RESUMO
Melatonin N-acetyl-5-methoxytriptamine is an ancient molecule which synchronizes the internal biologic activity with the environmental photoperiod. It is synthesized by the pineal gland during the night and released to the general circulation, where it reaches nanomolar concentrations. The indolamine acts through melatonin receptors and binds to different proteins such as calmodulin: a phylogenetically conserved protein which is the main transductor of the calcium signaling. In this review, we will describe evidence supporting that melatonin binds to calmodulin in presence of calcium, and we discuss the effects of this indolamine on the activity of calmodulin kinase II as an inhibitor and as stimulator of calmodulin-dependent protein kinase II activity. We also provide a literature review supporting the relevance of melatonin binding to calmodulin in the regulation of circadian rhythms in unicellular organisms, as well as in neuronal development in mammals as an ancient, conserved mechanism. Finally, we highlight the importance of antioxidant effects of melatonin on calmodulin preservation. SIGNIFICANCE STATEMENT: This review compiled evidence supporting that melatonin binds to calmodulin. We discuss the dual effect of melatonin on the activity of calmodulin kinase II, the possible mechanisms involved, and the relevance on regulation of circadian rhythms and neurodevelopment. Finally, we describe evidence supporting that the binding of melatonin to calmodulin hydrophobic pockets may prevent the oxidation of methionine species with a shielding effect that preserves the functionality of calmodulin.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Calmodulina , Ritmo Circadiano , Melatonina , Melatonina/metabolismo , Calmodulina/metabolismo , Humanos , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Ritmo Circadiano/fisiologia , Cálcio/metabolismo , Ligação ProteicaRESUMO
Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine secreted by the pineal gland during the dark phase of the photoperiod. Its main function is the synchronization of different body rhythms with the dark-light cycle. Research on melatonin has significantly advanced since its discovery and we now know that it has considerable significance in various physiological processes, including immunity, aging, and reproduction. Moreover, in recent years evidence of the pharmacological possibilities of melatonin has increased. Indoleamine, on the other hand, has antidepressant-like effects in rodents, which may be mediated by the activation of calcium-calmodulin-dependent kinase II (CaMKII) and are also related to the regulation of neuroplasticity processes, including neurogenesis, synaptic maintenance, and long-term potentiation. Remarkably, patients with major depression show decreased levels of circulating melatonin in plasma. This review presents evidence of the antidepressant-like effects of melatonin in preclinical models and the participation of CaMKII in these actions. CaMKII's role in cognition and memory processes, which are altered in depressive states, are part of the review, and the effects of melatonin in these processes are also reviewed. Furthermore, participation of CaMKII on structural and synaptic plasticity and the effects of melatonin are also described. Finally, the advantages of using melatonin in combination with other antidepressants such as ketamine for neuroplasticity are described. Evidence supports that CaMKII is activated by melatonin and downstream melatonin receptors and may be the common effector in the synergistic effects of melatonin with other antidepressants. SIGNIFICANCE STATEMENT: This review compiled evidence supporting that melatonin causes antidepressant-like effects in mice through calmodulin kinase II stimulation of downstream melatonin receptors as well as the participation of this enzyme in neuroplasticity, memory, and cognition. Finally, we describe evidence about the effectiveness of antidepressant-like effects of melatonin in combination with ketamine.
Assuntos
Antidepressivos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Melatonina , Plasticidade Neuronal , Melatonina/farmacologia , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Humanos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/metabolismoRESUMO
Idiopathic intellectual disability (IID) encompasses the cases of intellectual disability (ID) without a known cause and represents approximately 50% of all cases. Neural progenitor cells (NPCs) from the olfactory neuroepithelium (NEO) contain the same information as the cells found in the brain, but they are more accessible. Some miRNAs have been identified and associated with ID of known etiology. However, in idiopathic ID, the effect of miRNAs is poorly understood. The aim of this study was to determine the miRNAs regulating the expression of mRNAs that may be involved in development of IID. Expression profiles were obtained using NPC-NEO cells from IID patients and healthy controls by microarray. A total of 796 miRNAs and 28,869 mRNAs were analyzed. Several miRNAs were overexpressed in the IID patients compared to controls. miR-25 had the greatest expression. In silico analysis showed that ROBO2 was the target for miR-25, with the highest specificity and being the most down-regulated. In vitro assay showed an increase of miR-25 expression induced a decrease in ROBO2 expression. In neurodevelopment, ROBO2 plays a crucial role in episodic learning and memory, so its down-regulation, caused by miR-25, could have a fundamental role in the intellectual disability that, until now, has been considered idiopathic.
Assuntos
Deficiência Intelectual , MicroRNAs , Humanos , Deficiência Intelectual/genética , MicroRNAs/genética , Encéfalo , Regulação para Baixo/genética , Aprendizagem , RNA Mensageiro , Proteínas Roundabout , Receptores Imunológicos/genéticaRESUMO
Neoponcirin causes anxiolytic-like effects in mice when administered intraperitoneally but not orally. Neoponcirin is non-water-soluble and insoluble in solvents, and in medium acid, it isomerizes, reducing its bioavailability. To improve the pharmacological properties of neoponcirin, we formed a neoponcirin complex with beta-cyclodextrin (NEO/ßCD), which was characterized by FT-IR, UV-Vis, and NMR, and their solubility profile. We evaluated the antidepressant-like effects of NEO/ßCD acutely administered to mice orally in the behavioral paradigms, the tail suspension (TST) and the forced swimming (FST) tests. We also analyzed the benefits of repeated oral doses of NEO/ßCD on depression- and anxiety-like behaviors induced in mice by chronic unpredictable mild stress (CUMS), using the FST, hole board, and open field tests. We determined the stressed mice's expression of stress-related inflammatory cytokines (IL-1ß, IL-6, and TNFα) and corticosterone. Results showed that a single or chronic oral administration of NEO/ßCD caused a robust antidepressant-like effect without affecting the ambulatory activity. In mice under CUMS, NEO/ßCD also produced anxiolytic-like effects and avoided increased corticosterone and IL-1ß levels. The effects of the NEO/ßCD complex were robust in both the acute and the stress chronic models, improving brain neurochemistry and recovering immune responses previously affected by prolonged stress.
Assuntos
Antidepressivos , Depressão , Estresse Psicológico , beta-Ciclodextrinas , Animais , beta-Ciclodextrinas/farmacologia , beta-Ciclodextrinas/química , Camundongos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Masculino , Estresse Psicológico/tratamento farmacológico , Depressão/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Ansiedade/tratamento farmacológico , Ansiolíticos/farmacologia , Natação , Administração OralRESUMO
Melatonin (MEL) is a pleiotropic indolamine that reaches multiple intracellular targets. Among these, MEL binds to calmodulin (CaM) with high affinity. In presence of Ca2+, CaM binds to CaM-dependent kinase II (CaMKII). The Ca2+-CaM/CaMKII pathway regulates a myriad of brain functions in different cellular compartments. Evidence showing the regulation of this cellular pathway by MEL is scarce. Thus, our main objective was to study the interaction of MEL with CaM and its effects on CaMKII activity in two microenvironments (aqueous and lipidic) naturally occurring within the cell. In addition, colocalization of MEL with CaM in vivo was explored in mice brain hippocampus. In vitro CaM-MEL interaction and the structural conformations of CaM in the presence of this indoleamine were assessed through electrophoretic mobility and isoelectric point. The functional consequence of this interaction was evaluated by measuring CaMKII activity. Ca2+-CaM-MEL increased the activity of CaMKII in aqueous buffer but reduced the kinase activity in lipid buffer. Importantly, MEL colocalizes in vivo with Ca2+-CaM in the hippocampus. Our evidence suggests that MEL regulates the key cellular Ca2+-CaM/CaMKII pathway and might explain why physiological MEL concentrations reduce CaMKII activity in some experimental conditions, while in others it drives biological processes through activation of this kinase.
Assuntos
Calmodulina , Melatonina , Animais , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Calmodulina/metabolismo , Melatonina/farmacologia , Camundongos , FosforilaçãoRESUMO
Melatonin, N-acetyl-5-hydroxytryptamine, is a hormone that synchronizes the internal environment with the photoperiod. It is synthesized in the pineal gland and greatly depends on the endogenous circadian clock located in the suprachiasmatic nucleus and the retina's exposure to different light intensities. Among its most studied functions are the regulation of the waking-sleep rhythm and body temperature. Furthermore, melatonin has pleiotropic actions, which affect, for instance, the modulation of the immune and the cardiovascular systems, as well as the neuroprotection achieved by scavenging free radicals. Recent research has supported that melatonin contributes to neuronal survival, proliferation, and differentiation, such as dendritogenesis and axogenesis, and its processes are similar to those caused by Nerve Growth Factor, Brain-Derived Neurotrophic Factor, Neurotrophin-3, and Neurotrophin-4/5. Furthermore, this indolamine has apoptotic and anti-inflammatory actions in specific brain regions akin to those exerted by neurotrophic factors. This review presents evidence suggesting melatonin's role as a neurotrophic factor, describes the signaling pathways involved in these processes, and, lastly, highlights the therapeutic implications involved.
Assuntos
Melatonina , Glândula Pineal , Melatonina/farmacologia , Melatonina/metabolismo , Glândula Pineal/metabolismo , Fatores de Crescimento Neural/metabolismo , Núcleo Supraquiasmático/metabolismo , Sono/fisiologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Experimental autoimmune encephalomyelitis (EAE) is a relevant animal model of multiple sclerosis (MS). Oxidative stress and chronic inflammation play a major role in the pathogenesis of MS and EAE. Melatonin, a neurohormone, has potent anti-inflammatory properties. The aim of our study was to assess the therapeutic properties of melatonin alone or in combination with interferon ß-1b (IFNß-1b) or glatiramer acetate (GA) on EAE. EAE was induced in male Sprague-Dawley rats with an intraperitoneal injection of a homogenate of spinal cord and pig brain. At day 10 post immunization, rats were euthanized, and their brains were immediately excised and processed to measure oxidative stress markers and membrane fluidity. In addition, proinflammatory cytokines were quantified in plasma. Melatonin alone or in combination with GA and IFNß-1b inhibited the disease process of EAE and the synthesis of proinflammatory cytokines, caused a significant decrement in oxidative stress markers, and preserved the membrane fluidity in the motor cortex, midbrain, and spinal cord. The cumulative index score was significantly reduced in EAE rats treated with melatonin alone or in combination with GA and IFNß-1b. In conclusion, our findings provide preclinical evidence for the use of melatonin as an adjuvant therapeutic treatment for MS.
Assuntos
Encefalomielite Autoimune Experimental , Melatonina , Esclerose Múltipla , Animais , Biomarcadores , Citocinas , Encefalomielite Autoimune Experimental/patologia , Acetato de Glatiramer/farmacologia , Acetato de Glatiramer/uso terapêutico , Interferon beta-1b/uso terapêutico , Interferon beta , Masculino , Melatonina/farmacologia , Melatonina/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , SuínosRESUMO
Melatonin (MEL), an indolamine with diverse functions in the brain, has been shown to produce antidepressant-like effects, presumably through stimulating neurogenesis. We recently showed that the combination of MEL with ketamine (KET), an NMDA receptor antagonist, has robust antidepressant-like effects in mice, at doses that, by themselves, are non-effective and have no adverse effects. Here, we show that the KET/MEL combination increases neurogenesis in a clone derived from human olfactory neuronal precursors, a translational pre-clinical model for effects in the human CNS. Neurogenesis was assessed by the formation of cell clusters > 50 µm in diameter, positively stained for nestin, doublecortin, BrdU and Ki67, markers of progenitor cells, neurogenesis, and proliferation. FGF, EGF and BDNF growth factors increased the number of cell clusters in cultured, cloned ONPs. Similarly, KET or MEL increased the number of clusters in a dose-dependent manner. The KET/MEL combination further increased the formation of clusters, with a maximal effect obtained after a triple administration schedule. Our results show that the combination of KET/MEL, at subeffective doses that do not produce adverse effects, stimulate neurogenesis in human neuronal precursors. Moreover, the mechanism by which the combination elicits neurogenesis is meditated by melatonin receptors, CaM Kinase II and CaM antagonism. This could have clinical advantages for the fast treatment of depression.
Assuntos
Ketamina , Melatonina , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Hipocampo/metabolismo , Humanos , Ketamina/metabolismo , Ketamina/farmacologia , Melatonina/metabolismo , Melatonina/farmacologia , Camundongos , Neurogênese , NeurôniosRESUMO
Major depressive disorder is a disabling disease with the number of affected individuals increasing each year. Current antidepressant treatments take between three to six weeks to be effective with forty percent of patients being resistant to treatment, making it necessary to search for new antidepressant treatments. Ketamine, a phencyclidine hydrochloride derivative, given intravenously, induces a rapid antidepressant effect in humans. In mice, it causes increased neurogenesis and antidepressant-like effects. However, it also produces psychomimetic effects in humans and in rodents increases the locomotor activity. In contrast, melatonin, a hormone secreted by the pineal gland and synthesized in extrapineal sites, increases new neuron formation and causes antidepressant-like effects in adult rodents with no collateral effects. Here, we assessed the effects of a non-effective dose of ketamine in combination with melatonin (KET/MEL), both on neurogenesis as well as on the antidepressant-like effect in mice. Our results showed that KET/MEL combination increased neurogenesis and produced antidepressant-like effects without altering locomotor activity after both single and triple administration protocols. Our data strongly suggest that KET/MEL combination could be used to simultaneously promote neurogenesis, reverting neuronal atrophy and inducing antidepressant-like effects.
Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Ketamina/uso terapêutico , Melatonina/uso terapêutico , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Combinação de Medicamentos , Sinergismo Farmacológico , Ketamina/administração & dosagem , Ketamina/farmacologia , Masculino , Melatonina/administração & dosagem , Melatonina/farmacologia , Camundongos , Neurogênese/efeitos dos fármacosRESUMO
Histopathological hallmarks of dementia have been described postmortem in the brain of patients with Alzheimer's disease (AD). Tau, a microtubule associated protein, is abnormally arranged in neurofibrillary tangles. In living AD patients, total tau (t-tau) and hyperphosphorylated tau (p-tau) levels are increased in the cerebrospinal fluid obtained by lumbar puncture. Herein, we studied the t-tau and p-tau levels as well as the subcellular distribution of t-tau in olfactory neuronal precursors obtained by exfoliation of the nasal cavity of AD patients and control participants. Data showed that t-tau and p-tau levels were increased in cell homogenates from AD patients. Also, t-tau immunoreactivity was arranged in a punctate pattern in olfactory neuronal precursors derived from an AD participant with 5 years of evolution and in the oldest participants, either control subjects or those with Alzheimer's disease. Results support that exfoliated neuronal precursors have tau alterations demonstrated in postmortem brain and in the cerebrospinal fluid. This evidence and because the obtainment of olfactory neuronal precursors is a noninvasive procedure, detection of tau alterations shown here might be useful for an early diagnosis of AD-type dementia.
Assuntos
Doença de Alzheimer/diagnóstico , Células-Tronco Neurais/patologia , Bulbo Olfatório/patologia , Idoso , Idoso de 80 Anos ou mais , Calibragem , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cavidade Nasal/patologia , Fosforilação , Projetos Piloto , Proteínas Recombinantes/metabolismo , Proteínas tau/metabolismoRESUMO
The pro-oxidant compound okadaic acid (OKA) mimics alterations found in Alzheimer's disease (AD) as oxidative stress and tau hyperphosphorylation, leading to neurodegeneration and cognitive decline. Although loss of dendrite complexity occurs in AD, the study of this post-synaptic domain in chemical-induced models remains unexplored. Moreover, there is a growing expectation for therapeutic adjuvants to counteract these brain dysfunctions. Melatonin, a free-radical scavenger, inhibits tau hyperphosphorylation, modulates phosphatases, and strengthens dendritic arbors. Thus, we determined if OKA alters the dendritic arbors of hilar hippocampal neurons and whether melatonin prevents, counteracts, or reverses these damages. Rat organotypic cultures were incubated with vehicle, OKA, melatonin, and combined treatments with melatonin either before, simultaneously, or after OKA. DNA breaks were assessed by TUNEL assay and nuclei were counterstained with DAPI. Additionally, MAP2 was immunostained to assess the dendritic arbor properties by the Sholl method. In hippocampal hilus, OKA increased DNA fragmentation and reduced the number of MAP2(+) cells, whereas melatonin protected against oxidation and apoptosis. Additionally, OKA decreased the dendritic arbor complexity and melatonin not only counteracted, but also prevented and reversed the dendritic arbor retraction, highlighting its role in post-synaptic domain integrity preservation against neurodegenerative events in hippocampal neurons.
Assuntos
Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Melatonina/farmacologia , Ácido Okadáico/farmacologia , Oxidantes/farmacologia , Animais , Fragmentação do DNA , Dendritos/patologia , Imuno-Histoquímica , Fármacos Neuroprotetores/farmacologia , Organoides/efeitos dos fármacos , Oxirredução , Estresse Oxidativo , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Melatonin is synthesized by the pineal gland with a circadian rhythm in synchrony with the environmental light/dark cycle. A gradual increase in circulating levels of melatonin occur after lights off, reaching its maximum around the middle of the dark phase. Agonists of melatonin receptors have proved effectiveness as antidepressants in clinical trials. However, there is contradictory evidence about the potential antidepressant effect of melatonin itself. Herein we studied melatonin administration in mice at two zeitgeber times (ZT; ZT = 0 lights on; 12:12 L/D), one hour before the beginning (ZT11) and at the middle (ZT18) of the dark phase after either a single or a three-dose protocol. Behavioral despair was assessed through a forced-swimming test (FST) or a tail suspension test (TST), at ZT18.5. A single dose of 4 mg/kg melatonin at ZT11 was effective to reduce the immobility time in both tests. However, acute administration of melatonin at ZT18 was not effective in mice subjected to FST, and a higher dose (16 mg/kg) was required to reduce immobility time in the TST. A three-dose administration protocol of 16 mg/kg melatonin (ZT18, ZT11, and ZT18) significantly reduced immobility time in FST. Data indicate that the timely administration of melatonin could improve its antidepressant-like effect.
Assuntos
Antidepressivos/uso terapêutico , Melatonina/uso terapêutico , Animais , Antidepressivos/sangue , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Elevação dos Membros Posteriores , Masculino , Melatonina/sangue , Camundongos , Natação/fisiologiaRESUMO
Melatonin (MEL) is an ancient molecule, broadly distributed in nature from unicellular to multicellular species. MEL is an indoleamine that acts on a wide variety of cellular targets regulating different physiological functions. This review is focused on the role played by this molecule in the regulation of the circadian rhythms in crayfish. In these species, information about internal and external time progression might be transmitted by the periodical release of MEL and other endocrine signals acting through the pacemaker. We describe documented and original evidence in support of this hypothesis that also suggests that the rhythmic release of MEL contributes to the reinforcement of the temporal organization of nocturnal or diurnal circadian oscillators. Finally, we discuss how MEL might coordinate functions that converge in the performance of complex behaviors, such as the agonistic responses to establish social dominance status in Procambarus clarkii and the burrowing behavior in the secondary digging crayfish P. acanthophorus.
Assuntos
Astacoidea/fisiologia , Ritmo Circadiano , Melatonina/metabolismo , Animais , Astacoidea/metabolismo , Comportamento AnimalRESUMO
Dim light exposure of the mother during pregnancy has been proposed as one of the environmental factors that affect the fetal brain development in schizophrenia. Melatonin circulating levels are regulated by the environmental light/dark cycle. This hormone stimulates neuronal differentiation in the adult brain. However, little is known about its role in the fetal human brain development. Olfactory neuronal precursors (ONPs) are useful for studying the physiopathology of neuropsychiatric diseases because they mimic all the stages of neurodevelopment in culture. Here, we first characterized whether melatonin stimulates neuronal differentiation in cloned ONPs obtained from a healthy control subject (HCS). Then, melatonin effects were evaluated in primary cultures of ONPs derived from a patient diagnosed with schizophrenia (SZ) and an age- and gender-matched HCS. Axonal formation was evidenced morphologically by tau immunostaining and by GSK3ß phosphorylated state. Potassium-evoked secretion was assessed as a functional feature of differentiated neurons. As well, we report the expression of MT1/2 receptors in human ONPs for the first time. Melatonin stimulated axonal formation and ramification in cloned ONPs through a receptor-mediated mechanism and enhanced the amount and velocity of axonal and somatic secretion. SZ ONPs displayed reduced axogenesis associated with lower levels of pGSK3ß and less expression of melatonergic receptors regarding the HCS ONPs. Melatonin counteracted this reduction in SZ cells. Altogether, our results show that melatonin signaling is crucial for functional differentiation of human ONPs, strongly suggesting that a deficit of this indoleamine may lead to an impaired neurodevelopment which has been associated with the etiology of schizophrenia.
Assuntos
Melatonina/fisiologia , Células Neuroepiteliais/fisiologia , Crescimento Neuronal , Esquizofrenia/etiologia , Axônios/metabolismo , Estudos de Casos e Controles , Polaridade Celular , Células Cultivadas , Receptores de Melatonina/metabolismo , Sinapses/fisiologiaRESUMO
Second generation antipsychotics (SGA) are associated with adverse cardiometabolic side effects contributing to premature mortality in patients. While mechanisms mediating these cardiometabolic side effects remain poorly understood, three independent studies recently demonstrated that melatonin was protective against cardiometabolic risk in SGA-treated patients. As one of the main target areas of circulating melatonin in the brain is the suprachiasmatic nucleus (SCN), we hypothesized that the SCN is involved in SGA-induced early cardiovascular effects in Wistar rats. We evaluated the acute effects of olanzapine and melatonin in the biological clock, paraventricular nucleus and autonomic nervous system using immunohistochemistry, invasive cardiovascular measurements, and Western blot. Olanzapine induced c-Fos immunoreactivity in the SCN followed by the paraventricular nucleus and dorsal motor nucleus of the vagus indicating a potent induction of parasympathetic tone. The involvement of a SCN-parasympathetic neuronal pathway after olanzapine administration was further documented using cholera toxin-B retrograde tracing and vasoactive intestinal peptide immunohistochemistry. Olanzapine-induced decrease in blood pressure and heart rate confirmed this. Melatonin abolished olanzapine-induced SCN c-Fos immunoreactivity, including the parasympathetic pathway and cardiovascular effects while brain areas associated with olanzapine beneficial effects including the striatum, ventral tegmental area, and nucleus accumbens remained activated. In the SCN, olanzapine phosphorylated the GSK-3ß, a regulator of clock activity, which melatonin prevented. Bilateral lesions of the SCN prevented the effects of olanzapine on parasympathetic activity. Collectively, results demonstrate the SCN as a key region mediating the early effects of olanzapine on cardiovascular function and show melatonin has opposing and potentially protective effects warranting additional investigation.
Assuntos
Benzodiazepinas/toxicidade , Relógios Biológicos/efeitos dos fármacos , Melatonina/uso terapêutico , Animais , Depressores do Sistema Nervoso Central/farmacologia , Depressores do Sistema Nervoso Central/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Melatonina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Olanzapina , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Núcleo Supraquiasmático/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
The alterations that underlie the pathophysiology of schizophrenia (SCZ) include the dysregulation of structural and functional properties of neurons. Among these, the secretion of neurotransmitters and hormones, which plays a key role for neuronal communication and development, is altered. Neuronal precursors from the human olfactory epithelium have been recently characterized as a reliable model for studying the etiopathogenesis of neuropsychiatric diseases. Our previous work has shown that melatonin enhances the development of morphological and functional features of cloned olfactory neuronal precursors (ONPs) from a healthy subject. In this work we found that primary cultures of ONPs obtained from a schizophrenic patient display an increased potassium-evoked secretion, when compared with ONPs from an age- and gender-matched healthy control subject (HCS). Secretion was evaluated by FM1-43 fluorescence cumulative changes in response to depolarization. Interestingly, a 12 h-melatonin treatment modulated the abnormally increased secretion in SCZ ONPs and brought it to levels similar to those found in the HCS ONPs. Our results suggest that the actin cytoskeleton might be a target for melatonin effects, since it induces the thickening of actin microfilament bundles. Further research will address the mechanisms by which melatonin modulates neurochemical secretion from ONPs.
Assuntos
Melatonina/farmacologia , Células-Tronco Neurais/metabolismo , Mucosa Olfatória/patologia , Esquizofrenia/patologia , Citoesqueleto de Actina/metabolismo , Adulto , Cálcio/farmacologia , Humanos , Masculino , Células-Tronco Neurais/efeitos dos fármacos , Projetos Piloto , Potássio/farmacologia , Vesículas Secretórias/efeitos dos fármacos , Vesículas Secretórias/metabolismo , Sinapses/metabolismo , Proteína 1 Associada à Membrana da Vesícula/metabolismo , Proteína 2 Associada à Membrana da Vesícula/metabolismoRESUMO
In adulthood, differentiation of precursor cells into neurons continues in several brain structures as well as in the olfactory neuroepithelium. Isolated precursors allow the study of the neurodevelopmental process in vitro. The aim of this work was to determine whether the expression of functional Voltage-Activated Ca(2+) Channels (VACC) is dependent on the neurodevelopmental stage in neuronal cells obtained from the human olfactory epithelium of a single healthy donor. The presence of channel-forming proteins in Olfactory Sensory Neurons (OSN) was demonstrated by immunofluorescent labeling, and VACC functioning was assessed by microfluorometry and the patch-clamp technique. VACC were immunodetected only in OSN. Mature neurons responded to forskolin with a five-fold increase in Ca(2+). By contrast, in precursor cells, a subtle response was observed. The involvement of VACC in the precursors' response was discarded for the absence of transmembrane inward Ca(2+) movement evoked by step depolarizations. Data suggest differential expression of VACC in neuronal cells depending on their developmental stage and also that the expression of these channels is acquired by OSN during maturation, to enable specialized functions such as ion movement triggered by membrane depolarization. The results support that VACC in OSN could be considered as a functional marker to study neurodevelopment.
Assuntos
Canais de Cálcio/metabolismo , Células Neuroepiteliais/metabolismo , Neurogênese , Neurônios Receptores Olfatórios/metabolismo , Esquizofrenia/metabolismo , Biomarcadores/metabolismo , Canais de Cálcio/genética , Células Cultivadas , Feminino , Humanos , Células Neuroepiteliais/citologia , Neurônios Receptores Olfatórios/citologia , Esquizofrenia/diagnósticoRESUMO
Melatonin (MEL), the main product synthesized by the pineal gland, stimulates early and late stages of neurodevelopment in the adult brain. MEL increases dendrite length, thickness and complexity in the hilar and mossy neurons of hippocampus. Dendrite formation involves activation of Ca2+/Calmodulin (CaM)-dependent kinase II (CaMKII) by CaM. Previous work showed that MEL increased the synthesis and translocation of CaM, suggesting that MEL activates CaM-dependent enzymes by this pathway. In this work we investigated whether MEL stimulates dendrite formation by CaMKII activation in organotypic cultures from adult rat hippocampus. We found that the CaMKII inhibitor, KN-62, abolished the MEL stimulatory effects on dendritogenesis and that MEL increased the relative amount of CaM in the soluble fraction of hippocampal slices. Also, PKC inhibition abolished dendritogenesis, while luzindole, an antagonist of MEL receptors (MT1/2), partially blocked the effects of MEL. Moreover, autophosphorylation of CaMKII and PKC was increased in presence of MEL, as well as phosphorylation of ERK1/2. Our results indicate that MEL stimulates dendrite formation through CaMKII and the translocation of CaM to the soluble fraction. Dendritogenesis elicited by MEL also required PKC activation, and signaling through MT1/2 receptors was partially involved. Data strongly suggest that MEL could repair the loss of hippocampal dendrites that occur in neuropsychiatric disorders by increasing CaM levels and activation of CaMKII.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Calmodulina/metabolismo , Dendritos/metabolismo , Hipocampo/metabolismo , Melatonina/farmacologia , Animais , Dendritos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Neurogênese/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteína Quinase C/metabolismo , Ratos Wistar , Receptores de Melatonina/metabolismo , Triptaminas/farmacologiaRESUMO
Alzheimer's disease (AD), as the main cause of dementia, affects millions of people around the world, whose diagnosis is based mainly on clinical criteria. Unfortunately, the diagnosis is obtained very late, when the neurodegenerative damage is significant for most patients. Therefore, the exhaustive study of biomarkers is indispensable for diagnostic, prognostic, and even follow-up support. AD is a multifactorial disease, and knowing its underlying pathological mechanisms is crucial to propose new and valuable biomarkers. In this review, we summarize some of the main biomarkers described in AD, which have been evaluated mainly by imaging studies in cerebrospinal fluid and blood samples. Furthermore, we describe and propose neuronal precursors derived from the olfactory neuroepithelium as a potential resource to evaluate some of the widely known biomarkers of AD and to gear toward searching for new biomarkers. These neuronal lineage cells, which can be obtained directly from patients through a non-invasive and outpatient procedure, display several characteristics that validate them as a surrogate model to study the central nervous system, allowing the analysis of AD pathophysiological processes. Moreover, the ease of obtaining and harvesting endows them as an accessible and powerful resource to evaluate biomarkers in clinical practice.
RESUMO
There have been no studies reporting on the use of biological specimens in Mexico to analyze the prevalence of alcohol and drug use among Emergency Department (ED) patients with a road traffic injury (RTI). We report here on a sample of 304 adult patients, admitted to the ED of a public hospital in Mexico City from January to April 2022, after being involved in an RTI. Patients gave informed consent for a breath test measuring breath alcohol concentration (BAC) and a saliva screening test for six classes of drugs (amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, and methamphetamine). We found that at least one in every four patients (27.6%) had traces of alcohol or drugs in their body upon arrival in the ED. The breath test found a positive BAC in 16.1% of the sample; the most common substances detected in saliva were amphetamines or methamphetamine (8.6%), followed by cocaine (7.0%) and cannabis (6.9%). Only a few variables differentiated those with positive BAC from those with negative BAC (male, arriving on a weekend day or night, and arriving by ambulance), and even fewer variables differentiated those testing positives for drugs than those testing negative (less than 13 years of education and drivers of cars, bicycles, or other vehicles). While alcohol continues to be the single most used substance, our findings indicate that stimulants are of great concern. Since those testing positives for alcohol or drugs are so similar in their demographic pattern to those testing negative, the introduction of biological testing as a routine practice in the ED is highly recommended. Routine testing makes it possible to provide the patient with the best treatment and is also the best way to assess substance use.