Targeting Astrocytes for Treating Neurological Disorders: Carbon Monoxide and Noradrenaline-Induced Increase in Lactate

被引:13
作者
Horvat, Anemari [1 ]
Vardjan, Nina [1 ,2 ]
Zorec, Robert [1 ,2 ]
机构
[1] Univ Ljubljana, Fac Med, Inst Pathophysiol, LN MCP, Ljubljana 1000, Slovenia
[2] Celica Biomed LCI, Ljubljana 1000, Slovenia
关键词
Astrocytes; L-lactate; D-glucose; cAMP; vesicles; signalling; carbon monoxide; BETA-ADRENERGIC-RECEPTORS; BLOOD-BRAIN-BARRIER; INSULIN-DEGRADING ENZYME; HUMAN CEREBRAL-CORTEX; LOCUS-COERULEUS; VESICLE MOBILITY; REGULATED EXOCYTOSIS; CULTURED ASTROCYTES; SYNAPTIC PLASTICITY; FUSION PORE;
D O I
10.2174/1381612823666170622112734
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
There are at least three reasons why brain astrocytes represent a new target for treating neurological disorders. First, although the human neocortex represents over 80% of brain mass, neurons are outnumbered by non-neuronal cells, including astrocytes, a neuroglial cell type. Second, as in neurons, vesicle-based release of transmitters is present in astrocytes, however with much slower kinetics than in neurons. Third, astrocytes contain glycogen, which can be transformed to L-lactate in glycolysis. L-lactate is considered to be a fuel and a signalling molecule involved in cognition and neuroprotection. The mechanisms of neuroprotection are unclear but may be linked to carbon monoxide, a product of the heme oxygenase, an evolutionarily conserved cellular cytoprotectant. Increased levels of local carbon monoxide arising from heme oxygenase activity may increase L-lactate, but direct measurements of cytosolic L-lactate are lacking. A fluorescence resonance energy transfer-based nanosensor selective for L-lactate was used to monitor cytosolic levels of L-lactate while cultured astrocytes were exposed to carbon monoxide. The results revealed that in astrocytes exposed to carbon monoxide there is no significant increase in L-lactate, however, when noradrenaline, a potent glycogenolytic agent, is applied, cytosolic levels of L-lactate are increased, but strongly attenuated in astrocytes pretreated with carbon monoxide. These first measurements of carbon monoxide-modulated L-lactate levels in astrocytes provide evidence that the L-lactate and heme oxygenase neuroprotective systems may interact. In conclusion, not only the abundance of astrocytes but their signalling capacity using vesicles and metabolites, such as L-lactate, are valid targets for neurological disorders.
引用
收藏
页码:4969 / 4978
页数:10
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