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

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

Volume: 23 Issue: 33

Author(s): Anemari Horvat, Nina Vardjan*Robert Zorec*

Affiliation:

• Faculty of Medicine, University of Ljubljana, Institute of Pathophysiology, LN-MCP, 1000 Ljubljana,Slovenia

• Faculty of Medicine, University of Ljubljana, Institute of Pathophysiology, LN-MCP, 1000 Ljubljana,Slovenia

Keywords: Astrocytes, L-lactate, D-glucose, cAMP, vesicles, signalling, carbon monoxide.

Abstract: 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 Llactate 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.

Cite this article as:

Horvat Anemari , Vardjan Nina *, Zorec Robert*, Targeting Astrocytes for Treating Neurological Disorders: Carbon Monoxide and Noradrenaline-Induced Increase in Lactate, Current Pharmaceutical Design 2017; 23 (33) . https://dx.doi.org/10.2174/1381612823666170622112734