RESUMEN
Methadone is a synthetic long-acting opioid that is increasingly used in the replacement therapy of opioid-addicted patients, including pregnant women. However, methadone therapy in this population poses challenges, as it induces cognitive and behavioral impairments in infants exposed to this opioid during prenatal development. In animal models, prenatal methadone exposure results in detrimental consequences to the central nervous system, such as: (i) increased neuronal apoptosis; (ii) disruption of oligodendrocyte maturation and increased apoptosis and (iii) increased microglia and astrocyte activation. However, it remains unclear whether these deleterious effects result from a direct effect of methadone on brain cells. Therefore, our goal was to uncover the impact of methadone on single brain cell types in vitro. Primary cultures of rat neurons, oligodendrocytes, microglia, and astrocytes were treated for three days with 10 µM methadone to emulate a chronic administration. Apoptotic neurons were identified by cleaved caspase-3 detection, and synaptic density was assessed by the juxtaposition of presynaptic and postsynaptic markers. Apoptosis of oligodendrocyte precursors was determined by cleaved caspase-3 detection. Oligodendrocyte myelination was assessed by immunofluorescence, while microglia and astrocyte proinflammatory activation were assessed by both immunofluorescence and RT-qPCR. Methadone treatment increased neuronal apoptosis and reduced synaptic density. Furthermore, it led to increased oligodendrocyte apoptosis and a reduction in the myelinating capacity of these cells, and promoted the proinflammatory activation of microglia and astrocytes. We showed that methadone, the most widely used drug in opioid replacement therapy for pregnant women with opioid addiction, directly impairs brain cells in vitro, highlighting the need for developing alternative therapies to address opioid addiction in this population.
Asunto(s)
Apoptosis , Astrocitos , Metadona , Microglía , Neuronas , Oligodendroglía , Metadona/farmacología , Animales , Ratas , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Apoptosis/efectos de los fármacos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Células Cultivadas , Femenino , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Embarazo , Analgésicos Opioides/farmacología , Ratas Sprague-DawleyRESUMEN
Different investigations lead to the urgent need to generate validated clinical protocols as a tool for medical doctors to orientate patients under risk for a preventive approach to control Alzheimer's disease. Moreover, there is consensus that the combined effects of risk factors for the disease can be modified according to lifestyle, thus controlling at least 40% of cases. The other fraction of cases are derived from candidate genes and epigenetic components as a relevant factor in AD pathogenesis. At this point, it appears to be of critical relevance the search for molecular biomarkers that may provide information on probable pathological events and alert about early detectable risks to prevent symptomatic events of the disease. These precocious detection markers will then allow early interventions of non-symptomatic subjects at risk. Here, we summarize the status and potential avenues of prevention and highlight the usefulness of biological and reliable markers for AD.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/prevención & control , Biomarcadores , Estilo de Vida , Factores de Riesgo , Proteínas tauRESUMEN
Alzheimer's disease (AD) is the most common form of dementia in the elderly. AD is a multifactorial disease, affected by several factors including amyloid-ß42 oligomers, self-assembled tau, microbiota molecules, etc. However, inflammatory components are critical to trigger AD. Neuroinflammatory pathology links glial activation by "damage signals" with tau hyperphosphorylation, as explained by the Neuroimmunomodulation Theory, discovered by the ICC laboratory. This theory elucidates the onset and progression of several degenerative diseases and concept of "multitarget" therapy. These studies led to the rationale to identify inflammatory targets for the action of bioactive molecules or drugs against AD.