (PyNXL) did not develop signs of CM, were cured of the acute parasitic infection by chloroquine, and showed no persistent cognitive impairment. Reactive oxygen species have been reported to mediate neurological injury in CM. Increased production of malondialdehyde (MDA) and conjugated dienes was detected in the brains of PbA-infected C57BL/6 mice with CM, indicating high oxidative stress. Treatment of PbA-infected C57BL/6 mice with additive antioxidants together with chloroquine at the first signs of CM prevented the development of persistent cognitive damage. These studies provide new insights into the natural history of cognitive dysfunction after rescue therapy for CM that may have clinical relevance, and may also be relevant to cerebral sequelae of sepsis and other disorders.
Asunto(s)
Trastornos del Conocimiento/patología , Trastornos del Conocimiento/prevención & control , Malaria Cerebral/complicaciones , Malaria Cerebral/parasitología , Plasmodium berghei/efectos de los fármacos , Plasmodium yoelii/efectos de los fármacos , Animales , Antimaláricos/uso terapéutico , Antioxidantes/uso terapéutico , Conducta Animal , Combinación de Medicamentos , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Parasitemia/patología , Parasitemia/prevención & control , Especies Reactivas de Oxígeno/metabolismo , Tasa de SupervivenciaRESUMEN
UNLABELLED: Rezin GT, Gonçalves CL, Daufenbach JF, Carvalho-Silva M, Borges LS, Vieira JS, Hermani FV, Comim CM, Quevedo J, Streck EL. Effect of chronic administration of ketamine on the mitochondrial respiratory chain activity caused by chronic mild stress. OBJECTIVE: Recently, we reported that mitochondrial respiratory chain complexes I, III and IV were inhibited in the cerebral cortex and cerebellum of rats submitted to chronic mild stress (CMS) and that acute ketamine administration reversed this effect. Therefore, we investigated whether the inhibition of these enzymes may be reversed by chronic administration of ketamine. METHODS: Adult male Wistar rats were submitted to CMS and chronically treated with ketamine. After 40 days of CMS, consumption of sweet food, adrenal gland weight, body weight and enzymatic activity of the complexes were measured. RESULTS: We verified that CMS decreased the intake of sweet food, increased the adrenal gland weight and the control group gained weight after 40 days but the stressed group did not; ketamine administration reversed these effects. We also verified that chronic administration of ketamine reversed the inhibition of complexes I, III and IV in cerebral cortex. However, in cerebellum, only complex IV inhibition was reversed. The chronic ketamine administration partially reverses the inhibition caused by CMS. CONCLUSION: We hypothesise that CMS inhibits complexes I, III and IV activities and that chronic administration of ketamine administration partially reverses such an effect. Therefore, it seems reasonable to propose that ketamine administration might be a useful therapy for patients affected by major depression.
RESUMEN
Oxidative stress plays an important role in the development of cognitive impairment in sepsis. Here we assess the effects of acute and extended administration of cannabidiol (CBD) on oxidative stress parameters in peripheral organs and in the brain, cognitive impairment, and mortality in rats submitted to sepsis by cecal ligation and perforation (CLP). To this aim, male Wistar rats underwent either sham operation or CLP. Rats subjected to CLP were treated by intraperitoneal injection with "basic support" and CBD (at 2.5, 5, or 10mg/kg once or daily for 9days after CLP) or vehicle. Six hours after CLP (early times), the rats were killed and samples from lung, liver, kidney, heart, spleen, and brain (hippocampus, striatum, and cortex) were obtained and assayed for thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. On the 10th day (late times), the rats were submitted to the inhibitory avoidance task. After the test, the animals were killed and samples from lung, liver, kidney, heart, spleen, and brain (hippocampus) were obtained and assayed for TBARS formation and protein carbonyls. The acute and extended administration of CBD at different doses reduced TBARS and carbonyl levels in some organs and had no effects in others, ameliorated cognitive impairment, and significantly reduced mortality in rats submitted to CLP. Our data provide the first experimental demonstration that CBD reduces the consequences of sepsis induced by CLP in rats, by decreasing oxidative stress in peripheral organs and in the brain, improving impaired cognitive function, and decreasing mortality.
Asunto(s)
Cannabidiol/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Sepsis/complicaciones , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/etiología , Análisis de Varianza , Animales , Reacción de Prevención/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ciego/lesiones , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Carbonilación Proteica/efectos de los fármacos , Punciones/efectos adversos , Ratas , Ratas Wistar , Sepsis/etiología , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Factores de TiempoRESUMEN
Modulation and dysfunction of the glutamatergic system seems to be involved in depression. Recently a renewed interest in the glutamatergic system as a treatment option for major depression emerged by the finding that the glutamate N-methyl-D-aspartate (NMDA) antagonist ketamine leads to a rapid improvement of depressive symptoms. Several works support the hypothesis that metabolism impairment is involved in the pathophysiology of depression. We have also recently reported that mitochondrial respiratory chain complexes I, III and IV were inhibited in cerebral cortex and cerebellum of rats after 40 days of chronic mild stress (CMS), which is used as an animal model of depression. Thus, we investigated whether the inhibition of these enzymes may be reversed by acute administration of ketamine (15 mg/kg). We verified that CMS decreased the intake of sweet food and ketamine was not able to reverse such effect. Adrenal gland weight was increased in stressed rats and ketamine reversed this alteration. Control group gained weight after 40 days but stressed group did not gain weight after the same period. Stressed animals gained weight after acute administration of ketamine, when compared to the body weight assessed at the beginning of the experiment. Finally, we verified that complexes I, III and IV were inhibited after CMS in cerebral cortex and cerebellum and acute administration of ketamine reversed this inhibition. Based on the present findings, we hypothesized that CMS induces inhibition of mitochondrial respiratory chain (complexes I, III and IV) and that acute administration of ketamine reverses such effect.