Lithium has been used in the treatment of bipolar disorders for decades,but the exact mechanisms of action remain elusive to this day.Recent evidence suggests that lithium is critically involved in a variety of signal...Lithium has been used in the treatment of bipolar disorders for decades,but the exact mechanisms of action remain elusive to this day.Recent evidence suggests that lithium is critically involved in a variety of signaling pathways affecting apoptosis,inflammation,and neurogenesis,all of which contributing to the complex pathophysiology of various neurological diseases.As a matter of fact,preclinical work reports both acute and longterm neuroprotection in distinct neurological disease models such as Parkinson’s disease,traumatic brain injury,Alzheimer’s disease,and ischemic stroke.Lithium treatment reduces cell injury,decreasesα‑synuclein aggregation and Tau protein phosphorylation,modulates inflammation and even stimulates neuroregeneration under experimental conditions of Parkinson’s disease,traumatic brain injury,and Alzheimer’s disease.The therapeutic impact of lithium under conditions of ischemic stroke was also studied in numerous preclinical in vitro and in vivo studies,giving rise to a randomized double-blind clinical stroke trial.The preclinic data revealed a lithium-induced upregulation of anti-apoptotic proteins such as B-cell lymphoma 2,heat shock protein 70,and activated protein 1,resulting in decreased neuronal cell loss.Lithium,however,does not only yield postischemic neuroprotection but also enhances endogenous neuroregeneration by stimulating neural stem cell proliferation and by regulating distinct signaling pathways such as the RE1-silencing transcription factor.In line with this,lithium treatment has been shown to modulate postischemic cytokine secretion patterns,diminishing microglial activation and stabilizing blood-brain barrier integrity yielding reduced levels of neuroinflammation.The aforementioned observations culminated in a first clinical trial,which revealed an improved motor recovery in patients with cortical stroke after lithium treatment.Beside its well-known psychiatric indications,lithium is thus a promising neuroprotective candidate for the aforementioned neurological diseases.A detailed understanding of the lithium-induced mechanisms,however,is important for prospective clinical trials which may pave the way for a successful benchto-bedside translation in the future.In this review,we will give an overview of lithiuminduced neuroprotective mechanisms under various pathological conditions,with special emphasis on ischemic stroke.展开更多
Stem cell-based therapies and extracellular vesicle(EV)treatment have demonstrated significant potential for neuroprotection against ischemic stroke.Although the neuroprotective mechanisms are not yet fully under-stoo...Stem cell-based therapies and extracellular vesicle(EV)treatment have demonstrated significant potential for neuroprotection against ischemic stroke.Although the neuroprotective mechanisms are not yet fully under-stood,targeting microglia is central to promoting neuroprotection.Microglia are the resident immune cells of the central nervous system.These cells are crucial in the pathogenesis of ischemic stroke.They respond rapidly to the site of injury by releasing pro-inflammatory cytokines,phagocytizing dead cells and debris,and recruiting peripheral immune cells to the ischemic area.Although these responses are essential for clearing damage and initiating tissue repair,excessive or prolonged microglial activation can exacerbate brain injury,leading to secondary neuroinflammation and neurodegeneration.Moreover,microglia exhibit a dynamic range of activation states with the so-called M1 pro-inflammatory and M2 anti-inflammatory phenotypes,representing the two ends of the spectrum.The delivery of both EVs and stem cells modulates microglial activation,suppressing pro-inflammatory genes,influencing the expression of transcription factors,and altering receptor expression,ultimately contributing to neuroprotection.These findings underscore the importance of understanding the complex and dynamic role of microglia in the development of effective neuroprotective strategies to reduce the effects of ischemic stroke.In this review,we examine the current state of knowledge regarding the role of microglia in ischemic stroke,including their molecular and cellular mechanisms,activation states,and interactions with other cells.We also discuss the multifaceted contributions of microglia to stem cell-and EV-based neuroprotection during an ischemic stroke to provide a comprehensive understanding of microglial functions and their potential implications in stroke therapies.展开更多
文摘Lithium has been used in the treatment of bipolar disorders for decades,but the exact mechanisms of action remain elusive to this day.Recent evidence suggests that lithium is critically involved in a variety of signaling pathways affecting apoptosis,inflammation,and neurogenesis,all of which contributing to the complex pathophysiology of various neurological diseases.As a matter of fact,preclinical work reports both acute and longterm neuroprotection in distinct neurological disease models such as Parkinson’s disease,traumatic brain injury,Alzheimer’s disease,and ischemic stroke.Lithium treatment reduces cell injury,decreasesα‑synuclein aggregation and Tau protein phosphorylation,modulates inflammation and even stimulates neuroregeneration under experimental conditions of Parkinson’s disease,traumatic brain injury,and Alzheimer’s disease.The therapeutic impact of lithium under conditions of ischemic stroke was also studied in numerous preclinical in vitro and in vivo studies,giving rise to a randomized double-blind clinical stroke trial.The preclinic data revealed a lithium-induced upregulation of anti-apoptotic proteins such as B-cell lymphoma 2,heat shock protein 70,and activated protein 1,resulting in decreased neuronal cell loss.Lithium,however,does not only yield postischemic neuroprotection but also enhances endogenous neuroregeneration by stimulating neural stem cell proliferation and by regulating distinct signaling pathways such as the RE1-silencing transcription factor.In line with this,lithium treatment has been shown to modulate postischemic cytokine secretion patterns,diminishing microglial activation and stabilizing blood-brain barrier integrity yielding reduced levels of neuroinflammation.The aforementioned observations culminated in a first clinical trial,which revealed an improved motor recovery in patients with cortical stroke after lithium treatment.Beside its well-known psychiatric indications,lithium is thus a promising neuroprotective candidate for the aforementioned neurological diseases.A detailed understanding of the lithium-induced mechanisms,however,is important for prospective clinical trials which may pave the way for a successful benchto-bedside translation in the future.In this review,we will give an overview of lithiuminduced neuroprotective mechanisms under various pathological conditions,with special emphasis on ischemic stroke.
文摘Stem cell-based therapies and extracellular vesicle(EV)treatment have demonstrated significant potential for neuroprotection against ischemic stroke.Although the neuroprotective mechanisms are not yet fully under-stood,targeting microglia is central to promoting neuroprotection.Microglia are the resident immune cells of the central nervous system.These cells are crucial in the pathogenesis of ischemic stroke.They respond rapidly to the site of injury by releasing pro-inflammatory cytokines,phagocytizing dead cells and debris,and recruiting peripheral immune cells to the ischemic area.Although these responses are essential for clearing damage and initiating tissue repair,excessive or prolonged microglial activation can exacerbate brain injury,leading to secondary neuroinflammation and neurodegeneration.Moreover,microglia exhibit a dynamic range of activation states with the so-called M1 pro-inflammatory and M2 anti-inflammatory phenotypes,representing the two ends of the spectrum.The delivery of both EVs and stem cells modulates microglial activation,suppressing pro-inflammatory genes,influencing the expression of transcription factors,and altering receptor expression,ultimately contributing to neuroprotection.These findings underscore the importance of understanding the complex and dynamic role of microglia in the development of effective neuroprotective strategies to reduce the effects of ischemic stroke.In this review,we examine the current state of knowledge regarding the role of microglia in ischemic stroke,including their molecular and cellular mechanisms,activation states,and interactions with other cells.We also discuss the multifaceted contributions of microglia to stem cell-and EV-based neuroprotection during an ischemic stroke to provide a comprehensive understanding of microglial functions and their potential implications in stroke therapies.
