RESUMO
Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by progressive dopaminergic neuron loss. Animal models have been used to develop a better understanding of the pathophysiologic mechanisms of PD. However, these models are usually conducted with young animals diverging of the age of PD patients, suggesting a bias in translational science. Thus, the aim of the study was to evaluate the effect of the age on rats in a progressive parkinsonism model induced by reserpine (RES). Adult (6 - 8 month-old) or elderly (18 - 24 month-old) male rats were assigned to six groups: control-elderly (CTL-ELDERLY), reserpine-elderly (RES-ELDERLY), reserpine-elderly withdrawal (RES-ELDERLY WITHDRAWAL), control-adult (CTL-ADULT), reserpine-adult (RES-ADULT), and reserpine-adult withdrawal (RES-ADULT WITHDRAWAL). Animals received 15 injections every other day of RES (0.1 mg / kg) or vehicle during 30 days. Throughout treatment, animals were evaluated in the catalepsy test (every 48 h) and open field test (24 h after the second injection), and weight assessment (every 4 days) was also made. Upon completion of behavioral tests, rat brains were collected for tyrosine hydroxylase (TH) immunohistochemical analysis. Main results demonstrated that RES-treated animals spent more time in the catalepsy bar compared with control groups, moreover the RES-elderly group showed a longer catalepsy time compared with the RES-ADULT group. A shorter time from RES treatment to the development of symptoms was observed in the RES-ADULT group, compared with the RES-ELDERLY group. In addition, RES-induced weight loss in both RES-ELDERLY and RES-ADULT when compared with their corresponding controls. Cessation of RES treatment was followed by weight gain only in the RES-ADULT group. A significant decrease in TH-immunoreactive cells was observed in the substantia nigra pars compacta (SNpc) and dorsal striatum (STR) in the rats in both the RES-ADULT and RES-ELDERLY groups and in the ventral tegmental area in rats in the RES-ADULT group. Furthermore, TH immunoreactivity decrease was not reversible in SNpc and STR in the RES-ELDERLY. These results show that RES has an age-dependent effect in rats, suggesting a greater sensitivity of the dopaminergic pathway to RES with advancing age. These suggest that the RES rat model of parkinsonism can be useful in improving our knowledge on the effect of aging on neurodegeneration.
Assuntos
Transtornos Motores , Doença de Parkinson , Transtornos Parkinsonianos , Animais , Masculino , Ratos , Tirosina 3-Mono-Oxigenase/metabolismo , Reserpina/toxicidade , Catalepsia , Atividade Motora , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Dopamina/metabolismo , Envelhecimento , Substância Negra/metabolismo , Modelos Animais de DoençasRESUMO
Fear is an emotional reaction that arises in dangerous situations, inducing the adaptation to an existing condition. This behavior was conserved in all vertebrates throughout evolution and is observed in mammals, birds, fish, amphibians, and reptiles. The neurocircuitry of fear involves areas of the limbic system, cortical regions, midbrain, and brainstem. These areas communicate with each other so that there is an expression of fear and memory formation to deal with the same situation at another time. The effect of nitric oxide (NO) on fear modulation has been explored. NO is a gaseous compound that easily diffuses through the cell membrane and is produced through the oxidation reaction of l-Arginine to l-citrulline catalyzed by nitric oxide synthase (NOS). Activating the intracellular NO receptor (soluble guanylyl cyclase enzyme - sGC) triggers an enzymatic cascade that can culminate in plastic events in the neuron. NOS inhibitors induce anxiolytic-like responses in fear modulation, whereas NO donors promote fear- and anxiety-like behaviors. This review describes the neurobiology of fear in mammals and non-mammals, how NO is produced in the central nervous system, and how NO acts in fear-like behavior.
Assuntos
Guanilato Ciclase , Óxido Nítrico , Animais , Medo , Guanilato Ciclase/metabolismo , Mamíferos/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase , Guanilil Ciclase SolúvelRESUMO
Believed to cause damage to the nervous system and possibly being associated with neurodegenerative diseases, deltamethrin (DM) is a type II pyrethroid used in pest control, public health, home environment, and vector control. The objective of this study was to evaluate the motor, cognitive and emotional changes associated with dopaminergic and BDNF imbalance after DM exposure in rats. Sixty Wistar rats (9-10 months-old) were used, under Ethics Committee on Animal Research license (ID 19/2017). The animals were randomly divided into four groups: control (CTL, 0.9% saline), DM2 (2 mg DM in 1.6 mL 0.9% saline), DM4 (4 mg of DM in 1.6 mL of 0.9% saline), and DM8 (8 mg of DM in 1.6 mL of 0.9% saline). DM groups were submitted to 9 or 15 inhalations, one every 48 h. Half of the animals from each group were randomly selected and perfused 24 h after the 9th or 15th inhalation. Throughout the experiment, the animal's behavior were evaluated using catalepsy test, open field, hole-board test, Modified Elevated Plus Maze, and social interaction. At the end of the experiments, the rats were perfused transcardially and their brains were processed for Tyrosine Hydroxylase (TH) and Brain derived neurotrophic factor (BDNF) immunohistochemistries. The animals submitted to 9 inhalations of DM showed a reduction in immunoreactivity for TH in the Substantia nigra pars compacta (SNpc), ventral tegmental area (VTA), and dorsal striatum (DS) areas, and an increase in BDNF in the DS and CA1, CA3 and dentate gyrus (DG) hippocampal areas. Conversely, the animals submitted to 15 inhalations of DM showed immunoreactivity reduced for TH in the SNpc and VTA, and an increase in BDNF in the hippocampal areas (CA3 and DG). Our results indicate that the DM inhalation at different periods induce motor and cognitive impairments in rats. Such alterations were accompanied by dopaminergic system damage and a possible dysfunction on synaptic plasticity.
Assuntos
Ansiedade/induzido quimicamente , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Inseticidas/farmacologia , Transtornos da Memória/induzido quimicamente , Atividade Motora/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Nitrilas/farmacologia , Piretrinas/farmacologia , Tirosina 3-Mono-Oxigenase/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/metabolismo , Exposição por Inalação , Inseticidas/administração & dosagem , Nitrilas/administração & dosagem , Piretrinas/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Wistar , Comportamento SocialRESUMO
Nociception alterations are frequent non-motor symptoms of the prodromal phase of Parkinson's disease (PD). The period for the onset of symptoms and the pathophysiological mechanisms underlying these alterations remain unclear. We investigated the course of nociception alterations in a progressive model of parkinsonism induced by reserpine (RES) in rats. Male Wistar rats (6-7 months) received 5 or 10 subcutaneous injections of RES (0.1 mg/kg) or vehicle daily for 20 days. Motor evaluation and nociceptive assessment were performed throughout the treatment. At the end of the treatment rats were euthanized, the brains removed and processed for immunohistochemical analysis (TH and c-Fos). The RES-treated rats exhibited an increased nociceptive response to mechanical and chemical stimulation in the electronic von Frey and formalin tests, respectively. Moreover, these alterations preceded the motor impairment observed in the catalepsy test. In addition, the RES treatment reduced the TH-immunoreactivity in the ventral tegmental area (VTA) and increased the c-Fos expression in the ventral-lateral periaqueductal gray (vlPAG), rostral ventral medulla (RVM) and dorsal raphe nucleus (DRN) after noxious stimuli induced by formalin. Taken together, our results reinforce that nociceptive changes are one of the early signs of PD and monoamine depletion in basal ganglia can be involved in the abnormal processing of nociceptive information in PD.
Assuntos
Núcleo Dorsal da Rafe/metabolismo , Atividade Motora/fisiologia , Nociceptividade/fisiologia , Doença de Parkinson Secundária/fisiopatologia , Substância Cinzenta Periaquedutal/metabolismo , Área Tegmentar Ventral/metabolismo , Animais , Modelos Animais de Doenças , Núcleo Dorsal da Rafe/fisiopatologia , Masculino , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Substância Cinzenta Periaquedutal/fisiopatologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Reserpina , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/fisiopatologiaRESUMO
The purpose of the present study was to investigate balance alterations and the possible role of the cholinergic neurons in the pedunculopontine nucleus (PPN) in the early stages of a progressive animal model of Parkinson's disease (PD). Twenty-eight middle-aged (8-9 months) male Wistar rats received 4 or 10 subcutaneous vehicle (control, CTL) or reserpine (RES) injections (0.1 mg/kg). The animals were submitted to different behavioral tests. Forty-eight hours after the 4th injection, half of the animals of each group (n = 7) were perfused and submitted to immunohistochemical analysis for tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT). The remaining animals (n = 7 per group) were killed 48 h after the 10th injection. RES group presented motor deficits in the catalepsy and open field tests starting at days 12 and 20 of treatment, respectively (only for the animals that received 10 injections). On the other hand, dynamic and static balance changes were observed at earlier stages of RES treatment, starting at days 6 and 4, respectively. At this point of the treatment, there was no decrease in the number of TH immunoreactivity neurons in the substantia nigra pars compacta (SNpc), ventral tegmental area (VTA) and dorsal striatum (DS). However, a decrease was observed in SNpc and dorsal striatum of animals that received 10 injections. In contrast, there was a decrease in the number of ChAT immunoreactive cells in PPN concomitantly to the balance alterations at the early stages of treatment (after 4 RES injections). Thus, by mimicking the progressiveness of PD, the reserpine model made it possible to identify static and dynamic balance impairments prior to the motor alterations in the catalepsy and open field tests. In addition, changes in balance were accompanied by a reduction in the number of ChAT immunoreactive cells in NPP in the early stages of treatment.
Assuntos
Transtornos Parkinsonianos , Animais , Colina O-Acetiltransferase/metabolismo , Neurônios Colinérgicos/metabolismo , Masculino , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Ratos , Ratos Wistar , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Environmental enrichment (EE) has been used to investigate behavioral changes and neuroplasticity in brain in normal and pathological conditions. Besides, the EE has been used to understand the neurobehavioral systems involved in learning experiences, visual inputs, defensive responses, social interactions and memory. However, the required exposure duration to remove aversive memories remains lacking. Therefore, the purpose of the present study was to investigate the time-course effect of EE exposure on the extinction of aversive memory. Young adult male Wistar rats were exposed to two different EE protocols: short-term environmental enrichment (EE2 - animal kept under enriched conditions for two weeks) and long-term environmental enrichment (EE4 - animal kept under enriched conditions for four weeks). The contextual fear conditioning test was used to assess aversive memory. The both EE protocols provide changes in Zif-268 immunoreactivity in mesocorticolimbic areas such as CA1 and central amygdala; however, only short-term EE reduces the ZIF-268 immunoreactivity in VTA. Besides, both EE protocols also provide an increase in TH immunoreactivity in VTA and nucleus accumbens, but only the short-term EE modifies the TH immunoreactivity in CA1 and infralimbic region of the prefrontal cortex. The time-course effect of EE interferes differently on the extinction of aversive memory, being two weeks of exposure with EE sufficient to cause improvement in coping during aversive situations, favoring the extinction of conditioned fear memory.
Assuntos
Meio Ambiente , Extinção Psicológica/fisiologia , Memória/fisiologia , Animais , Região CA1 Hipocampal/fisiologia , Núcleo Central da Amígdala/fisiologia , Proteína 1 de Resposta de Crescimento Precoce/análise , Masculino , Núcleo Accumbens/fisiologia , Ratos Wistar , Área Tegmentar Ventral/fisiologiaRESUMO
Amyotrophic Lateral Sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper motor neurons (UMN) and lower motor neurons (LMN). Disease affects people all over the world and is more prevalent in men. Patients with ALS develop extensive muscle wasting, paralysis and ultimately death, with a median survival of usually fewer than five years after disease onset. ALS may be sporadic (sALS, 90%) or familial (fALS, 10%). The large majority of fALS cases are associated with genetic alterations, which are mainly related to the genes SOD1, TDP-43, FUS, and C9ORF72. In vitro and in vivo models have helped elucidate ALS etiology and pathogenesis, as well as its molecular, cellular, and physiological mechanisms. Many studies in cell cultures and animal models, such as Caenorhabditis elegans, Drosophila melanogaster, zebrafish, rodents, and non-human primates have been performed to clarify the relationship of these genes to ALS disease. However, there are inherent limitations to consider when using experimental models. In this review, we provide an updated overview of the most used in vitro and in vivo studies that have contributed to a better understanding of the different ALS pathogenic mechanisms.
Assuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Modelos Animais de Doenças , Neurônios Motores/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Humanos , Neurônios Motores/patologia , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismoRESUMO
Deltamethrin (DM) is widely used in agriculture, veterinary medicine and control of domestic pests. Epidemiological studies suggest that DM exposure is a risk factor for neurodegenerative disorders such as Parkinson's (PD) and Alzheimer diseases; however the mechanisms are elusive. In the present study we evaluated the effects of intracerebroventricular (i.c.v.) administration of DM on locomotion activity, spatial working memory and dopaminergic pathway in the rat. Middle-aged male Wistar rats received three i.c.v. injections of DM 0.5 µg, DM 5 µg or vehicle, every other day. Across the treatment, the animals were submitted to behavioral evaluation in the catalepsy test, open field test, and spontaneous alternation task. Following completion of behavioral tests, rats were perfused and their brains were processed to tyrosine hydroxylase (TH) immunohistochemistry. We observed that i.c.v. administration of DM 5 µg increased locomotion activity (open field) and caused spatial working memory impairment (spontaneous alternation task). These alterations were accompanied by reduction TH immunoreactivity in the substantia nigra pars compacta (SNpc), ventral tegmental area (VTA) and dorsal striatum. Conversely, no motor change was observed in the catalepsy test. These results indicate that i.c.v. administration of DM can cause hyperactivity and cognitive alteration which may be related to disruption of the dopaminergic pathway.
Assuntos
Atividade Motora/efeitos dos fármacos , Nitrilas/farmacologia , Piretrinas/farmacologia , Memória Espacial/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Infusões Intraventriculares , Locomoção/efeitos dos fármacos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Nitrilas/efeitos adversos , Nitrilas/metabolismo , Parte Compacta da Substância Negra/efeitos dos fármacos , Piretrinas/efeitos adversos , Piretrinas/metabolismo , Ratos , Ratos Wistar , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
Parkinson's disease (PD) exhibits sexual differences in susceptibility and pathogenesis in humans, with a high incidence in men and a high severity of motor symptoms in male rodents. Furthermore, studies showed that the administration of low dose of reserpine (RES) induces a progressive appearance of motor alterations similar with parkinsonism in male rodents. Here, we investigated sex differences in motor deficits and tyrosine hydroxylase (TH) immunoreactivity induced by a progressive model of parkinsonism. Gonadally intact male and female Wistar rats and ovariectomized female rats received 15 subcutaneous injections (s.c.) every other day of 0.1 mg/kg of RES or vehicle. The repeated administration of low doses of RES (0.1 mg/kg) produces sexually dimorphic impairments on motor performance (catalepsy and open field test). Intact and ovariectomized females were more resistant to the deleterious effect of repeated administration of reserpine in the early, but this resistance in intact female disappears over time. However, intact females showed a reduction of the TH immunoreactivity in substantia nigra pars compacta, but not in ventral tegmental area and dorsal striatum. These results suggest a possible application of this model in the study of sexual dimorphism throughout the progression of PD.
Assuntos
Atividade Motora/efeitos dos fármacos , Transtornos Parkinsonianos/patologia , Fatores Sexuais , Animais , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/metabolismo , Dopamina/fisiologia , Feminino , Masculino , Doença de Parkinson/patologia , Transtornos Parkinsonianos/metabolismo , Ratos , Ratos Wistar , Reserpina/farmacologia , Caracteres Sexuais , Substância Negra/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/farmacologiaRESUMO
Geraniol is a monoterpene alcohol that is derived from the essential oils of aromatic plants, with anti-inflammatory, antimicrobial, antioxidant and neuroprotective properties. This study characterized the effect of geraniol on behavior and brainwave patterns in rats. Male rats were submitted to administration of geraniol (25, 50 and 100 mg/kg). The hole board (HB) and open field (OF) tests were performed to evaluate anxiety and motor behavior, respectively. In addition, barbiturate-induced sleeping time (BIST) was used to analyze sedative effect. Finally, electrocorticogram (ECoG) recordings were used to characterize brain-wave patterns. The results showed that geraniol treatment in rats decreased the distance traveled, rearing numbers and lead to increase in immobility time in HB and OF tests. In BIST test, geraniol treatment increased sleep duration but not sleep latency in the animals. Furthermore, geraniol-treated animals demonstrated an increase in the percentage of delta waves in the total spectrum power. Taken together, our results suggested that geraniol exerted a depressant effect on the central nervous system of rats.