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1.
Clin Sci (Lond) ; 137(2): 149-161, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36598165

RESUMO

The placenta represents a non-neuronal organ capable of transporting and metabolizing monoamines. Since these bioactive molecules participate in numerous processes essential for placental and fetal physiology, any imbalance in their levels during pregnancy may affect brain development, projecting a higher risk of behavioral disorders in childhood or adulthood. Notably, the monoamine system in the placenta is a target of various psychoactive drugs and can be disrupted in several pregnancy pathologies. As research in pregnant women poses significant ethical restrictions, animal models are widely employed to study monoamine homeostasis as a mechanism involved in fetal programming. However, detailed knowledge of monoamine transport in the rat placenta is still lacking. Moreover, relatability to the human placental monoamine system is not examined. The present study provides insights into the transplacental monoamine dynamics between maternal and fetal circulation. We show that norepinephrine maternal-to-fetal transport is <4% due to high metabolism within the trophoblast. In contrast, dopamine maternal-to-fetal transport exceeds 25%, likely through passive transport across the membrane. In addition, we show high clearance of norepinephrine and dopamine from the fetal circulation mediated by the organic cation transporter 3 (OCT3). Altogether, we present transcriptional and functional evidence that the in situ rat placenta perfusion represents a suitable model for (patho)physiological investigation of dopamine and norepinephrine homeostasis in the fetoplacental unit. With the rapid advancements in drug discovery and environmental toxicity, the use of rat placenta as a preclinical model could facilitate screening of possible xenobiotic effects on monoamine homeostasis in the placenta.


Assuntos
Dopamina , Placenta , Animais , Feminino , Gravidez , Ratos , Transporte Biológico , Dopamina/metabolismo , Dopamina/farmacologia , Troca Materno-Fetal , Norepinefrina/metabolismo , Placenta/metabolismo , Trofoblastos/metabolismo
2.
Int J Mol Sci ; 24(2)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36674892

RESUMO

Renal vasculature, which is highly innervated by sympathetic fibers, contributes to cardiovascular homeostasis. This renal sympathetic outflow is inhibited by 5-HT in normoglycaemic rats. Considering that diabetes induces cardiovascular complications, we aimed to determine whether diabetic state modifies noradrenergic input at renal level and its serotonergic modulation in rats. Alloxan diabetic rats were anaesthetized (pentobarbital; 60 mg/kg i.p.) and prepared for in situ autoperfusion of the left kidney to continuously measure systemic blood pressure (SBP), heart rate (HR), and renal perfusion pressure (RPP). Electrical stimulation of renal sympathetic outflow induces frequency-dependent increases (Δ) in RPP (23.9 ± 2.1, 59.5 ± 1.9, and 80.5 ± 3.5 mm Hg at 2, 4, and 6 Hz, respectively), which were higher than in normoglycaemic rats, without modifying HR or SBP. Intraarterial bolus of 5-HT and 5-CT (5-HT1/5/7 agonist) reduced electrically induced ΔRPP. Only L-694,247 (5-HT1D agonist) reproduced 5-CT inhibition on sympathetic-induced vasoconstrictions, whereas it did not modify exogenous noradrenaline-induced ΔRPP. 5-CT inhibition was exclusively abolished by i.v. bolus of LY310762 (5-HT1D antagonist). An inhibitor of guanylyl cyclase, ODQ (i.v.), completely reversed the L-694,247 inhibitory effect. In conclusion, diabetes induces an enhancement in sympathetic-induced vasopressor responses at the renal level. Prejunctional 5-HT1D receptors, via the nitric oxide pathway, inhibit noradrenergic-induced vasoconstrictions in diabetic rats.


Assuntos
Diabetes Mellitus Experimental , Serotonina , Ratos , Animais , Serotonina/metabolismo , Ratos Wistar , Receptor 5-HT1D de Serotonina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Rim , Norepinefrina/farmacologia , Norepinefrina/metabolismo , Sistema Nervoso Simpático/metabolismo , Estimulação Elétrica , Pressão Sanguínea
3.
Nat Commun ; 14(1): 38, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36596796

RESUMO

Recent studies implicate macrophages in regulation of thermogenic, sympathetic neuron-mediated norepinephrine (NE) signaling in adipose tissues, but understanding of such non-classical macrophage activities is incomplete. Here we show that male mice lacking the allograft inflammatory factor-1 (AIF1) protein resist high fat diet (HFD)-induced obesity and hyperglycemia. We link this phenotype to higher adipose NE levels that stem from decreased monoamine oxidase A (MAOA) expression and NE clearance by AIF1-deficient macrophages, and find through reciprocal bone marrow transplantation that donor Aif1-/- vs WT genotype confers the obesity phenotype in mice. Interestingly, human sequence variants near the AIF1 locus associate with obesity and diabetes; in adipose samples from participants with obesity, we observe direct correlation of AIF1 and MAOA transcript levels. These findings identify AIF1 as a regulator of MAOA expression in macrophages and catecholamine activity in adipose tissues - limiting energy expenditure and promoting energy storage - and suggest how it might contribute to human obesity.


Assuntos
Tecido Adiposo , Obesidade , Masculino , Humanos , Camundongos , Animais , Obesidade/genética , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Adiposidade , Norepinefrina/metabolismo , Catecolaminas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Aloenxertos/metabolismo , Camundongos Endogâmicos C57BL , Inflamação/metabolismo
4.
Biomed Pharmacother ; 158: 114181, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36592494

RESUMO

Subjects suffering from psychosis frequently experience anxiety. However, mechanisms underlying this comorbidity remain still unclear. We investigated whether neurochemical and neuroendocrine dysfunctions were involved in the development of anxiety-like behavior in a rodent model of psychotic-like symptoms, obtained by exposing male rats to social isolation rearing from postnatal day 21 to postnatal day 70. In the elevated zero maze test, isolated rats showed a significant reduction in the time spent in the open arms, as well as an increase in the time spent in the closed arms, compared to controls. An increased grooming time in the open field test was also observed in isolated animals. Isolation-induced anxiety-like behavior was accompanied by a decrease of plasmatic oxytocin, prolactin, ghrelin and melatonin levels, whereas plasmatic amount of Neuropeptide S was not altered. Social isolation also caused a reduction of noradrenaline, serotonin and GABA levels, together with an increase of serotonin turnover and glutamate levels in the amygdala of isolated animals. No significant differences were found in noradrenaline and serotonin levels, as well as in serotonin turnover in hippocampus, while glutamate amount was increased and GABA levels were reduced in isolated rats. Furthermore, there was a reduction in plasmatic serotonin content, and an increase in plasmatic kynurenine levels following social isolation, while no significant changes in serotonin turnover were observed. Taken together, our data provide novel insights in the neurobiological alterations underlying the comorbidity between psychosis and anxiety, and open new perspectives for multi-target therapies acting on both neurochemical and neuroendocrine pathways. DATA AVAILABILITY STATEMENT: The data presented in this study are available on request from the corresponding author.


Assuntos
Ansiedade , Serotonina , Ratos , Animais , Masculino , Serotonina/metabolismo , Ansiedade/metabolismo , Isolamento Social , Norepinefrina/metabolismo , Ácido gama-Aminobutírico/metabolismo , Comportamento Animal
5.
eNeuro ; 10(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36635251

RESUMO

The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (two doses of 50 mg/kg, one week apart) induced LC axon degeneration, triggered neuroinflammation and oxidative stress, and reduced tissue NE levels. There was no LC cell death or changes to LC firing, but transcriptomics revealed reduced expression of genes that define noradrenergic identity and other changes relevant to neurodegenerative disease. Despite the dramatic loss of LC fibers, NE turnover and signaling were elevated in terminal regions and were associated with anxiogenic phenotypes in multiple behavioral tests. These results represent a comprehensive analysis of how the LC-NE system responds to axon/terminal damage reminiscent of early AD and PD at the molecular, cellular, systems, and behavioral levels, and provides potential mechanisms underlying prodromal neuropsychiatric symptoms.


Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , Camundongos , Masculino , Feminino , Animais , Locus Cerúleo , Norepinefrina/metabolismo , Doenças Neurodegenerativas/patologia , Neurotoxinas/metabolismo , Neurotoxinas/farmacologia , Sintomas Prodrômicos , Doença de Parkinson/metabolismo
6.
Behav Brain Res ; 437: 114157, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36241070

RESUMO

Vocal communication, cognition, and affective state are key features of sustained health and wellness, and because vocalizations are often socially-motivated, social experience likely plays a role in these behaviors. The monoaminergic systems of the ventral tegmental area (VTA) and the locus coeruleus (LC) are associated with social and reward processing, vocalization production, and neurotransmitter changes in response to environmental stressors. The effect of social isolation on these complex behaviors and the underlying neural mechanisms is relatively unknown. To add to this body of literature, we randomized adult male Long-Evans rats to control (housed with a cagemate) or isolated (housed individually) conditions and assayed ultrasonic vocalizations, cognition (novel object recognition test), anxiety (elevated plus maze) and anhedonia (sucrose preference test) at 2, 4, 6, 8, and 10 months of age. At 10 months, VTA and LC samples were assayed for dopamine, norepinephrine, and serotonin using high performance liquid chromatography. We tested the hypotheses that isolation 1) diminishes vocalizations and cognition, 2) increases anxiety and depression, and 3) increases levels of dopamine, norepinephrine, and serotonin in the VTA and LC. Results showed isolation significantly reduced vocalization tonality (signal-to-noise ratio) and increased maximum frequency. There were no significant findings for cognition, anxiety, or anhedonia. Dopamine and serotonin and their respective metabolites were significantly increased in the VTA in isolated rats. These findings suggest chronic changes to social condition such as isolation affects vocalization production and levels of VTA neurotransmitters.


Assuntos
Locus Cerúleo , Ultrassom , Animais , Masculino , Ratos , Anedonia , Cognição , Dopamina/metabolismo , Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Ratos Long-Evans , Serotonina/metabolismo , Isolamento Social , Área Tegmentar Ventral , Vocalização Animal/fisiologia
7.
Neurotoxicol Teratol ; 95: 107146, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36481438

RESUMO

Tyrosine hydroxylase (Th) is an allosteric rate-limiting enzyme in catecholamine (CA) biosynthesis. The CAs, dopamine (DA), norepinephrine (NE), and epinephrine are important neurotransmitters wherein DA contributes a key role in the central nervous system of vertebrates. The present study evaluated DA and Th's significance in DA-ergic activity and neurodegeneration upon 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure in catfish. Further, the expression of certain brain-and ovary-related genes measured through qPCR were downregulated upon MPTP treatment which is in accordance with the decreased levels of L-Dopa, DA, and NE levels estimated through HPLC-ECD. Additionally, TEM analysis depicted structural disarray of brain upon MPTP exposure and also decreased serum levels of testosterone, 11-ketotestosterone, and estradiol-17ß. MPTP treatment, in vitro, using primary brain cell culture resulted in diminished cell viability and increased ROS levels leading to elevated apoptotic cells significantly. Consequently, the study highlights the MPTP-induced neurodegeneration of the Th and DA-ergic activity in corroboration with female brain-related genes downregulation, also gonadal function as evidenced by depleted sex steroids level and low expression of ovary-related genes.


Assuntos
Dopamina , Intoxicação por MPTP , Animais , Feminino , Camundongos , Dopamina/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Encéfalo/metabolismo , Levodopa/metabolismo , Norepinefrina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Camundongos Endogâmicos C57BL , Corpo Estriado/metabolismo , Intoxicação por MPTP/metabolismo
8.
Diabetes ; 72(1): 3-15, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36538602

RESUMO

Catecholamine neurotransmitters dopamine (DA) and norepinephrine (NE) are essential for a myriad of functions throughout the central nervous system, including metabolic regulation. These molecules are also present in the pancreas, and their study may shed light on the effects of peripheral neurotransmission on glycemic control. Though sympathetic innervation to islets provides NE that signals at local α-cell and ß-cell adrenergic receptors to modify hormone secretion, α-cells and ß-cells also synthesize catecholamines locally. We propose a model where α-cells and ß-cells take up catecholamine precursors in response to postprandial availability, preferentially synthesizing DA. The newly synthesized DA signals in an autocrine/paracrine manner to regulate insulin and glucagon secretion and maintain glycemic control. This enables islets to couple local catecholamine signaling to changes in nutritional state. We also contend that the DA receptors expressed by α-cells and ß-cells are targeted by antipsychotic drugs (APDs)-some of the most widely prescribed medications today. Blockade of local DA signaling contributes significantly to APD-induced dysglycemia, a major contributor to treatment discontinuation and development of diabetes. Thus, elucidating the peripheral actions of catecholamines will provide new insights into the regulation of metabolic pathways and may lead to novel, more effective strategies to tune metabolism and treat diabetes.


Assuntos
Antipsicóticos , Ilhotas Pancreáticas , Catecolaminas/metabolismo , Antipsicóticos/efeitos adversos , Antipsicóticos/metabolismo , Controle Glicêmico , Norepinefrina/metabolismo , Dopamina/metabolismo , Ilhotas Pancreáticas/metabolismo , Neurotransmissores/metabolismo
9.
Nature ; 613(7943): 317-323, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36544024

RESUMO

Cochlear implants (CIs) are neuroprosthetic devices that can provide hearing to deaf people1. Despite the benefits offered by CIs, the time taken for hearing to be restored and perceptual accuracy after long-term CI use remain highly variable2,3. CI use is believed to require neuroplasticity in the central auditory system, and differential engagement of neuroplastic mechanisms might contribute to the variability in outcomes4-7. Despite extensive studies on how CIs activate the auditory system4,8-12, the understanding of CI-related neuroplasticity remains limited. One potent factor enabling plasticity is the neuromodulator noradrenaline from the brainstem locus coeruleus (LC). Here we examine behavioural responses and neural activity in LC and auditory cortex of deafened rats fitted with multi-channel CIs. The rats were trained on a reward-based auditory task, and showed considerable individual differences of learning rates and maximum performance. LC photometry predicted when CI subjects began responding to sounds and longer-term perceptual accuracy. Optogenetic LC stimulation produced faster learning and higher long-term accuracy. Auditory cortical responses to CI stimulation reflected behavioural performance, with enhanced responses to rewarded stimuli and decreased distinction between unrewarded stimuli. Adequate engagement of central neuromodulatory systems is thus a potential clinically relevant target for optimizing neuroprosthetic device use.


Assuntos
Implantes Cocleares , Surdez , Locus Cerúleo , Animais , Ratos , Implante Coclear , Surdez/fisiopatologia , Surdez/terapia , Audição/fisiologia , Aprendizagem/fisiologia , Locus Cerúleo/citologia , Locus Cerúleo/fisiologia , Plasticidade Neuronal , Norepinefrina/metabolismo , Córtex Auditivo/citologia , Córtex Auditivo/fisiologia , Córtex Auditivo/fisiopatologia , Neurônios/fisiologia , Recompensa , Optogenética , Fotometria
10.
Nat Commun ; 13(1): 7032, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36396637

RESUMO

Familial dysautonomia (FD), a rare neurodevelopmental and neurodegenerative disorder affects the sympathetic and sensory nervous system. Although almost all patients harbor a mutation in ELP1, it remains unresolved exactly how function of sympathetic neurons (symNs) is affected; knowledge critical for understanding debilitating disease hallmarks, including cardiovascular instability or dysautonomic crises, that result from dysregulated sympathetic activity. Here, we employ the human pluripotent stem cell (hPSC) system to understand symN disease mechanisms and test candidate drugs. FD symNs are intrinsically hyperactive in vitro, in cardiomyocyte co-cultures, and in animal models. We report reduced norepinephrine transporter expression, decreased intracellular norepinephrine (NE), decreased NE re-uptake, and excessive extracellular NE in FD symNs. SymN hyperactivity is not a direct ELP1 mutation result, but may connect to NET via RAB proteins. We found that candidate drugs lowered hyperactivity independent of ELP1 modulation. Our findings may have implications for other symN disorders and may allow future drug testing and discovery.


Assuntos
Disautonomia Familiar , Animais , Humanos , Disautonomia Familiar/genética , Disautonomia Familiar/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Neurônios/metabolismo , Norepinefrina/metabolismo , Mutação
11.
Neuropsychopharmacol Hung ; 24(3): 120-125, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36356194

RESUMO

In their recently published systematic "umbrella" review, Moncrieff and colleagues conclude that there is no consistent evidence that depression is caused by decreased serotonin activity in the central nervous system (CNS). However, this paper - which was extensively publicized and received a lot of attention on the social media - can cause misunderstandings, since the serotonin hypothesis of depression in its original form (i.e. reduced serotonin activity in the CNS = depression) formulated more than 50 years ago has been considered outdated for several decades. It has long been known that depression is a heterogeneous disorder not only genetically, clinically and biologically but also from a pharmacotherapeutic perspective. The decreased activity of serotonin, which undoubtedly plays an essential role in the pathogenesis of depression, is characteristic of only a subgroup of depressed subjects whose clinical picture is mostly dominated by intensified negative emotions, agitation, anxiety, insomnia, decreased appetite, self-blame and suicidality and these individuals are primarily responsive to SSRIs. By contrast, depression cases with reduced positive affects (characterized by anhedonia, anergia, inhibition and reduced cognitive functions) are mainly caused by a disturbance in the metabolism of dopamine and/or noradrenaline. These patients are primarily responsive to dual-action (e.g. SNRI) antidepressants. Results of serotonin and catecholamine (dopamine, noradrenaline) depletion studies also suggest that that the dysregulation of serotonin and dopamine/noradrenaline in the CNS is characteristic of different subgroups of depressed patients. In addition to the serotonergic, dopaminergic and noradrenergic systems, many other neurotransmitter systems (e.g. cholinergic, glutamatergic, GABAergic) and other mechanisms (e.g. neuroinfl ammation) have also been proven to play a role in the development of the disorder. Knowledge of the data presented in our publication is important since the simplistic interpretation by Moncrieffetal. of the role of serotonin in the pathogenesis of depression may undermine confidence in SSRIs in many patients. (Neuropsychopharmacol Hung 2022; 24(3): 120-125).


Assuntos
Dopamina , Serotonina , Humanos , Serotonina/fisiologia , Depressão/tratamento farmacológico , Antidepressivos/efeitos adversos , Norepinefrina/metabolismo
12.
Nutrients ; 14(19)2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-36235619

RESUMO

BACKGROUND: Aerobic exercise training (ExT) is beneficial for hypertension, however, its central mechanisms in improving hypertension remain unclear. Since the importance of the up-regulation of angiotensin II type 1 receptor (AT-1R) in the paraventricular nucleus (PVN) of the hypothalamic in sympathoexcitation and hypertension has been shown, we testified the hypothesis that aerobic ExT decreases blood pressure in hypertensive rats by down-regulating the AT-1R through reactive oxygen species (ROS)/mitogen-activated protein kinase (MAPK)/nuclear factors κB (NF-κB) pathway within the PVN. METHODS: Forty-eight male Sprague-Dawley (SD) rats were assigned to the following groups: sham operation (SHAM) + kept sedentary (Sed), SHAM + exercise training (ExT), two kidney-one clamp (2K1C) + Sed, and 2K1C + ExT groups. RESULTS: The 2K1C + Sed hypertensive rats showed higher systolic blood pressure (SBP), upregulated ROS, phosphorylated (p-) p44/42 MAPK, p-p38 MAPK, NF-κB p65 activity, and AT-1R expression in the PVN, and increased circulating norepinephrine (NE) than those of SHAM rats. After eight weeks of aerobic ExT, the 2K1C + ExT hypertensive rats showed attenuated NE and SBP levels, suppressed NF-κB p65 activity, and reduced expression of ROS, p-p44/42 MAPK, p-p38 MAPK, and AT-1R in the PVN, relatively to the 2K1C + Sed group. CONCLUSIONS: These data are suggestive of beneficial effects of aerobic ExT in decreasing SBP in hypertensive rats, via down-regulating the ROS/MAPK/NF-κB pathway that targets AT-1R in the PVN, and eventually ameliorating 2K1C-induced hypertension.


Assuntos
Hipertensão , Núcleo Hipotalâmico Paraventricular , Condicionamento Físico Animal , Animais , Masculino , Ratos , Hipertensão/prevenção & controle , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Norepinefrina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Sistema Nervoso Simpático
13.
Int J Mol Sci ; 23(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36293486

RESUMO

High-calorie diets and chronic stress are major contributors to the development of obesity and metabolic disorders. These two risk factors regulate the activity of the sympathetic nervous system (SNS). The present study showed a key role of the cannabinoid type 1 receptor (CB1) in dopamine ß-hydroxylase (dbh)-expressing cells in the regulation of SNS activity. In a diet-induced obesity model, CB1 deletion from these cells protected mice from diet-induced weight gain by increasing sympathetic drive, resulting in reduced adipogenesis in white adipose tissue and enhanced thermogenesis in brown adipose tissue. The deletion of CB1 from catecholaminergic neurons increased the plasma norepinephrine levels, norepinephrine turnover, and sympathetic activity in the visceral fat, which coincided with lowered neuropeptide Y (NPY) levels in the visceral fat of the mutant mice compared with the controls. Furthermore, the mutant mice showed decreased plasma corticosterone levels. Our study provided new insight into the mechanisms underlying the roles of the endocannabinoid system in regulating energy balance, where the CB1 deletion in dbh-positive cells protected from diet-induced weight gain via multiple mechanisms, such as increased SNS activity, reduced NPY activity, and decreased basal hypothalamic-pituitary-adrenal (HPA) axis activity.


Assuntos
Canabinoides , Neuropeptídeo Y , Camundongos , Animais , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Endocanabinoides/metabolismo , Dopamina beta-Hidroxilase/genética , Dopamina beta-Hidroxilase/metabolismo , Canabinoides/metabolismo , Corticosterona/metabolismo , Obesidade/genética , Obesidade/metabolismo , Dieta Hiperlipídica/efeitos adversos , Neurônios/metabolismo , Norepinefrina/metabolismo , Aumento de Peso
14.
Nutrients ; 14(19)2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36235829

RESUMO

BACKGROUND: The hypothalamic paraventricular nucleus (PVN) is an important nucleus in the brain that plays a key role in regulating sympathetic nerve activity (SNA) and blood pressure. Silent mating-type information regulation 2 homolog-1 (sirtuin1, SIRT1) not only protects cardiovascular function but also reduces inflammation and oxidative stress in the periphery. However, its role in the central regulation of hypertension remains unknown. It is hypothesized that SIRT1 activation by resveratrol may reduce SNA and lower blood pressure through the regulation of intracellular reactive oxygen species (ROS) and neurotransmitters in the PVN. METHODS: The two-kidney one-clip (2K1C) method was used to induce renovascular hypertension in male Sprague-Dawley rats. Then, bilaterally injections of vehicle (artificial cerebrospinal fluid, aCSF, 0.4 µL) or resveratrol (a SIRT1 agonist, 160 µmol/L, 0.4 µL) into rat PVN were performed for four weeks. RESULTS: PVN SIRT1 expression was lower in the hypertension group than the sham surgery (SHAM) group. Activated SIRT1 within the PVN lowered systolic blood pressure and plasma norepinephrine (NE) levels. It was found that PVN of 2K1C animals injected with resveratrol exhibited increased expression of SIRT1, copper-zinc superoxide dismutase (SOD1), and glutamic acid decarboxylase (GAD67), as well as decreased activity of nuclear factor-kappa B (NF-κB) p65 and NAD(P)H oxidase (NOX), particularly NOX4. Treatment with resveratrol also decreased expression of ROS and tyrosine hydroxylase (TH). CONCLUSION: Resveratrol within the PVN attenuates hypertension via the SIRT1/NF-κB pathway to decrease ROS and restore the balance of excitatory and inhibitory neurotransmitters.


Assuntos
Hipertensão , Núcleo Hipotalâmico Paraventricular , Animais , Cobre/metabolismo , Glutamato Descarboxilase/metabolismo , Masculino , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/metabolismo , Resveratrol/farmacologia , Sirtuína 1/genética , Sirtuína 1/metabolismo , Superóxido Dismutase-1/metabolismo , Sistema Nervoso Simpático/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Zinco/metabolismo
15.
Front Neural Circuits ; 16: 895481, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36247730

RESUMO

The brainstem nucleus locus coeruleus (LC) sends projections to the forebrain, brainstem, cerebellum and spinal cord and is a source of the neurotransmitter norepinephrine (NE) in these areas. For more than 50 years, LC was considered to be homogeneous in structure and function such that NE would be released uniformly and act simultaneously on the cells and circuits that receive LC projections. However, recent studies have provided evidence that LC is modular in design, with segregated output channels and the potential for differential release and action of NE in its projection fields. These new findings have prompted a radical shift in our thinking about LC operations and demand revision of theoretical constructs regarding impact of the LC-NE system on behavioral outcomes in health and disease. Within this context, a major gap in our knowledge is the relationship between the LC-NE system and CNS motor control centers. While we know much about the organization of the LC-NE system with respect to sensory and cognitive circuitries and the impact of LC output on sensory guided behaviors and executive function, much less is known about the role of the LC-NE pathway in motor network operations and movement control. As a starting point for closing this gap in understanding, we propose using an intersectional recombinase-based viral-genetic strategy TrAC (Tracing Axon Collaterals) as well as established ex vivo electrophysiological assays to characterize efferent connectivity and physiological attributes of mouse LC-motor network projection neurons. The novel hypothesis to be tested is that LC cells with projections to CNS motor centers are scattered throughout the rostral-caudal extent of the nucleus but collectively display a common set of electrophysiological properties. Additionally, we expect to find these LC projection neurons maintain an organized network of axon collaterals capable of supporting selective, synchronous release of NE in motor circuitries for the purpose of coordinately regulating operations across networks that are responsible for balance and movement dynamics. Investigation of this hypothesis will advance our knowledge of the role of the LC-NE system in motor control and provide a basis for treating movement disorders resulting from disease, injury, or normal aging.


Assuntos
Locus Cerúleo , Neurônios , Animais , Locus Cerúleo/metabolismo , Camundongos , Neurônios/fisiologia , Norepinefrina/metabolismo , Recombinases/metabolismo , Medula Espinal/metabolismo
16.
Commun Biol ; 5(1): 1097, 2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36253525

RESUMO

Social recognition memory (SRM) is critical for maintaining social relationships and increasing the survival rate. The medial prefrontal cortex (mPFC) is an important brain area associated with SRM storage. Norepinephrine (NE) release regulates mPFC neuronal intrinsic excitability and excitatory synaptic transmission, however, the roles of NE signaling in the circuitry of the locus coeruleus (LC) pathway to the mPFC during SRM storage are unknown. Here we found that LC-mPFC NE projections bidirectionally regulated SRM consolidation. Propranolol infusion and ß-adrenergic receptors (ß-ARs) or ß-arrestin2 knockout in the mPFC disrupted SRM consolidation. When carvedilol, a ß-blocker that can mildly activate ß-arrestin-biased signaling, was injected, the mice showed no significant suppression of SRM consolidation. The impaired SRM consolidation caused by ß1-AR or ß-arrestin2 knockout in the mPFC was not rescued by activating LC-mPFC NE projections; however, the impaired SRM by inhibition of LC-mPFC NE projections or ß1-AR knockout in the mPFC was restored by activating the ß-arrestin signaling pathway in the mPFC. Furthermore, the activation of ß-arrestin signaling improved SRM consolidation in aged mice. Our study suggests that LC-mPFC NE projections regulate SRM consolidation through ß-arrestin-biased ß-AR signaling.


Assuntos
Norepinefrina , Propranolol , Animais , Carvedilol/metabolismo , Camundongos , Norepinefrina/metabolismo , Norepinefrina/farmacologia , Córtex Pré-Frontal/fisiologia , Propranolol/metabolismo , Propranolol/farmacologia , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais , beta-Arrestinas/metabolismo
17.
Sci Rep ; 12(1): 17854, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36284120

RESUMO

Hepatic encephalopathy (HE) is a deterioration of brain function in patients suffering from chronic liver disease, cirrhosis as a result of elevated blood ammonia and the production of pseudo-neurotransmitters. Herein, we investigated the chemical composition of hexane extract from Origanum vulgare (O. vulgare) leaves as well as its possible protective effects against thioacetamide (TAA)-induced HE in rats. GC-MS analysis of the extract revealed tentative identification of twenty-five compounds (82.93%), predominated by cholesten-3-one (27.30%), followed by γ-tocopherol (13.52%), α-tocopherol (5.01%), ß-amyrin (5.24%) and α-amyrin (4.89%). Albino rats were distributed into seven groups (n = 7). G1 served as negative control; G2 and G3 served as controls treated with O. vulgare (100 and 200 mg/kg/p.o b.w, respectively); G4 served as TAA-positive control group (100 mg/kg/day/i.p., three alternative days per week for six weeks); G5, G6, and G7 served as TAA -induced HE rat model that received O. vulgare 100, O. vulgare 200, and silymarin (100 mg/kg of SILY, as standard drug), respectively. TAA showed depressive and anxiety-like behaviors in forced swimming test (FST) and reduction of cognitive score in elevated plus-maze test (EPMT) as well as impairment of locomotor and exploratory activities in open-field test (OFT). TAA caused a significant decline in body weight gain; however, the relative liver weight and brain water content were statistically increased. TAA-intoxicated rats showed significant increase of serum biomarker enzymes, proinflammatory cytokines, blood ammonia levels, brain serotonin, acetyl cholinesterase and cellular lipid peroxidation with significant decrease of brain dopamine, norepinephrine, antioxidant status. The hepatoprotective/neuro-protective activities of O. vulgare was found to be comparable with that of SILY in HE rats model. Where, treatment of TAA-intoxicated rats with O. vulgare attenuated anxiety, depressive-related behaviors, and reduced the biochemical changes in HE-induced by TAA. Therefore, O. vulgare could be an excellent hepato-/neuroprotective against hepatic injury and HE via improving the oxidative/inflammatory status through its antioxidant and neuro-modulatory properties and its effect is equal to that of SILY.


Assuntos
Encefalopatia Hepática , Origanum , Silimarina , Animais , Ratos , alfa-Tocoferol/metabolismo , Amônia/metabolismo , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Colinesterases/metabolismo , Citocinas/metabolismo , Dopamina/metabolismo , gama-Tocoferol/farmacologia , Encefalopatia Hepática/metabolismo , Hexanos , Fígado/metabolismo , Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Origanum/química , Estresse Oxidativo , Ratos Wistar , Serotonina/metabolismo , Silimarina/farmacologia , Tioacetamida , Água/metabolismo
18.
Int J Mol Sci ; 23(19)2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36233200

RESUMO

Reduction in the levels of monoamines, such as serotonin and dopamine in the brain, were reported in patients and animals with depression. SAMe, a universal methyl donor and an epigenetic modulator, is successfully used as an adjunct treatment of depression. We previously found that prenatal treatment with SAMe of Submissive (Sub) mice that serve as a model for depression alleviated many of the behavioral depressive symptoms. In the present study, we treated pregnant Sub mice with 20 mg/kg of SAMe on days 12-15 of gestation and studied the levels of monoamines and the expression of genes related to monoamines metabolism in their prefrontal cortex (PFC) at the age of 3 months. The data were compared to normal saline-treated Sub mice that exhibit depressive-like symptoms. SAMe increased the levels of serotonin in the PFC of female Sub mice but not in males. The levels of 5-HIAA were not changed. SAMe increased the levels of dopamine and of DOPAC in males and females but increased the levels of HVA only in females. The levels of norepinephrine and its metabolite MHPG were unchanged. SAMe treatment changed the expression of several genes involved in the metabolism of these monoamines, also in a sex-related manner. The increase in several monoamines induced by SAMe in the PFC may explain the alleviation of depressive-like symptoms. Moreover, these changes in gene expression more than 3 months after treatment probably reflect the beneficial effects of SAMe as an epigenetic modulator in the treatment of depression.


Assuntos
Dopamina , Serotonina , Ácido 3,4-Di-Hidroxifenilacético/farmacologia , Animais , Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Catecolaminas/metabolismo , Depressão/tratamento farmacológico , Depressão/genética , Dopamina/metabolismo , Epigênese Genética , Feminino , Hierarquia Social , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Metoxi-Hidroxifenilglicol , Camundongos , Norepinefrina/metabolismo , Solução Salina , Serotonina/metabolismo
19.
Int J Mol Sci ; 23(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36232489

RESUMO

We aimed to investigate the efficacy of exercise on preventing arterial stiffness and the potential role of sympathetic nerves within perivascular adipose tissue (PVAT) in pressure-overload-induced heart failure (HF) mice. Eight-week-old male mice were subjected to sham operation (SHAM), transverse aortic constriction-sedentary (TAC-SE), and transverse aortic constriction-exercise (TAC-EX) groups. Six weeks of aerobic exercise training was performed using a treadmill. Arterial stiffness was determined by measuring the elastic modulus. The elastic and collagen fibers of the aorta and sympathetic nerve distribution in PVAT were observed. Circulating noradrenaline (NE), expressions of ß3-adrenergic receptor (ß3-AR), and adiponectin in PVAT were quantified. During the recovery of cardiac function by aerobic exercise, thoracic aortic collagen elastic modulus (CEM) and collagen fibers were significantly decreased (p < 0.05, TAC-SE vs. TAC-EX), and elastin elastic modulus (EEM) was significantly increased (p < 0.05, TAC-SE vs. TAC-EX). Circulating NE and sympathetic nerve distribution in PVAT were significantly decreased (p < 0.05, TAC-SE vs. TAC-EX). The expression of ß3-AR was significantly reduced (p < 0.05, TAC-SE vs. TAC-EX), and adiponectin was significantly increased (p < 0.05, TAC-SE vs. TAC-EX) in PVAT. Regular aerobic exercise can effectively prevent arterial stiffness and extracellular matrix (ECM) remodeling in the developmental course of HF, during which sympathetic innervation and adiponectin within PVAT might be strongly implicated.


Assuntos
Insuficiência Cardíaca , Condicionamento Físico Animal , Sistema Nervoso Simpático , Rigidez Vascular , Animais , Masculino , Camundongos , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Constrição , Elastina/metabolismo , Insuficiência Cardíaca/metabolismo , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Sistema Nervoso Simpático/fisiologia
20.
Acta Physiol (Oxf) ; 236(3): e13887, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36073023

RESUMO

Brainstem noradrenergic neuron clusters form a node integrating efferents projecting to distinct areas such as those regulating cognition and skeletal muscle structure and function, and receive dissimilar afferents through established circuits to coordinate organismal responses to internal and environmental challenges. Genetic lineage tracing shows the remarkable heterogeneity of brainstem noradrenergic neurons, which may explain their varied functions. They project to the locus coeruleus, the primary source of noradrenaline in the brain, which supports learning and cognition. They also project to pre-ganglionic neurons, which lie within the spinal cord and form synapses onto post-ganglionic neurons. The synapse between descending brainstem noradrenergic neurons and pre-ganglionic spinal neurons, and these in turn with post-ganglionic noradrenergic neurons located at the paravertebral sympathetic ganglia, support an anatomical hierarchy that regulates skeletal muscle innervation, neuromuscular transmission, and muscle trophism. Whether any noradrenergic neuron subpopulation is more susceptible to damaged protein deposit and death with ageing and neurodegeneration is a relevant question that answer will help us to detect neurodegeneration at an early stage, establish prognosis, and anticipate disease progression. Loss of muscle mass and strength with ageing, termed sarcopenia, may predict impaired cognition with ageing and neurodegeneration and establish an early time to start interventions aimed at reducing central noradrenergic neurons hyperactivity. Complex multidisciplinary approaches, including genetic tracing, specific circuit labelling, optogenetics and chemogenetics, electrophysiology, and single-cell transcriptomics and proteomics, are required to test this hypothesis pre-clinical.


Assuntos
Neurônios Adrenérgicos , Neurônios Adrenérgicos/metabolismo , Locus Cerúleo/metabolismo , Tronco Encefálico , Norepinefrina/metabolismo , Cognição , Músculo Esquelético/metabolismo
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