RESUMEN
Three outbreaks of herpesvirus meningoencephalitis in cattle have been reported in three municipalities in the northern region of the State of Tocantins, Brazil. In one outbreak, 41 predominantly young bovines were affected, with 2-3 deaths in some cases. The animals showed neurological signs of incoordination, blindness, and recumbency, with death occurring within approximately 4-5 d. At necropsy, hyperemia and leptomeningeal hemorrhages were observed in the brain. Histology revealed more intense lesions in the rostral portions of the brain, mainly affecting the frontoparietal cerebral cortex, with nonsuppurative encephalitis and meningitis, glial nodules, neuronophagia, and eosinophilic intranuclear inclusion bodies in the astrocytes and neurons. This study shows the presence of bovine herpesvirus in Tocantins, probably the highly neurotropic type 5 strain, and emphasizes its importance in the differential diagnosis of bovine neuropathies.
Três surtos de meningoencefalite por herpesvírus em bovinos são relatados em três municípios da região norte do Estado do Tocantins, Brasil. Num surto, 41 animais predominantemente jovens foram afetados, com 2-3 mortes nos outros casos. Os animais apresentaram sinais neurológicos de incoordenação, cegueira e decúbito, com a morte ocorrendo em aproximadamente 4 a 5 dias. Na necropsia foram observadas hiperemia e hemorragias leptomeníngeas no encéfalo. A histologia revelou lesões mais intensas nas porções rostrais do encéfalo, principalmente no córtex cerebral frontoparietal, com encefalite e meningite não supurativas, nódulos gliais, neuronofagia e corpúsculos de inclusão intranucleares eosinofílicos nos astrócitos e neurônios. Este estudo demonstra a presença do herpesvírus bovino no Tocantins, provavelmente a cepa tipo 5 altamente neurotrópica, e enfatiza sua importância no diagnóstico diferencial das neuropatias bovinas.
RESUMEN
At present, thiamine deficiency (TD) is managed with administration of high doses of thiamine. Even so, severe and permanent neurological disorders can occur in recurrent episodes of TD. In this study, we used a murine model to assess the efficacy of TD recovery treatments using thiamine with or without additional administration of the antioxidant Trolox or the anti-inflammatory dimethyl sulfoxide (DMSO) after a single or recurrent episode of TD. TD was induced for 9 days with deficient chow and pyrithiamine, and the recovery period was 7 days with standard amounts of chow and thiamine, Trolox, and/or DMSO. After these periods, we evaluated behavior, histopathology, and ERK1/2 modulation in the brain. Deficient animals showed reductions in locomotor activity, motor coordination, and spatial memory. Morphologically, after a single episode of TD and recovery, deficient mice showed neuronal vacuolization in the dorsal thalamus and, after two episodes, a reduction in neuronal cell number. These effects were attenuated or reversed by the recovery treatments, mainly in the treatments with thiamine associated with Trolox or DMSO. Deficient animals showed a strong increase in ERK1/2 phosphorylation in the thalamus, hippocampus, and cerebral cortex after one deficiency episode and recovery. Interestingly, after recurrent TD and recovery, ERK1/2 phosphorylation remained high only in the deficient mice treated with thiamine and/or Trolox or thiamine with DMSO. Our data suggest that a protocol for TD treatment with thiamine in conjunction with Trolox or DMSO enhances the recovery of animals and possibly minimizes the late neurological sequelae.
Asunto(s)
Cromanos/farmacología , Dimetilsulfóxido/farmacología , Deficiencia de Tiamina/tratamiento farmacológico , Tiamina/administración & dosificación , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Conducta Animal/efectos de los fármacos , Cromanos/administración & dosificación , Dimetilsulfóxido/administración & dosificación , Modelos Animales de Enfermedad , Locomoción/efectos de los fármacos , Masculino , Ratones , Recurrencia , Memoria Espacial/efectos de los fármacosRESUMEN
Thiamine deficiency (TD) produces severe neurodegenerative lesions. Studies have suggested that primary neurodegenerative events are associated with both oxidative stress and inflammation. Very little is known about the downstream effects on intracellular signaling pathways involved in neuronal death. The primary aim of this work was to evaluate the modulation of p38MAPK and the expression of heme oxygenase 1 (HO-1) in the central nervous system (CNS). Behavioral, metabolic, and morphological parameters were assessed. Mice were separated into six groups: control (Cont), TD with pyrithiamine (Ptd), TD with pyrithiamine and Trolox (Ptd + Tr), TD with pyrithiamine and dimethyl sulfoxide (Ptd + Dmso), Trolox (Tr) and DMSO (Dmso) control groups and treated for 9 days. Control groups received standard feed (AIN-93M), while TD groups received thiamine deficient feed (AIN-93DT). All the groups were subjected to behavioral tests, and CNS samples were collected for cell viability, histopathology and western blot analyses. The Ptd group showed a reduction in weight gain and feed intake, as well as a reduction in locomotor, grooming, and motor coordination activities. Also, Ptd group showed a robust increase in p38MAPK phosphorylation and mild HO-1 expression in the cerebral cortex and thalamus. The Ptd group showed a decreased cell viability, hemorrhage, spongiosis, and astrocytic swelling in the thalamus. Groups treated with Trolox and DMSO displayed diminished p38MAPK phosphorylation in both the structures, as well as attenuated thalamic lesions and behavioral activities. These data suggest that p38MAPK and HO-1 are involved in the TD-induced neurodegeneration in vivo, possibly modulated by oxidative stress and neuroinflammation.
Asunto(s)
Encéfalo/metabolismo , Hemo-Oxigenasa 1/metabolismo , Proteínas de la Membrana/metabolismo , Deficiencia de Tiamina/fisiopatología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Conducta Animal/fisiología , Peso Corporal/fisiología , Encéfalo/patología , Supervivencia Celular/fisiología , Cromanos/farmacología , Dimetilsulfóxido/farmacología , Ingestión de Alimentos/fisiología , Inflamación/etiología , Inflamación/fisiopatología , Masculino , Ratones , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/fisiología , Piritiamina , Deficiencia de Tiamina/inducido químicamente , Deficiencia de Tiamina/complicaciones , Deficiencia de Tiamina/patologíaRESUMEN
The molecular mechanisms mediating manganese (Mn)-induced neurotoxicity, particularly in the immature central nervous system, have yet to be completely understood. In this study, we investigated whether mitogen-activated protein kinases (MAPKs) and tyrosine hydroxylase (TH) could represent potential targets of Mn in striatal and hippocampal slices obtained from immature rats (14 days old). The aim of this study was to evaluate if the MAPK pathways are modulated after subtoxic Mn exposure, which do not significantly affect cell viability. The concentrations of manganese chloride (MnCl2; 10-1,000 µM) caused no change in cell viability in slices exposed for 3 or 6 hours. However, Mn exposure significantly increased extracellular signal-regulated kinase (ERK) 1/2, as well as c-Jun N-terminal kinase (JNK) 1/2/3 phosphorylation at both 3 and 6 hours incubations, in both brain structures. Furthermore, Mn exposure did not change the total content or phosphorylation of TH at the serine 40 site in striatal slices. Thus, Mn at concentrations that do not disrupt cell viability causes activation of MAPKs (ERK1/2 and JNK1/2/3) in immature hippocampal and striatal slices. These findings suggest that altered intracellular MAPKs signaling pathways may represent an early event concerning the effects of Mn in the immature brain.
Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Manganeso/toxicidad , Quinasas de Proteína Quinasa Activadas por Mitógenos/biosíntesis , Transducción de Señal , Animales , Mapeo Encefálico , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , RatasRESUMEN
The pilocarpine model in rodents reproduces the main features of mesial temporal lobe epilepsy related to hippocampus sclerosis (MTLE-HS) in humans. It has been demonstrated in this model that the phosphorylation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR1 subunit is increased 1 h after pilocarpine treatment. Moreover, alterations in the levels of glutamate transporters have been associated with chronic epilepsy in humans. Despite these studies, the profile of these changes has not yet been addressed. We analyzed the protein content and phosphorylation profile of the AMPA receptor GluR1 subunit by western blotting. We also used quantitative real-time polymerase chain reaction to analyze the expression of glial glutamate transporters and the N-methyl-D-aspartate receptor NR1 subunit in the hippocampus (Hip) and cerebral cortex (Ctx) at different time points after pilocarpine-induced status epilepticus (Pilo-SE) in male adult Wistar rats. Biochemical analysis was performed in the Hip and Ctx at 1, 3, 12 h (acute period), 5 days (latent period), and 50 days (chronic period) after Pilo-SE. Key findings include an increase in the phosphorylation of GluR1-Ser(845) in the Ctx and GluR1-Ser(831) in the Hip at different times during the acute period, and a decrease in the total content of the GluR1 subunit in the Ctx in the latent period. There was a down-regulation of the mRNA expression and protein levels of EAAT1 and EAAT2, and a decrease of the NR1 mRNA expression, in the Ctx during the latent period. Notably, during the chronic period, the EAAT2 mRNA expression and protein levels decreased while the NR1 mRNA levels increased in the Hip. Taken together, our findings suggest a time- and structure-dependent imbalance of glutamatergic transmission in response to Pilo-SE, which might be associated with either epileptogenesis or the seizure threshold in MTLE-HS.
Asunto(s)
Epilepsia del Lóbulo Temporal/metabolismo , Transportador 1 de Aminoácidos Excitadores/biosíntesis , Transportador 2 de Aminoácidos Excitadores/biosíntesis , Neuroglía/metabolismo , Receptores AMPA/biosíntesis , Receptores de N-Metil-D-Aspartato/biosíntesis , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/genética , Transportador 1 de Aminoácidos Excitadores/genética , Transportador 2 de Aminoácidos Excitadores/genética , Regulación de la Expresión Génica , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Pilocarpina/toxicidad , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Wistar , Receptores AMPA/genética , Receptores de N-Metil-D-Aspartato/genética , Factores de TiempoRESUMEN
The epileptogenesis may involve a variety of signaling events that culminate with synaptic reorganization. Mitogen-activated protein kinases (MAPKs) and AKT may be activated by diverse stimulus including neurotransmitter, oxidative stress, growth factors and cytokines and are involved in synaptic plasticity in the hippocampus and cerebral cortex. The pilocarpine model in rodents reproduces the main features of mesial temporal lobe epilepsy related to hippocampus sclerosis (MTLE-HS) in humans. We analyze the phosphorylation profile of MAPKs (ERK1/2, p38(MAPK), JNK1/2/3) and AKT by western blotting in the hippocampus (Hip) and cortex (Ctx) of male adult wistar rats in different periods, after pilocarpine induced status epilepticus (Pilo-SE) and compared with control animals. Biochemical analysis were done in the Hip and Ctx at 1, 3, 12 h (acute period), 5 days (latent period) and 50 days (chronic period) after Pilo-SE onset. Hence, the main findings include increased phosphorylation of ERK1 and p38(MAPK) in the Hip and Ctx 1 and 12 h after the Pilo-SE onset. The JNK2/3 isoform (54 kDa) phosphorylation was decreased at 3 h after the Pilo-SE onset and in the chronic period in the Hip and Ctx. The AKT phosphorylation increased only in the Hip during the latent period. Our study demonstrates, in a systematic manner, the profile of MAPKs and AKT modulation in the hippocampus and cerebral cortex in response to pilocarpine. Based in the role of each signaling enzyme is possible that these changes may be related, at least partially, to modifications in the intrinsic neuronal physiology and epileptogenic synaptic network that appears in the MTLE-HS.