RESUMO
Vincristine is a vinca alkaloid anti-mitotic drug with a broad spectrum of effects on solid and hematologic cancers. The major dose-limiting factor of this anti-cancer regimen is painful peripheral neuropathy. However, no gold-standard analgesic option has been used clinically. In this study, we investigated the effects and mechanism of bee venom acupuncture (BVA) to alleviate peripheral neuropathic pain induced by repeated intraperitoneal infusions of vincristine (1 mg/kg/day, days 1-5 and 8-12) in rats. Subcutaneous injection with bee venom (BV, 1.0 mg/kg) at the ST36 acupoint ameliorated cold and mechanical hypersensitivity (i.e., aberrant withdrawal responses in acetone drop and von Frey hair tests, respectively). In vivo extracellular recording demonstrated that BVA inhibited cutaneous cold (acetone) and mechanical (brush, press, and pinch) stimuli-elicited abnormal hyperexcitation of the spinal wide dynamic range (WDR) neurons in vincristine-treated rats. In addition, the microinjection of lidocaine into the ipsilateral locus coeruleus or the antagonism of the spinal α2-adrenergic receptors clearly reversed the effects of BVA on cold and mechanical hypersensitivity, indicating a vital role of the descending noradrenergic modulation in analgesia. These findings suggest that BVA could be a potential therapeutic option for vincristine-induced peripheral neuropathy.
Assuntos
Pontos de Acupuntura , Neurônios Adrenérgicos/efeitos dos fármacos , Venenos de Abelha/administração & dosagem , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Vincristina/toxicidade , Terapia por Acupuntura/métodos , Neurônios Adrenérgicos/metabolismo , Animais , Antineoplásicos Fitogênicos/toxicidade , Masculino , Microinjeções/métodos , Doenças do Sistema Nervoso Periférico/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Stress-induced cortical alertness is maintained by a heightened excitability of noradrenergic neurons innervating, notably, the prefrontal cortex. However, neither the signaling axis linking hypothalamic activation to delayed and lasting noradrenergic excitability nor the molecular cascade gating noradrenaline synthesis is defined. Here, we show that hypothalamic corticotropin-releasing hormone-releasing neurons innervate ependymal cells of the 3rd ventricle to induce ciliary neurotrophic factor (CNTF) release for transport through the brain's aqueductal system. CNTF binding to its cognate receptors on norepinephrinergic neurons in the locus coeruleus then initiates sequential phosphorylation of extracellular signal-regulated kinase 1 and tyrosine hydroxylase with the Ca2+-sensor secretagogin ensuring activity dependence in both rodent and human brains. Both CNTF and secretagogin ablation occlude stress-induced cortical norepinephrine synthesis, ensuing neuronal excitation and behavioral stereotypes. Cumulatively, we identify a multimodal pathway that is rate-limited by CNTF volume transmission and poised to directly convert hypothalamic activation into long-lasting cortical excitability following acute stress.
Assuntos
Neurônios Adrenérgicos/metabolismo , Fator Neurotrófico Ciliar/metabolismo , Hipotálamo/metabolismo , Locus Cerúleo/metabolismo , Estresse Fisiológico , Neurônios Adrenérgicos/patologia , Animais , Fator Neurotrófico Ciliar/genética , Hipotálamo/patologia , Locus Cerúleo/patologia , Camundongos , Camundongos Knockout , RatosRESUMO
Gonadotrophin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that inhibits gonadotrophin synthesis and release in birds and mammals. In Japanese quail, GnIH neurones express the noradrenergic receptor and receive noradrenergic innervation. Treatment with noradrenaline (NA) stimulates GnIH release from diencephalic tissue blocks in vitro. However, the effects of NA on hypothalamic GnIH gene expression have not been determined. We investigated noradrenergic regulation of GnIH gene expression in the brain of male quail using the selective noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4). We first showed that DSP-4 reduced the number of noradrenergic (dopamine-ß-hydroxylase immunoreactive) cells in the locus coeruleus (LoC) and specifically lowered the NA concentration in the hypothalamus of male quail. Other monoamines, such as dopamine and serotonin, were not affected by drug treatment. DSP-4 did not decrease the numbers of noradrenergic cells of the lateral tegmental cell group, nor the plasma NA concentration. Decreased hypothalamic NA levels after DSP-4 treatment did not change GnIH gene expression in the brains of quail during their interaction with conspecifics. On the other hand, GnIH gene expression increased in the brains of quail socially isolated for 1 hour after DSP-4 treatment. These results suggest that some noradrenergic neurones have inhibitory effects on GnIH gene expression of the hypothalamus in solitary quail.
Assuntos
Neurônios Adrenérgicos/metabolismo , Proteínas Aviárias/genética , Coturnix , Hormônios Hipotalâmicos/genética , Hipotálamo/metabolismo , Animais , Benzilaminas/administração & dosagem , Glicemia/metabolismo , Diencéfalo/efeitos dos fármacos , Diencéfalo/metabolismo , Expressão Gênica , Hipotálamo/efeitos dos fármacos , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Masculino , Norepinefrina/sangue , RNA Mensageiro/metabolismo , Isolamento SocialRESUMO
During adolescence, the increased susceptibility to stress-related dysfunctions (e.g., anxiety, drug use, obesity) may be influenced by changes in the hormonal stress response mediated by the hypothalamic-pituitary-adrenal (HPA) axis. We have previously reported that restraint stress leads to significantly prolonged HPA responses in pre-adolescent compared to adult rats. Further, pre-adolescent animals exposed to restraint show greater levels of neural activation than adults in the paraventricular nucleus of the hypothalamus (PVN), a key nucleus integrating information from brain regions that coordinate HPA responses. Here, we examined the potential contribution of the noradrenergic A2 region of the nucleus of the solitary tract (NST) as a contributor to these age-dependent shifts in HPA reactivity. Specifically, we used double-labeled immunohistochemistry for FOS and dopamine-ß-hydroxylase (DßH) to measure cellular activation and noradrenergic cells, respectively, before or after restraint stress in pre-adolescent (30days old) and adult (70days old) male rats. We also measured the density of DßH-immunoreactive fibers in the PVN as an index of noradrenergic inputs to this area. We found that pre-adolescent animals have a greater number of DßH-positive cells in the A2 region compared to adults, yet the number and percentage of double-labeled DßH/FOS cells were similar between these two ages. We found no differences between the ages in the staining intensity of DßH-immunoreactive fibers in the PVN. These data indicate there are adolescent-related changes in the number of noradrenergic cells in the A2 region, but no clear association between the increased stress reactivity prior to pubertal maturation and activation of A2 noradrenergic afferents to the PVN.
Assuntos
Neurônios Adrenérgicos/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Rombencéfalo/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Envelhecimento , Animais , Hipotálamo/metabolismo , Masculino , Ratos Sprague-DawleyRESUMO
The morphogenesis of individual organs and the whole organism occurs under the control of intercellular chemical signals mainly during the perinatal period of ontogenesis in rodents. In this study, we tested our hypothesis that the biologically active concentration of noradrenaline (NA) in blood in perinatal ontogenesis of rats is maintained due to humoral interaction between its central and peripheral sources based on their plasticity. As one of the mechanisms of plasticity, we examined changes in the secretory activity (spontaneous and stimulated release of NA) of NA-producing organs under deficiency of its synthesis in the brain. The destruction of NA-ergic neurons was provoked by administration of a hybrid molecular complex - antibodies against dopamine-ß-hydroxylase associated with the cytotoxin saporin - into the lateral cerebral ventricles of neonatal rats. We found that 72 h after the inhibition of NA synthesis in the brain, its spontaneous release from hypothalamus increased, which was most likely due to a compensatory increase of NA secretion from surviving neurons and can be considered as one of the mechanisms of neuroplasticity aimed at the maintenance of its physiological concentration in peripheral blood. Noradrenaline secretion from peripheral sources (adrenal glands and the organ of Zuckerkandl) also showed a compensatory increase in this model. Thus, during the critical period of morphogenesis, the brain is integrated into the system of NA-producing organs and participates in their reciprocal humoral regulation as manifested in compensatory enhancement of NA secretion in each of the studied sources of NA under specific inhibition of NA production in the brain.
Assuntos
Glândulas Suprarrenais , Neurônios Adrenérgicos/metabolismo , Ventrículos Cerebrais , Hipotálamo , Norepinefrina/metabolismo , Glomos Para-Aórticos/metabolismo , Glândulas Suprarrenais/crescimento & desenvolvimento , Glândulas Suprarrenais/metabolismo , Animais , Ventrículos Cerebrais/crescimento & desenvolvimento , Ventrículos Cerebrais/metabolismo , Dopamina beta-Hidroxilase/metabolismo , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Masculino , Ratos , Ratos Wistar , Proteínas Inativadoras de Ribossomos Tipo 1/toxicidade , SaporinasRESUMO
Recent studies describe taxol as a candidate treatment for promoting central nerve regeneration. However, taxol has serious side effects including peripheral neurotoxicity, and little information is known about the effect of taxol on peripheral nerve regeneration. We investigated the effects of taxol on regeneration in a rat sciatic nerve transection model. Rats were divided into four groups (n = 10): normal saline (i.p.) as the control, Cremophor EL vehicle, and 2 or 6 mg/kg of taxol in the Cremophor EL solution (four times in day-2, 4, 6, and 8), respectively. We evaluated neuronal electrophysiology, animal behaviour, neuronal connectivity, macrophage infiltration, location and expression levels of calcitonin gene-related peptide (CGRP), and expression levels of both nerve growth factors and immunoregulatory factors. In the high-dose taxol group (6 mg/kg), neuronal electrophysiological function was significantly impaired. Licking latencies were significantly changed while motor coordination was unaffected. Neuronal connectivity, macrophage density, and expression levels of CGRP was dramatically reduced. Expression levels of nerve growth factors and immunoregulatory factors was also reduced, while it was increased in the low-dose taxol group (2 mg/kg). These results indicate that taxol can modulate local inflammatory conditions, impair nerve regeneration, and impede recovery of a severe peripheral nerve injury.
Assuntos
Regeneração Nervosa/efeitos dos fármacos , Paclitaxel/farmacologia , Nervo Isquiático/lesões , Nervo Isquiático/fisiopatologia , Neurônios Adrenérgicos/efeitos dos fármacos , Neurônios Adrenérgicos/metabolismo , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos , Regulação da Expressão Gênica/efeitos dos fármacos , Temperatura Alta , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Atividade Motora/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Elastômeros de Silicone , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/metabolismo , Corno Dorsal da Medula Espinal/patologia , Estilbamidinas/químicaRESUMO
Schisandra chinensis (Turcz.) Baill., as a Chinese functional food, has been widely used in neurological disorders including insomnia and Alzheimer's disease. The treatment of classical neuropsychiatric disorder depression is to be developed from Schisandra chinensis. The antidepressant-like effects of the Schisandra chinensis extracts (SCE), and their probable involvement in the serotonergic, noradrenergic, dopaminergic, GABAergic and glutamatergic systems were investigated by the forced swim test (FST). Acute administration of SCE (600 mg kg(-1), i.g.), a combination of SCE (300 mg kg(-1), i.g.) and reboxetine (a noradrenalin reuptake inhibitor, 2.5 mg kg(-1), i.p.) or imipramine (a TCA, 2 mg kg(-1), i.p.) reduced the immobility time in the FST. Pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4, a selective noradrenergic neurotoxin, 50 mg kg(-1), i.p., 4 days), haloperidol (a non-selective D2 receptor antagonist, 0.2 mg kg(-1), i.p.), SCH 23390 (a selective D1 receptor antagonist, 0.03 mg kg(-1), i.p.), bicuculline (a competitive GABA antagonist, 4 mg kg(-1), i.p.) and N-methyl-d-aspartic acid (NMDA, an agonist at the glutamate site, 75 mg kg(-1), i.p.) effectively reversed the antidepressant-like effect of SCE (600 mg kg(-1), i.g.). However, p-chlorophenylalanine (pCPA, an inhibitor of 5-HT synthesis, 100 mg kg(-1), i.p., 4 days,) did not eliminate the reduced immobility time induced by SCE (600 mg kg(-1), i.g.). Moreover, the treatments did not change the locomotor activity. Altogether, these results indicated that SCE produced antidepressant-like activity, which might be mediated by the modification of noradrenergic, dopaminergic, GABAergic and glutamatergic systems.
Assuntos
Neurônios Adrenérgicos/efeitos dos fármacos , Depressão/tratamento farmacológico , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios GABAérgicos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Schisandra/química , Neurônios Adrenérgicos/metabolismo , Animais , Antidepressivos/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Relação Dose-Resposta a Droga , Fluoxetina/farmacologia , Neurônios GABAérgicos/metabolismo , Imipramina/farmacologia , Masculino , Camundongos , Condicionamento Físico AnimalRESUMO
The gene CUG-BP, Elav-like factor 6 (CELF6) appears to be important for proper functioning of neurocircuitry responsible for behavioral output. We previously discovered that polymorphisms in or near CELF6 may be associated with autism spectrum disorder (ASD) in humans and that the deletion of this gene in mice results in a partial ASD-like phenotype. Here, to begin to understand which circuits might mediate these behavioral disruptions, we sought to establish in what structures, with what abundance, and at which ages Celf6 protein is present in the mouse brain. Using both a knockout-validated antibody to Celf6 and a novel transgenic mouse line, we characterized Celf6 expression in the mouse brain across development. Celf6 gene products were present early in neurodevelopment and in adulthood. The greatest protein expression was observed in distinct nuclei of the diencephalon and neuromodulatory cell populations of the midbrain and hindbrain, with clear expression in dopaminergic, noradrenergic, histaminergic, serotonergic and cholinergic populations, and a variety of presumptive peptidergic cells of the hypothalamus. These results suggest that disruption of Celf6 expression in hypothalamic nuclei may impact a variety of behaviors downstream of neuropeptide activity, while disruption in neuromodulatory transmitter expressing areas such as the ventral tegmental area, substantia nigra, raphe nuclei and locus coeruleus may have far-reaching influences on overall brain activity.
Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Proteínas CELF/metabolismo , Diencéfalo/crescimento & desenvolvimento , Diencéfalo/metabolismo , Neurônios/metabolismo , Neurônios Adrenérgicos/metabolismo , Animais , Proteínas CELF/genética , Neurônios Colinérgicos/metabolismo , Neurônios Dopaminérgicos/metabolismo , Hipotálamo/metabolismo , Mesencéfalo/crescimento & desenvolvimento , Mesencéfalo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Rombencéfalo/crescimento & desenvolvimento , Rombencéfalo/metabolismo , Neurônios Serotoninérgicos/metabolismoRESUMO
CONTEXT: The traditional uses of Alpinia zerumbet (Pers.) B.L.Burtt & R.m.SM (Zingiberaceae), popularly known as colonia or pacová, suggest that the species has antihypertensive, diuretic, and sedative properties. We previously reported that an ethanol extract of Alpinia zerumbet (HEA) significantly reduced the immobility time in the tail suspension test (TST), similar to the tricyclic antidepressant imipramine. Moreover, HEA presented antioxidant and anxiolytic-like effects in mice. OBJECTIVE: The objective of this study is to investigate the involvement of monoaminergic and glutamatergic systems in the antidepressant-like effects of this species. MATERIALS AND METHODS: A hydroethanolic extract prepared with the leaves of A. zerumbet was assayed in the TST in male Swiss mice (800 mg/kg, p.o.). Synthesis inhibitors (AMPT, inhibitor of tyrosine hydroxylase, 100 mg/kg, i.p.; and PCPA, irreversible tryptophan hydroxylase inhibitor, 100 mg/kg, i.p.) and a specific glutamate antagonist (AMPA receptor antagonist NBQX, 10 mg/kg, i.p.) were used prior testing. RESULTS: Pre-treatment with the noradrenergic/dopaminergic inhibitor AMPT fully abolished the anti-immobility effects of HEA, with the two-way ANOVA yielding a significant interaction between pre-treatment and treatment (F1,32 = 10.0, p < 0.01); no interaction was observed with the serotonergic inhibitor PCPA (F1,32 = 0.33, p > 0.05) or NBQX (F1,32 = 0.21, p > 0.05). CONCLUSION: These results indicated that HEA most likely acts through the dopaminergic and/or noradrenergic system but not through the serotoninergic or glutamatergic systems. This study reinforces the idea that the available biodiversity in Brazil can serve as a basis for innovation in the development of new drugs.
Assuntos
Neurônios Adrenérgicos/efeitos dos fármacos , Alpinia/química , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Extratos Vegetais/farmacologia , Neurônios Adrenérgicos/metabolismo , Animais , Antidepressivos/química , Antidepressivos/isolamento & purificação , Neurônios Dopaminérgicos/metabolismo , Etanol/química , Masculino , Camundongos , Fitoterapia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta , Plantas Medicinais , Solventes/químicaRESUMO
Olfactory bulb granule cells are modulated by both acetylcholine (ACh) and norepinephrine (NE), but the effects of these neuromodulators have not been clearly distinguished. We used detailed biophysical simulations of granule cells, both alone and embedded in a microcircuit with mitral cells, to measure and distinguish the effects of ACh and NE on cellular and microcircuit function. Cholinergic and noradrenergic modulatory effects on granule cells were based on data obtained from slice experiments; specifically, ACh reduced the conductance densities of the potassium M current and the calcium-dependent potassium current, whereas NE nonmonotonically regulated the conductance density of an ohmic potassium current. We report that the effects of ACh and NE on granule cell physiology are distinct and functionally complementary to one another. ACh strongly regulates granule cell firing rates and afterpotentials, whereas NE bidirectionally regulates subthreshold membrane potentials. When combined, NE can regulate the ACh-induced expression of afterdepolarizing potentials and persistent firing. In a microcircuit simulation developed to investigate the effects of granule cell neuromodulation on mitral cell firing properties, ACh increased spike synchronization among mitral cells, whereas NE modulated the signal-to-noise ratio. Coapplication of ACh and NE both functionally improved the signal-to-noise ratio and enhanced spike synchronization among mitral cells. In summary, our computational results support distinct and complementary roles for ACh and NE in modulating olfactory bulb circuitry and suggest that NE may play a role in the regulation of cholinergic function.
Assuntos
Acetilcolina/farmacologia , Neurônios Adrenérgicos/fisiologia , Neurônios Colinérgicos/fisiologia , Modelos Neurológicos , Norepinefrina/farmacologia , Bulbo Olfatório/fisiologia , Potenciais de Ação , Neurônios Adrenérgicos/efeitos dos fármacos , Neurônios Adrenérgicos/metabolismo , Animais , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Potenciais da Membrana , Camundongos , Bulbo Olfatório/citologia , RatosRESUMO
AIM: Neuropeptide Y (NPY) co-localized with noradrenaline in central and sympathetic nervous systems seems to play a role in the control of energy metabolism. In this study, the aim was to elucidate the effects and pathophysiological mechanisms of increased NPY in catecholaminergic neurones on accumulation of body adiposity. METHODS: Transgenic mice overexpressing NPY under the dopamine-beta-hydroxylase promoter (OE-NPY(DßH) ) and wild-type control mice were followed for body weight gain and body fat content. Food intake, energy expenditure, physical activity, body temperature, serum lipid content and markers of glucose homoeostasis were monitored. Thermogenic and lipolytic responses in adipose tissues, and urine catecholamine and tissue catecholamine synthesizing enzyme levels were analysed as indices of sympathetic tone. RESULTS: Homozygous OE-NPY(DßH) mice showed significant obesity accompanied with impaired glucose tolerance and insulin resistance. Increased adiposity was explained by neither increased food intake or fat absorption nor by decreased total energy expenditure or physical activity. Adipocyte hypertrophy and decreased circulating lipid levels suggested decreased lipolysis and increased lipid uptake. Brown adipose tissue thermogenic capacity was decreased and brown adipocytes filled with lipids. Enhanced response to adrenergic stimuli, downregulation of catecholamine synthesizing enzyme expressions in the brainstem and lower adrenaline excretion supported the notion of low basal catecholaminergic activity. CONCLUSION: Increased NPY in catecholaminergic neurones induces obesity that seems to be a result of preferential fat storage. These results support the role of NPY as a direct effector in peripheral tissues and an inhibitor of sympathetic activity in the pathogenesis of obesity.
Assuntos
Neurônios Adrenérgicos/metabolismo , Neuropeptídeo Y/metabolismo , Obesidade/metabolismo , Sistema Nervoso Simpático/fisiologia , Tecido Adiposo Marrom , Animais , Metabolismo Energético , Regulação da Expressão Gênica , Hipotálamo/metabolismo , Camundongos , Camundongos Transgênicos , Neuropeptídeo Y/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Cell-type compartmentation of glucose metabolism in the brain involves trafficking of the oxidizable glycolytic end product, l-lactate, by astrocytes to fuel neuronal mitochondrial aerobic respiration. Lactate availability within the hindbrain medulla is a monitored function that regulates systemic glucostasis as insulin-induced hypoglycemia (IIH) is exacerbated by lactate repletion of that brain region. A2 noradrenergic neurons are a plausible source of lactoprivic input to the neural gluco-regulatory circuit as caudal fourth ventricular (CV4) lactate infusion normalizes IIH-associated activation, e.g. phosphorylation of the high-sensitivity energy sensor, adenosine 5'-monophosphate-activated protein kinase (AMPK), in these cells. Here, we investigated the hypothesis that A2 neurons are unique among medullary catecholamine cells in directly screening lactate-derived energy. Adult male rats were injected with insulin or vehicle following initiation of continuous l-lactate infusion into the CV4. Two hours after injections, A1, C1, A2, and C2 neurons were collected by laser-microdissection for Western blot analysis of AMPKα1/2 and phosphoAMPKα1/2 proteins. Results show that AMPK is expressed in each cell group, but only a subset, e.g. A1, C1, and A2 neurons, exhibit increased sensor activity in response to IIH. Moreover, hindbrain lactate repletion reversed hypoglycemic augmentation of pAMPKα1/2 content in A2 and C1 but not A1 cells, and normalized hypothalamic norepinephrine and epinephrine content in a site-specific manner. The present evidence for discriminative reactivity of AMPK-expressing medullary catecholamine neurons to the screened energy substrate lactate implies that that lactoprivation is selectively signaled to the hypothalamus by A2 noradrenergic and C1 adrenergic cells.
Assuntos
Neurônios Adrenérgicos/metabolismo , Epinefrina/metabolismo , Hipoglicemia/metabolismo , Hipotálamo/metabolismo , Lactatos/metabolismo , Bulbo/metabolismo , Norepinefrina/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Neurônios Adrenérgicos/efeitos dos fármacos , Animais , Glicemia , Corticosterona/sangue , Epinefrina/análise , Hipoglicemia/induzido quimicamente , Insulina/farmacologia , Lactatos/farmacologia , Masculino , Bulbo/efeitos dos fármacos , Norepinefrina/análise , Fosforilação , Ratos , Ratos Sprague-DawleyRESUMO
Nerve cell metabolic activity is monitored in multiple brain regions, including the hypothalamus and hindbrain dorsal vagal complex (DVC), but it is unclear if individual metabolosensory loci operate autonomously or interact to coordinate central nervous system (CNS) reactivity to energy imbalance. This research addressed the hypothesis that hypoglycemia-associated DVC lactoprivation stimulates hypothalamic AMPK activity and metabolic neurotransmitter expression. As DVC catecholaminergic neurons express biomarkers for metabolic monitoring, we investigated whether these cells are a source of lactate deficit signaling to the hypothalamus. Caudal fourth ventricle (CV4) infusion of the glucose metabolite l-lactate during insulin-induced hypoglycemia reversed changes in DVC A2 noradrenergic, arcuate neuropeptide Y (NPY) and pro-opiomelanocortin (POMC), and lateral hypothalamic orexin-A (ORX) neuronal AMPK activity, coincident with exacerbation of hypoglycemia. Hindbrain lactate repletion also blunted hypoglycemic upregulation of arcuate NPY mRNA and protein. This treatment did not alter hypoglycemic paraventricular oxytocin (OT) and lateral hypothalamic ORX mRNA profiles, but exacerbated or reversed adjustments in OT and ORX neuropeptide synthesis, respectively. CV4 delivery of the monocarboxylate transporter inhibitor, 4-CIN, increased A2 phosphoAMPK (pAMPK), elevated circulating glucose, and stimulated feeding, responses that were attenuated by 6-hydroxydopamine pretreatment. 4-CIN-infused rats exhibited increased (NPY, ORX neurons) or decreased (POMC neurons) pAMPK concurrent with hyperglycemia. These data show that hindbrain lactoprivic signaling regulates hypothalamic AMPK and key effector neurotransmitter responses to hypoglycemia. Evidence that A2 AMPK activity is lactate-dependent, and that DVC catecholamine cells are critical for lactoprivic control of glucose, feeding, and hypothalamic AMPK, implies A2 derivation of this metabolic regulatory stimulus.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Metabolismo Energético , Hipoglicemia/enzimologia , Hipotálamo/enzimologia , Ácido Láctico/metabolismo , Neuropeptídeos/metabolismo , RNA Mensageiro/metabolismo , Rombencéfalo/metabolismo , Neurônios Adrenérgicos/metabolismo , Animais , Modelos Animais de Doenças , Ativação Enzimática , Comportamento Alimentar , Regulação da Expressão Gênica , Hipoglicemia/induzido quimicamente , Hipoglicemia/genética , Hipoglicemia/fisiopatologia , Hipoglicemia/psicologia , Hipotálamo/fisiopatologia , Infusões Intraventriculares , Insulina , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ácido Láctico/administração & dosagem , Masculino , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Neuropeptídeos/genética , Orexinas , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Ratos , Ratos Sprague-Dawley , Rombencéfalo/fisiopatologia , Transdução de SinaisRESUMO
INTRODUCTION: The study objective was to determine the effect of central noradrenergic system lesions performed in the early extrafetal life period on dopamine synthesis in the rat brain. The content of L-dihydroxyphenylalanine (L-DOPA) was assessed in the frontal lobe, thalamus, hypothalamus and brain stem of rats by high-pressure chromatography with electrochemical detection (HPLC/ED) after administration of 5-HT3 receptor ligands. MATERIAL AND METHODS: Adult male Wistar rats which underwent central noradrenergic lesions by DSP-4 administration (50 mg/kg m.c. i.p.) on day 1 and 3 of life received i.p. injections of the aromatic amino acid decarboxylase inhibitor (NSD-1050) in a dose of 100 mg/kg b.w. Next, 30 min after NSD-1050 injection, the animals were decapitated by guillotine. Selected brain structures were dissected and L-DOPA content was determined by HPLC/ED. RESULTS AND CONCLUSIONS: A statistically significant reduction was found in DA synthesis in the group of animals with DSP-4 lesions induced by PBG (1-phenylbiguanide, 7.5 mg/kg b.w. i.p.) and ondansetron (1.0 mg/kg b.w. i.p.). Morphine and PBG had no major effect on DA synthesis in the cerebral cortex of both control animals and in rats with noradrenergic lesions. The assessment of the effect of DSP-4 lesions on L-DOPA content in the brain stem after administration of morphine (7.5 mg/kg b.w. s.c.), PBG (7.5 mg/kg b.w. i.p.) or ondansetron (1.0 mg/kg b.w. i.p.) separately or jointly showed a statistically significant increase in the synthesis of DA in animals with DSP-4 lesions, as compared to the control group exposed to 0.9% NaCl and morphine. The analysis of the effect of DSP-4 lesions on L-DOPA content in the thalamus and hypothalamus revealed no statistically significant differences between the control groups of rats and those with DSP-4 lesions. As shown by this model, permanent noradrenergic lesions in animals in the early extra-fetal period result in increased reactivity of the central dopamine system.
Assuntos
Neurônios Adrenérgicos/efeitos dos fármacos , Neurônios Adrenérgicos/metabolismo , Carboxiliases/antagonistas & inibidores , Dopamina/biossíntese , Lobo Frontal/química , Lobo Frontal/metabolismo , Levodopa/análise , Animais , Benzilaminas , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/metabolismo , Tronco Encefálico/química , Tronco Encefálico/efeitos dos fármacos , Hipotálamo/química , Hipotálamo/metabolismo , Masculino , Morfina/farmacologia , Ondansetron/farmacologia , Ratos , Ratos Wistar , Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Receptores 5-HT3 de Serotonina/metabolismo , Tálamo/química , Tálamo/metabolismoRESUMO
OBJECTIVES: Asparagus racemosus (AR) is classified as an adaptogen, an important medicinal plant and food. Even though AR is widely used as food and nutraceutical, it has only been evaluated in the context of experimental disorders. Hence, the present study was designed to evaluate the effect of standardized methanolic extract of AR (MAR) on experimentally un-manipulated animals to observe the per se effects on stress pathways. METHODS: MAR (50, 100, and 200 mg/kg, per oral) was administered for 7 days. Lorazepam (0.5 mg/kg, intraperitoneal) was used as a positive control. On the seventh day, plasma was collected for the estimation of corticosterone (CORT) and norepinephrine (NE), and brain was microdissected into hippocampus, hypothalamus (HYP), pre-frontal cortex, amygdala, and nucleus accumbens to estimate tissue level of monoamines (serotonin, dopamine, and NE), their metabolites, and turnover. RESULTS: MAR dose-dependently decreased the plasma CORT and NE levels, indicating its effects on the hypothalamic-pituitary-adrenal cortex axis and the sympathetic-noradrenergic system, respectively. MAR increased the levels of all monoamines in the HYP. However, MAR showed region-specific changes in monoamines and their metabolites, and turnover in other brain regions. DISCUSSION: MAR showed a physiological modulation of the stress pathways. Interestingly, in most brain regions the change in monoaminergic systems was limited by a ceiling effect at a dose of 100 mg/kg. These observations could explain the traditional use of AR as an adaptogen and a functional food.
Assuntos
Ansiolíticos/uso terapêutico , Asparagus/química , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Raízes de Plantas/química , Estresse Psicológico/tratamento farmacológico , Neurônios Adrenérgicos/efeitos dos fármacos , Neurônios Adrenérgicos/metabolismo , Animais , Ansiolíticos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Monoaminas Biogênicas/sangue , Monoaminas Biogênicas/metabolismo , Corticosterona/sangue , Corticosterona/metabolismo , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Etnofarmacologia , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Ayurveda , Microdissecção , Norepinefrina/sangue , Norepinefrina/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Extratos Vegetais/administração & dosagem , Ratos , Ratos Endogâmicos , Estresse Psicológico/sangue , Estresse Psicológico/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismoRESUMO
Arterial blood pressure circadian rhythm: significance and clinical implications Arterial blood pressure exhibits a circadian rhythm characterized by a decrease during the sleep period and a steep increase in the early morning hours that can be characterized by 24 h ambulatory blood pressure monitoring (ABPM). The absence of a nocturnal dipping or an excessive morning surge, commonly observed in hypertensive patients, is associated with an increased cardiovascular and renal risk. Numerous studies show that a better control of nocturnal blood pressure can be obtained by the administration of anti-hypertensive medication at the evening time, improving microalbuminuria, left heart hypertrophy, or arterial intima-media thickness, but only one study has so far demonstrated a decrease of major cardiovascular events. In this context, the decision on restoring or not the nocturnal dipping should be left to the judgement of the clinician, and applied in an individual manner to each patient.