RESUMEN
Studies from our lab demonstrated that 1 × 105 intra-arterial mesenchymal stem cells (IA MSCs) at 6 h following ischemic stroke are efficacious owing to its maximum homing due to elevated stromal derived factor 1 (SDF1) in the tissue. Further, IA MSCs could abate the infarct progression, improve functional outcome, and decrease expression of calcineurin by modifying neuronal Ca2+ channels following ischemic stroke. Since stroke pathology also encompasses acidosis that worsens the condition; hence, the role of acid sensing ion channels (ASICs) in this context could not be overlooked. ASIC1a being the major contributor towards acidosis triggers Ca2+ ions overload which progressively contributes towards exacerbation of neuronal injury following ischemic insult. Inflammasome involvement in ischemic stroke is well reported as activated ASIC1a increases the expression of inflammasome in a pH-dependent manner to trigger inflammatory cascade. Hence, the current study aimed to identify if IA MSCs can decrease the production of inflammasome by attenuating ASIC1a expression to render neuroprotection. Ovariectomized Sprague Dawley (SD) rats exposed to middle cerebral artery occlusion (MCAo) for 90 min were treated with phosphate-buffered saline (PBS) or 1 × 105 MSCs IA at 6 h to check for the expression of ASIC1a and inflammasome in different groups. Inhibition studies were carried out to explore the underlying mechanism. Our results demonstrate that IA MSCs improves functional outcome and oxidative stress parameters, and decreases the expression of ASIC1a and inflammasomes in the cortical brain region after ischemic stroke. This study offers a preliminary evidence of the role of IA MSCs in regulating inflammasome by modulating ASIC1a.
Asunto(s)
Canales Iónicos Sensibles al Ácido/fisiología , Infarto de la Arteria Cerebral Media/terapia , Inflamasomas/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos , Proteínas del Tejido Nervioso/fisiología , Amilorida/uso terapéutico , Animales , Daño Encefálico Crónico/etiología , Daño Encefálico Crónico/prevención & control , Femenino , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/inmunología , Infarto de la Arteria Cerebral Media/metabolismo , Inyecciones Intraarteriales , Células Madre Mesenquimatosas/fisiología , Ovariectomía , Ratas , Ratas Sprague-Dawley , Prueba de Desempeño de Rotación con Aceleración Constante , Trastornos Somatosensoriales/etiología , Trastornos Somatosensoriales/prevención & controlRESUMEN
Aim: Calcineurin (CaN) is a threonine/phosphatase which play roles in neuronal homeostasis. Ischemic stroke induces hyperactivation of CaN which further triggers apoptotic signaling. CaN inhibition has limited therapeutic output and neurotoxicity due to its intricate roles in the neuronal network and requires a strategic modulation. Intra-arterial (IA) mesenchymal stem cells (MSCs) have shown to interact with the milieu in a paracrine manner as compared to CaN inhibitors to ameliorate the neuronal damage triggered by ischemia/reperfusion injury. The present study investigates the role of IA MSCs in modulating neuronal CaN after stroke onset. Materials and methods: To validate, middle-aged ovariectomized female rats exposed to MCAo (90 min) were treated with IA MSCs (1 × 105 MSCs) or phosphate-buffered saline (PBS) at 6 hours to check CaN expression in different groups.Tests for assessing functional and motor coordination were performed along with biochemical estimations. Furthermore, an inhibition study by non-selective inhibitor of neuronal calcium channel, flunarizine, was performed to explore the possible underlying mechanism by which IA MSCs may interact with CaN. Results: The study suggests that IA MSCs seemingly reduce the expression of CaN after ischemic stroke. IA MSCs have shown to improve the functional outcome and normalize oxidative parameters. Conclusion: Our study provides a preliminary evidence of role of IA MSCs in modulating CaN expression.
Asunto(s)
Isquemia Encefálica/metabolismo , Calcineurina/biosíntesis , Trasplante de Células Madre Mesenquimatosas/métodos , Neuronas/metabolismo , Neuroprotección/fisiología , Accidente Cerebrovascular/metabolismo , Animales , Isquemia Encefálica/terapia , Femenino , Infusiones Intraarteriales , Ovariectomía/efectos adversos , Ovariectomía/tendencias , Ratas , Ratas Sprague-Dawley , Accidente Cerebrovascular/terapiaRESUMEN
Ischemic stroke is devastating and a major cause of morbidity and mortality worldwide. To date, only clot retrieval devices and/or intravenous tissue plasminogen activators (tPA) have been approved by the US-FDA for the treatment of acute ischemic stroke. Therefore, there is an urgent need to develop an effective treatment for stroke that can have limited shortcomings and broad spectrum of applications. Interferon-beta (IFN-ß), an endogenous cytokine and a key anti-inflammatory agent, contributes toward obviating deleterious stroke outcomes. Therefore, exploring the role of IFN-ß may be a promising alternative approach for stroke intervention in the future. In the present review, we have discussed about IFN-ß along with its different mechanistic roles in ischemic stroke. Furthermore, therapeutic approaches targeting the inflammatory cascade with IFN-ß therapy that may be helpful in improving stroke outcome are also discussed.
Asunto(s)
Isquemia Encefálica/fisiopatología , Interferón beta/fisiología , Accidente Cerebrovascular/fisiopatología , Animales , Isquemia Encefálica/metabolismo , Humanos , Interferón beta/clasificación , Interferón beta/metabolismo , Accidente Cerebrovascular/metabolismoRESUMEN
AIM: Stroke is devastating with a limited choice of intervention. Many pharmacological entities are available but none of them have evolved successfully in counteracting the multifaceted molecular alterations following stroke. Myeloperoxidase (MPO) has been reported to play an important role in neuroinflammation following neurodegenerative diseases. Therefore, using it as a therapeutic target may be a strategy to confer neuroprotection in stroke. Trigonelline (TG), a plant alkaloid has shown neuroprotective effects in the past. Here we explore its neuroprotective effects and its role in glutathione mediated MPO inhibition in ischemic stroke. METHODS: An in silico study was performed to confirm effective TG and MPO interaction. An in vitro evaluation of toxicity with biochemical estimations was performed. Further, in vivo studies were undertaken where rats were treated with 25, 50 and 100â¯mg/kg TG or standard MPO inhibiting drug4Aminobenzoic hydrazide (4ABH) at 60â¯min prior, post immediate and an hour post 90â¯min of middle cerebral artery occlusion (MCAo) followed by 24â¯h reperfusion. Rats were evaluated for neurodeficit and motor function tests. Brains were further harvested for infarct size evaluation, biochemical analysis, and western blot experiments. KEY FINDINGS: TG at 100â¯mg/kg dose i.p. administered immediately post ischemia confers neuroprotection by reducing cerebral infarct with improvement in motor and neurodeficit scores. Furthermore, elevated nitrite and MDA levels were also found to be reduced in brain regions in the treated group. TG also potentiated intrinsic antioxidant status and markedly inhibited reduced glutathione mediated myeloperoxidase expression in the cortical brain region. SIGNIFICANCE: TG confers neuroprotection by reduced glutathione mediated myeloperoxidase inhibition in ischemic stroke.
Asunto(s)
Alcaloides/farmacología , Isquemia Encefálica/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Peroxidasa/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Alcaloides/administración & dosificación , Compuestos de Anilina/farmacología , Animales , Antioxidantes/metabolismo , Western Blotting , Isquemia Encefálica/patología , Infarto Cerebral/tratamiento farmacológico , Infarto Cerebral/patología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Glutatión/metabolismo , Masculino , Fármacos Neuroprotectores/administración & dosificación , Ratas , Ratas Sprague-Dawley , Accidente Cerebrovascular/patologíaRESUMEN
Stroke is a debilitating condition which is also the second leading cause of death and disability worldwide. Despite the benefits and promises shown by numerous neuroprotective agents in animal stroke models, their clinical translation has not been a complete success. Hence, search for treatment options have directed researchers towards utilising stem cells. Mitochondria has a major involvement in the pathophysiology of stroke and a number of other conditions. Stem cells have shown the ability to transfer mitochondria to the damaged cells and to help revive cell energetics in the recipient cell. The present review discusses how stem cells could be employed to protect neurons and mitochondria in stroke and also the various mechanisms involved in neuroprotection.
RESUMEN
Stroke is devastating and a major cause of morbidity and mortality around the world. The innate immune response plays an important role in various brain injuries, including stroke, and targeting it for therapeutic interventions would likely prove beneficial. The panoply of inflammatory cells, which induce various cellular, hormonal, and biochemical alterations, mediates the rapid progression of injury in stroke. The inflammasome, a multiprotein oligomer and a key component of specific innate immune responses, contributes toward the worsening of stroke outcomes by activating inflammatory cytokines. Acidotoxicity, mediated by acid-sensing ion channels (ASICs), also contributes toward exacerbating the condition. A role for ASICs in stroke, through the activation of the inflammasome, is emerging, which opens new avenues for understanding and intervening in stroke. In this review, we describe the various types of inflammasomes and their mechanisms of activation in stroke. Furthermore, therapeutic approaches targeting the inflammasome and that may be helpful in improving stroke outcome are discussed.
Asunto(s)
Canales Iónicos Sensibles al Ácido/metabolismo , Encéfalo/metabolismo , Inflamasomas/metabolismo , Accidente Cerebrovascular/metabolismo , Animales , Humanos , Inflamación/metabolismoRESUMEN
Stroke is devastating and a major cause of morbidity and mortality around globe. Current interventions for ischemic stroke include thrombolytics, clot retrieval devices and/or intravenous tissue plasminogen activators (tPA), the latter two becoming the first line of treatment. Owing to the limitations of tPA to elicit therapeutic benefits in a narrow time window, new pharmacological interventions are needed. Exploring noncoding RNAs (ncRNAs) may be a promising option for stroke treatment. ncRNAs are endogenous molecules that play key roles in the pathophysiology of many functions and diseases, including during ischemic stroke. Small ncRNAs such as microRNAs, Piwi-interacting RNAs, and long ncRNAs affect the genetic machinery at molecular levels. These small ncRNAs, along with their target genes and RNA transcripts, are involved in repair and recovery mechanisms after stroke. The potential of ncRNAs to regulate physiological processes highlights their potential therapeutic importance. Here, we enumerate the details and roles of different types of ncRNAs as biomarkers and targets for future stroke intervention.