RESUMO
Neurons rely on mitochondrial energy metabolism for essential functions like neurogenesis, neurotransmission, and synaptic plasticity. Mitochondrial dysfunctions are associated with neurodevelopmental disorders including Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, which also presents with motor skill deficits. However, the precise role of mitochondria in the pathophysiology of FXS remains largely unknown. Notably, previous studies have linked the serotonergic system and mitochondrial activity to FXS. Our study investigates the potential therapeutic role of serotonin receptor 1A (5-HT1A) in FXS. Using the Drosophila model of FXS, we demonstrated that treatment with eltoprazine, a 5-HT1A agonist, can ameliorate synaptic transmission, correct mitochondrial deficits, and ultimately improve motor behavior. While these findings suggest that the 5-HT1A-mitochondrial axis may be a promising therapeutic target, further investigation is needed in the context of FXS.
Assuntos
Modelos Animais de Doenças , Síndrome do Cromossomo X Frágil , Mitocôndrias , Receptor 5-HT1A de Serotonina , Animais , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Drosophila , Piperazinas/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Drosophila melanogaster/efeitos dos fármacos , Atividade Motora/efeitos dos fármacosRESUMO
BACKGROUND: Prolonged dopaminergic replacement therapy in PD results in pulsatile dopamine receptors stimulation in both dorsal and ventral striatum causing wearing off, motor fluctuations, and nonmotor side effects such as behavioral addictions. Among impulse control disorders, binge eating can be easily modeled in laboratory animals. OBJECTIVES: We hypothesize that manipulation of dopamine levels in a 6-hydroxydopamine-lesioned rats, as a model of PD characterized by a different extent of dopamine denervation between dorsal and ventral striatum, would influence both synaptic plasticity of the nucleus accumbens and binge-like eating behavior. METHODS: Food preference, food intake, and weight gain were monitored in sham-operated and unilaterally lesioned rats, subjected to a modified version of Corwin's limited access protocol, modelling binge eating disorder. Electrophysiological properties and long-term potentiation of GABAergic spiny projection neurons of the nucleus accumbens core were studied through ex vivo intracellular and patch-clamp recordings from corticostriatal slices of naïve and l-dopa-treated rats. RESULTS: Sham-operated animals with intact nucleus accumbens core plasticity reliably developed food-addiction-like behavior when exposed to intermittent access to a highly palatable food. In contrast, parkinsonian rats were unresponsive to such restriction regimens, and also plasticity was lost in ventral spiny neurons. Chronic l-dopa reestablished long-term potentiation and compulsive eating, but with a different temporal dynamic that follows that of drug administration. CONCLUSIONS: Our data indicate that endogenous and exogenous dopamine drive binge-like consumption of a palatable food in healthy and parkinsonian rats with distinct temporal dynamics, providing new insights into the complexity of l-dopa effects on the mesolimbic dopaminergic system. © 2019 International Parkinson and Movement Disorder Society.
Assuntos
Dopaminérgicos/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Levodopa/farmacologia , Transtornos Parkinsonianos/fisiopatologia , Animais , Preferências Alimentares/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiopatologia , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Ratos , Ratos Wistar , Aumento de Peso/efeitos dos fármacosRESUMO
BACKGROUND: Recent studies support the therapeutic utility of repetitive transcranial magnetic stimulation in Parkinson's disease (PD), whose progression is correlated with loss of corticostriatal long-term potentiation and long-term depression. Glial cell activation is also a feature of PD that is gaining increasing attention in the field because astrocytes play a role in chronic neuroinflammatory responses but are also able to manage dopamine (DA) levels. METHODS: Intermittent theta-burst stimulation protocol was applied to study the effect of therapeutic neuromodulation on striatal DA levels measured by means of in vivo microdialysis in 6-hydroxydopamine-hemilesioned rats. Effects on corticostriatal synaptic plasticity were studied through in vitro intracellular and whole-cell patch clamp recordings while stepping test and CatWalk were used to test motor behavior. Immunohistochemical analyses were performed to analyze morphological changes in neurons and glial cells. RESULTS: Acute theta-burst stimulation induced an increase in striatal DA levels in hemiparkinsonian rats, 80 minutes post-treatment, correlated with full recovery of plasticity and amelioration of motor performances. With the same timing, immediate early gene activation was restricted to striatal spiny neurons. Intense astrocytic and microglial responses were also significantly reduced 80 minutes following theta-burst stimulation. CONCLUSION: Taken together, these results provide a first glimpse on physiological adaptations that occur in the parkinsonian striatum following intermittent theta-burst stimulation and may help to disclose the real potential of this technique in treating PD and preventing DA replacement therapy-associated disturbances. © 2017 International Parkinson and Movement Disorder Society.
Assuntos
Astrócitos/fisiologia , Córtex Cerebral , Corpo Estriado , Dopamina/metabolismo , Microglia/fisiologia , Atividade Motora/fisiologia , Plasticidade Neuronal/fisiologia , Transtornos Parkinsonianos/terapia , Estimulação Magnética Transcraniana/métodos , Adrenérgicos/farmacologia , Animais , Comportamento Animal/fisiologia , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Genes Precoces/fisiologia , Masculino , Microdiálise , Oxidopamina/farmacologia , Transtornos Parkinsonianos/induzido quimicamente , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Ritmo Teta/fisiologiaRESUMO
L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs) represent the main side effect of Parkinson's Disease (PD) therapy. Among the various pharmacological targets for novel therapeutic approaches, the serotonergic system represents a promising one. In experimental models of PD and in PD patients the development of abnormal involuntary movements (AIMs) and LIDs, respectively, is accompanied by the impairment of bidirectional synaptic plasticity in key structures such as striatum. Recently, it has been shown that the 5-HT1A/1B receptor agonist, eltoprazine, significantly decreased LIDs in experimental PD and human patients. Despite the fact that several papers have tested this and other serotonergic drugs, nothing is known about the electrophysiological consequences on this combined serotonin receptors modulation at striatal neurons. The present study demonstrates that activation of 5-HT1A/1B receptors reduces AIMs via the restoration of Long-Term Potentiation (LTP) and synaptic depotentiation in a sub-set of striatal spiny projection neurons (SPNs). This recovery is associated with the normalization of D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways, and the recovery of NMDA receptor subunits balance, indicating these events as key elements in AIMs induction. Moreover, we analyzed whether the manipulation of the serotonergic system might affect motor behavior and cognitive performances. We found that a defect in locomotor activity in parkinsonian and L-DOPA-treated rats was reversed by eltoprazine treatment. Conversely, the impairment in the striatal-dependent learning was found exacerbated in L-DOPA-treated rats and eltoprazine failed to recover it.
Assuntos
Comportamento Animal/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Discinesia Induzida por Medicamentos/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Transtornos Parkinsonianos/complicações , Piperazinas/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Animais , Corpo Estriado/metabolismo , Discinesia Induzida por Medicamentos/metabolismo , Discinesia Induzida por Medicamentos/psicologia , Levodopa , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Ratos , Ratos Wistar , Sinapses/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismoRESUMO
OBJECTIVE: To compare the effectiveness of 2 insulin protocols to treat glucocorticoid-induced hyperglycemia in the nonintensive care hospital setting. METHODS: A randomized, open-label, parallel-arm study was conducted comparing standard recommended care of complete insulin orders (CIO) (i.e., 3-part insulin regimen of long-acting basal [background], rapid-acting bolus [mealtime], and rapid-acting correction factor) to an experimental group following a regimen of Neutral Protamine Hagedorn (NPH) plus CIO (NPH-CIO). The primary outcome was mean blood glucose (BG), and the secondary outcome was percent of BG in target range of 70 to 180 mg/dL. Hypoglycemia was also evaluated. RESULTS: Sixty-one patients completed 2 to 5 consecutive inpatient days (31 CIO; 30 NPH-CIO). Baseline mean BG results were 237.2 ± 50.2 and 221.9 ± 35.8 mg/dL (P = .30) in the CIO and NPH-CIO groups, respectively. No significant difference in overall mean BG between the 2 groups was detected; however, a significant difference arose on day 3: mean BG 181.8 ± 32.6 mg/dL (CIO) versus 157.2 ± 6.1 mg/dL (NPH-CIO) (P = .03). Moreover, the total daily doses (TDDs) of insulin did not differ: 34.8 ± 43.0 units (CIO) versus 35.8 ± 25.0 units (NPH-CIO) (P = .13). Percent of BG in target was 54.6% (CIO) and 62% (NPH-CIO) (P = .24). Incidence of severe hypoglycemia (<50 mg/dL) was the same in both groups (0.1%). CONCLUSION: NPH added to 3-part insulin regimen (CIO) may be an effective way to a combat glucocorticoid-induced hyperglycemia, though further research is needed in a larger population.
Assuntos
Algoritmos , Glicemia/metabolismo , Glucocorticoides/efeitos adversos , Hospitalização , Hiperglicemia/induzido quimicamente , Hiperglicemia/terapia , Planejamento de Assistência ao Paciente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Hiperglicemia/sangue , Hiperglicemia/epidemiologia , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
PURPOSE: To determine the effectiveness of a shared decision-making (SDM) tool versus guideline-informed usual care in translating evidence into primary care, and to explore how use of the tool changed patient perspectives about diabetes medication decision making. METHODS: In this mixed methods multicenter cluster randomized trial, we included patients with type 2 diabetes mellitus and their primary care clinicians. We compared usual care with or without a within-encounter SDM conversation aid. We assessed participant-reported decisions made and quality of SDM (knowledge, satisfaction, and decisional conflict), clinical outcomes, adherence, and observer-based patient involvement in decision-making (OPTION12-scale). We used semi-structured interviews with patients to understand their perspectives. RESULTS: We enrolled 350 patients and 99 clinicians from 20 practices and interviewed 26 patients. Use of the conversation aid increased post-encounter patient knowledge (correct answers, 52% vs. 45%, p = 0.02) and clinician involvement of patients (Mean between-arm difference in OPTION12, 7.3 (95% CI 3, 12); p = 0.003). There were no between-arm differences in treatment choice, patient or clinician satisfaction, encounter length, medication adherence, or glycemic control. Qualitative analyses highlighted differences in how clinicians involved patients in decision making, with intervention patients noting how clinicians guided them through conversations using factors important to them. CONCLUSIONS: Using an SDM conversation aid improved patient knowledge and involvement in SDM without impacting treatment choice, encounter length, medication adherence or improved diabetes control in patients with type 2 diabetes. Future interventions may need to focus specifically on patients with signs of poor treatment fit. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov: NCT01502891.
Assuntos
Diabetes Mellitus Tipo 2 , Tomada de Decisões , Técnicas de Apoio para a Decisão , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Adesão à Medicação , Participação do PacienteRESUMO
Copy-number variants of the CYFIP1 gene in humans have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), two neuropsychiatric disorders characterized by defects in brain connectivity. Here, we show that CYFIP1 plays an important role in brain functional connectivity and callosal functions. We find that Cyfip1-heterozygous mice have reduced functional connectivity and defects in white matter architecture, similar to phenotypes found in patients with ASD, SCZ and other neuropsychiatric disorders. Cyfip1-deficient mice also present decreased myelination in the callosal axons, altered presynaptic function, and impaired bilateral connectivity. Finally, Cyfip1 deficiency leads to abnormalities in motor coordination, sensorimotor gating and sensory perception, which are also known neuropsychiatric disorder-related symptoms. These results show that Cyfip1 haploinsufficiency compromises brain connectivity and function, which might explain its genetic association to neuropsychiatric disorders.
Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Predisposição Genética para Doença/genética , Proteínas do Tecido Nervoso/metabolismo , Esquizofrenia/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Transtorno do Espectro Autista/diagnóstico por imagem , Axônios , Comportamento Animal , Encéfalo/diagnóstico por imagem , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Estudos de Associação Genética , Haploinsuficiência , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Sistema Nervoso/metabolismo , Fenômenos Fisiológicos do Sistema Nervoso/genética , Fenótipo , Desempenho Psicomotor , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética , Filtro Sensorial , Substância BrancaRESUMO
Memantine is an open channel blocker that antagonizes NMDA receptors reducing the inappropriate calcium (Ca(2+)) influx occurring in presence of moderately increased glutamate levels. At the same time, memantine has the ability to preserve the transient physiological activation of NMDA receptor, essential for learning and memory formation at synaptic level. In the present study we investigated the effects exerted by memantine on striatal synaptic plasticity in rat striatal spiny projection neurons (SPNs). In vitro application of memantine in striatal slices elicited a disruption of long-term potentiation (LTP) induction and maintenance, and revealed, in the majority of the recorded neurons, a long-term depression (LTD), whose amplitude was concentration-dependent (0.3-10 µM). Interestingly, preincubation with the dopamine (DA) D2 receptor antagonist sulpiride (10 µM) prevented memantine-induced LTD and restored LTP. Moreover, the DA D2 agonist quinpirole (10 µM), similarly to memantine, induced LTD in a subgroup of SPNs. In addition, memantine-induced LTD was also prevented by the CB1 endocannabinoid receptor antagonist AM 251 (1 µM). These results suggest that the actions exerted by memantine on striatal synaptic plasticity, and in particular the induction of LTD observed in SPNs, could be attributed to its ability to activate DA D2 receptors. By contrast, blockade of NMDA receptor is not involved in memantine-induced LTD since APV (30 µM) and MK801 (10 µM), two NMDA receptor antagonists, failed to induce this form of synaptic plasticity. Our data indicate that memantine could be used as treatment of neurological disorders in which DA D2 receptor represents a possible therapeutic target.