The Acid Sphingomyelinase/ Ceramide System as Target for Ischemic Stroke Therapies
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Abstract:
In this review, we summarize implications of the acid sphingomyelinase/ ceramide system in ischemic stroke. Acid sphingomyelinase catalyzes the formation of the bioactive sphingolipid ceramide which coalesces into membrane platforms and has a pivotal role in inflammation, cell signaling and death. Cerebral ischemia increases acid sphingomyelinase activity and elevates brain ceramide levels, which has been associated with the exacerbation of ischemic injury and deterioration of stroke outcome. In view of the fact that lowering acid sphingomyelinase activity and ceramide level was shown to protect against ischemic injury and ameliorate neurological deficits, the acid sphingomyelinase/ ceramide system might represent a promising target for stroke therapies.Keywords:
Acid sphingomyelinase
Sphingolipid
Sphingomyelin phosphodiesterase
Stroke
Brain ischemia
Sphingolipid
Acid sphingomyelinase
Sphingomyelin phosphodiesterase
Second messenger system
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Ceramide is a bioactive lipid involved in the induction of apoptosis and is the precursor to several sphingolipids, including sphingomyelin, the gangliosides, and sphingosine. Ceramide production is increased in response to stress and toxic agents. Because modulation of ceramide levels has been shown to affect sensitivity and/or resistance to therapeutic agents, it will be important to assess the activity of sphingolipid metabolic pathways when investigating the mode of action of antitumor drugs. This chapter summarizes protocols for quantitating the level of apoptosis, the activities of acidic sphingomyelinase, neutral sphingomyelinase, glycosylceramide synthase, sphingomyelin synthase, and ceramidase, and the amount of ceramide in tumor xenografts in nude mice.
Sphingolipid
Ceramide synthase
Mode of Action
Sphingomyelin phosphodiesterase
Acid sphingomyelinase
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Introduction: Sphingomyelinases, which catalyze the hydrolysis of sphingomyelin to ceramide and phosphorylcholine, are abundant in the brain. These enzymes are a major, rapid source of ceramide production not only during physiological responses to receptor stimulation, but also in neurological disorders.Areas covered: We covered an introduction to sphingomyelinases and its enzymatic product ceramide, in membrane domains or lipid rafts and the nucleus; followed by crosstalk between sphingomyelinase and cytosolic phospholipase A2 (cPLA2) catalysed products including arachidonic acid, functions of acid sphingomyelinase (aSMase) and neutral sphingomyelinase (N-SMase) in neurons, neuronal progenitor cells, glial cells, and brain endothelial cells; alterations in acid and N-SMases in Niemann Pick Disease Type A, major depression, Alzheimer's disease, cerebral ischemia, and pain; and recent developments in identification of inhibitors to sphingomyelinases. As literature search methodology, we did key word searches using Pubmed.Expert opinion: More research needs to be carried out to develop pharmacological agents that act on sphingomyelinases, for the prevention or treatment of neurological disorders.
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Mediator
Sphingolipid
Second messenger system
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Sphingolipid
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Acid sphingomyelinase
Ceramide synthase
Sphingomyelin phosphodiesterase
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Phosphocholine
Sphingomyelin phosphodiesterase
Second messenger system
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Ceramide synthase
Sphingosine Kinase
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Sphingomyelinase can hydrolyze the sphingomyelin to ceramide. And sphingomyelinase play important roles in diverse physiological. Acid sphingomyelinase is the most important type of sphin-gomyelinase.
Acid sphingomyelinase
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Ceramide has been recognized as a structural component to consist of the cell membrane. Since we reported that ceramide content increased in vitamin-D3-induced cell differentiation of human leukemia HL-60 cells, it has become evident that ceramide acts as an intracellular lipid mediator to transduce an extracellular stress into the cells. Ceramide is synthesized through serine-palmitoyl CoA transferase. Diversity of ceramide species derives from the changes of carbon length of fatty acid binding to amine part of sphingosine. A variety of stresses induce apoptosis through activation of pro-apoptotic signals as well as inhibition of antiapoptotic/survival signals by an increase of intracellular ceramide. Here, the recent problems and innovation in the medication of hematological malignancy are summarized, and it is suggested that the induction of apoptotic cell death by ceramide action is a potent, novel molecular targeting therapy for a chemoresistant and refractory hematological malignancy.
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Ceramide synthase
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