RESUMO
BACKGROUND: Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation (WBI) in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are highly connected to the hypothalamus and its regulatory processes. METHODS: Male Wistar rats were exposed to WBI with 11 Gy (Biologically Effective Dose = 72 Gy). After 1 month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, and glutamine in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann-Whitney U test (p < 0.05). RESULTS: WBI with 11 Gy induced significantly lower levels of GABA, glycine, taurine, aspartate, and GABAa receptor in the hypothalamus. Also, in the hypothalamus, a higher Glutamate/GABA ratio was found after irradiation. In the prefrontal cortex, WBI induced significant increases of glutamine and glutamate, Glutamine/Glutamate ratio, and increased expression of both GABAa receptor and NMDA receptor NR1 subunit. The brainstem showed no statistically significant changes after irradiation. CONCLUSION: Our findings confirm that WBI can affect rat brain regions differently and opens new avenues for study. After 1 month, WBI decreases inhibitory neurotransmitters and receptors in the hypothalamus and, conversely, increases excitatory neurotransmitters and receptors in the prefrontal cortex. Increments in Glutamate/GABA in the hypothalamus and Glutamine/Glutamate in the frontal cortex indicate a neurochemical imbalance. Found changes could be related to several reported radiotherapy secondary effects, suggesting new prospects for therapeutic targets.
Assuntos
Irradiação Craniana , Hipotálamo/efeitos da radiação , Neurotransmissores/análise , Córtex Pré-Frontal/efeitos da radiação , Receptores de GABA/análise , Receptores de N-Metil-D-Aspartato/análise , Animais , Química Encefálica/efeitos da radiação , Hipotálamo/química , Masculino , Córtex Pré-Frontal/química , Ratos , Ratos WistarRESUMO
Safe exposure to a context that was previously associated with threat leads to extinction of defensive responses. Such contextual fear extinction involves the formation of a new memory that inhibits a previously acquired contextual fear memory. However, fear-related responses often return with the simple passage of time (spontaneous fear recovery). Given that contextual fear and extinction memories are hippocampus-dependent and hippocampal neurogenesis has been reported to modify preexisting memories, we hypothesized that neurogenesis-mediated modification of preexisting extinction memory would modify spontaneous fear recovery. To test this, rats underwent contextual fear conditioning followed by extinction. Subsequently, we exposed rats to an enriched environment or focal X-irradiation to enhance or ablate hippocampal neurogenesis, respectively. Over a month later, rats were tested to evaluate spontaneous fear recovery. We found that enhancing neurogenesis after, but not before, extinction prevented fear recovery. In contrast, neurogenesis ablation after, but not before, extinction promoted fear recovery. Using the neuronal activity marker c-Fos, we identified brain regions recruited in these opposing neurogenesis-mediated changes during fear recovery. Together, our findings indicate that neurogenesis manipulation after extinction learning modifies fear recovery by recruiting brain network activity that mediates the expression of preexisting contextual fear and extinction memories.
Assuntos
Condicionamento Psicológico/fisiologia , Extinção Psicológica/fisiologia , Hipocampo/crescimento & desenvolvimento , Memória/fisiologia , Neurogênese/fisiologia , Animais , Comportamento Animal/fisiologia , Medo/fisiologia , Masculino , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos WistarRESUMO
It has been widely described that chronic intake of fructose causes metabolic alterations which can be associated with brain function impairment. In this study, we evaluated the effects of fructose intake on the sleepâ»wake cycle, locomotion, and neurochemical parameters in Wistar rats. The experimental group was fed with 10% fructose in drinking water for five weeks. After treatment, metabolic indicators were quantified in blood. Electroencephalographic recordings were used to evaluate the sleep architecture and the spectral power of frequency bands. Likewise, the locomotor activity and the concentrations of orexin A and monoamines were estimated. Our results show that fructose diet significantly increased the blood levels of glucose, cholesterol, and triglycerides. Fructose modified the sleepâ»wake cycle of rats, increasing the waking duration and conversely decreasing the non-rapid eye movement sleep. Furthermore, these effects were accompanied by increases of the spectral power at different frequency bands. Chronic consumption of fructose caused a slight increase in the locomotor activity as well as an increase of orexin A and dopamine levels in the hypothalamus and brainstem. Specifically, immunoreactivity for orexin A was increased in the ventral tegmental area after the intake of fructose. Our study suggests that fructose induces metabolic changes and stimulates the activity of orexinergic and dopaminergic neurons, which may be responsible for alterations of the sleepâ»wake cycle.
Assuntos
Encéfalo/efeitos dos fármacos , Açúcares da Dieta/farmacologia , Dopamina/metabolismo , Comportamento Alimentar , Frutose/farmacologia , Orexinas/metabolismo , Sono/efeitos dos fármacos , Animais , Glicemia/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/metabolismo , Dieta , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Lipídeos/sangue , Locomoção/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Ratos Wistar , Fases do Sono/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo , Vigília/efeitos dos fármacosRESUMO
Objective Quinine (QUIN) and carbenoxolone (CNX) elicit anticonvulsant effects typically characterized by the reduction of the epileptiform activity as well as changes in behavioral parameters related to seizures. Therefore, the aim of this study was to analyze the effects of these molecules on the anticonvulsant activity of some classical antiepileptic drugs. Methods Male Wistar rats were used. Valproate (VPA), phenytoin (PHT), or carbamazepine (CBZ) was administered at sub-therapeutic doses for intraperitoneal via. Subsequently, animals were administered with a single dose of QUIN or CNX. The anticonvulsant activity was evaluated with the maximal electroshock (MES) test and pentylenetetrazole (PTZ) administration. Additionally, the plasma levels of CBZ were determined using an HPLC method. Results All the control rats presented generalized tonic-clonic seizures after the MES test or the administration of PTZ. For the MES test, all of the antiepileptic drugs increased their anticonvulsant activity when were co-administered with QUIN. For the PTZ test, only the combination CBZ plus QUIN significantly increased the percentage of protection against the generalized tonic-clonic seizures. The co-administration of CBZ plus QUIN resulted in an augmented concentration of CBZ in plasma. Discussion The present study shows that QUIN and CNX enhance the anticonvulsant activity of some classical antiepileptic drugs. However, only the combination CBZ/QUIN had significant effects on both MES and PTZ models. Such anticonvulsant activity could be attributed to increased levels of CBZ in plasma. We propose that these molecules could improve the pharmacological actions of antiepileptic drugs administered at sub-therapeutic doses.
Assuntos
Anticonvulsivantes/uso terapêutico , Carbenoxolona/uso terapêutico , Epilepsia/tratamento farmacológico , Quinina/uso terapêutico , Animais , Carbenoxolona/sangue , Convulsivantes/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Eletrochoque/efeitos adversos , Epilepsia/etiologia , Masculino , Pentilenotetrazol/toxicidade , Ratos , Ratos WistarRESUMO
Pontine reticular formation (PRF) is involved in the generation and maintenance of generalized epileptic seizures. Carbenoxolone (CBX) is a gap junction blocker with anticonvulsant properties. Therefore, the present study was designed to explore the effects of CBX microinjected into the pontis caudalis nucleus (PnC) on generalized tonic-clonic seizures (GTCS) and epileptiform activity induced by pentylenetetrazole (PTZ). All control rats presented GTCS after a single dose of PTZ. The microinjection of CBX into the PnC reduced the GTCS incidence induced by PTZ. Moreover, the CBX significantly increased the latency to the first myoclonic jerk. Additionally, CBX significantly decreased the spectral power and the amplitude of the epileptiform activity induced by PTZ. By contrast, the microinjection of a gap junction opener (trimethylamine) did not cause anticonvulsant effects and even increased the duration of the GTCS. These findings suggest that the PnC is a particular nucleus where the CBX could exert its action mechanisms and elicit anticonvulsant effects.
Assuntos
Anticonvulsivantes/farmacologia , Carbenoxolona/farmacologia , Epilepsia/fisiopatologia , Pentilenotetrazol , Tegmento Pontino/efeitos dos fármacos , Animais , Anticonvulsivantes/uso terapêutico , Carbenoxolona/uso terapêutico , Epilepsia/induzido quimicamente , Masculino , Microinjeções , Tegmento Pontino/fisiopatologia , Ratos Wistar , Convulsões/fisiopatologiaRESUMO
BACKGROUND: Mefloquine can cross the blood-brain barrier and block the gap junction intercellular communication in the brain. Enhanced electrical coupling mediated by gap junctions is an underlying mechanism involved in the generation and maintenance of seizures. For this reason, the aim of this study was to analyze the effects of the systemic administration of mefloquine on tonic-clonic seizures induced by two acute models such as pentylenetetrazole and maximal electroshock. RESULTS: All the control rats presented generalized tonic-clonic seizures after the administration of pentylenetetrazole. However, the incidence of seizures induced by pentylenetetrazole significantly decreased in the groups administered systematically with 40 and 80 mg/kg of mefloquine. In the control group, none of the rats survived after the generalized tonic-clonic seizures induced by pentylenetetrazole, but survival was improved by mefloquine. Besides, mefloquine significantly modified the total spectral power as well as the duration, amplitude and frequency of the epileptiform activity induced by pentylenetetrazole. For the maximal electroshock model, mefloquine did not change the occurrence of tonic hindlimb extension. However, this gap junction blocker significantly decreased the duration of the tonic hindlimb extension induced by the acute electroshock. CONCLUSIONS: These data suggest that mefloquine at low doses might be eliciting some anticonvulsant effects when is systemically administered to rats.
Assuntos
Anticonvulsivantes/farmacologia , Mefloquina/farmacologia , Convulsões/tratamento farmacológico , Doença Aguda , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletrodos Implantados , Eletroencefalografia , Eletrochoque , Membro Posterior/efeitos dos fármacos , Membro Posterior/fisiopatologia , Masculino , Pentilenotetrazol , Distribuição Aleatória , Ratos , Ratos Wistar , Convulsões/fisiopatologia , Análise de SobrevidaRESUMO
A CVD based radiation detector has recently become commercially available from the manufacturer PTW-Freiburg (Germany). This detector has a sensitive volume of 0.004 mm(3), a nominal sensitivity of 1 nC Gy(-1) and operates at 0 V. Unlike natural diamond based detectors, the CVD diamond detector reports a low dose rate dependence. The dosimetric properties investigated in this work were dose rate, angular dependence and detector sensitivity and linearity. Also, percentage depth dose, off-axis dose profiles and total scatter ratios were measured and compared against equivalent measurements performed with a stereotactic diode. A Monte Carlo simulation was carried out to estimate the CVD small beam correction factors for a 6 MV photon beam. The small beam correction factors were compared with those obtained from stereotactic diode and ionization chambers in the same irradiation conditions The experimental measurements were performed in 6 and 15 MV photon beams with the following square field sizes: 10 × 10, 5 × 5, 4 × 4, 3 × 3, 2 × 2, 1.5 × 1.5, 1 × 1 and 0.5 × 0.5 cm. The CVD detector showed an excellent signal stability (<0.2%) and linearity, negligible dose rate dependence (<0.2%) and lower response angular dependence. The percentage depth dose and off-axis dose profiles measurements were comparable (within 1%) to the measurements performed with ionization chamber and diode in both conventional and small radiotherapy beams. For the 0.5 × 0.5 cm, the measurements performed with the CVD detector showed a partial volume effect for all the dosimetric quantities measured. The Monte Carlo simulation showed that the small beam correction factors were close to unity (within 1.0%) for field sizes ≥1 cm. The synthetic diamond detector had high linearity, low angular and negligible dose rate dependence, and its response was energy independent within 1% for field sizes from 1.0 to 5.0 cm. This work provides new data showing the performance of the CVD detector compared against a high spatial resolution diode. It also presents a comparison of the CVD small beam correction factors with those of diode and ionization chamber for a 6 MV photon beam.
Assuntos
Diamante/análise , Diamante/química , Fótons/uso terapêutico , Radiometria/instrumentação , Radiometria/métodos , Radioterapia/instrumentação , Radioterapia/métodos , Humanos , Método de Monte Carlo , Aceleradores de PartículasRESUMO
BACKGROUND AND AIMS: HIV-1 viral load is used to monitor AIDS progression and effect of antiretroviral therapy (ART). Several reports have indicated that the HIV-1 viral load of infected individuals is lower in females than in males. There are no reports exploring this issue in the Mexican population. We analyzed the relationship between sex and viral load in Mexican patients differing in CD4 T-cell count, age and treatment status. METHODS: A retrospective study was performed in 3949 male and 696 female HIV-1-infected individuals. Statistical distributions were compared using the Mann-Whitney U nonparametric test. RESULTS: Among the antiretroviral-untreated group, females had a significantly lower viral load than males (0.52 female/male median viral load ratio, p = 0.008). When classified according to different ranges of CD4⺠T cell counts, females had consistently lower viral loads than males, although statistical significance was achieved only for the group in the range of 201-350 (p = 0.014). Patients with the lowest CD4⺠T-cell counts showed similar viral loads for both sexes. No differences were observed in the ART group. CONCLUSIONS: This study demonstrates a baseline difference in viral load between male and female ART-untreated Mexican patients. The overall tendency indicating a lower viral load in females in the same ranges of CD4⺠T-cell counts than males, suggests that the lower viral load in females is not indicative of a lower risk of developing AIDS. These observations suggest a significant influence of sex on viral dynamics and immune response despite variations in demographic factors.
Assuntos
Infecções por HIV/virologia , HIV-1/fisiologia , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Estudos Transversais , Progressão da Doença , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Sexuais , Carga ViralRESUMO
Neuronal activity in the central nervous system undergoes a variety of electrophysiological changes along the sleep-wake cycle. These changes are modulated by a complex interaction between different neurochemical systems located throughout the brain. Within brainstem and hypothalamus there are a number of neuronal populations that promote wakefulness through the action of different neurotransmitters like noradrenaline, serotonin, histamine and orexin. These systems act together in the generation and maintenance of wakefulness, however although each one contributes in a unique way no neurotransmitter seems to be absolutely necessary because wakefulness is not completely inhibited in the absence of any of them. On the other hand, neurons located in the hypothalamus and brainstem are involved in initiating and maintaining sleep. These neurons contain neurotransmitters such as acetylcholine and GABA and have projections to nuclei involved in wakefulness regulation. Recently, models have been proposed suggesting that sleep is modulated by flip-flop switches which are characterized by neuronal circuits with different neurotransmitters and that interacting to regulate the initiation and maintenance of the different stages of sleep wake cycle. This review is based on pharmacological, electrophysiological and neurochemical studies with the aim of analyze the major neurotransmitters and the cerebral regions involved in the regulation of wakefulness and different states of sleep.