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Purinergic Receptor Stimulation Decreases Ischemic Brain Damage by Energizing Astrocyte Mitochondria

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Glutamate and ATP at the Interface of Metabolism and Signaling in the Brain

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 11))

Abstract

As a leading cause of death in the world, cerebral ischemic stroke has limited treatment options. The lack of glucose and oxygen after stroke is particularly harmful in the brain because neuronal metabolism accounts for significantly more energy consumption per gram of body weight compared to other organs. Our laboratory has identified mitochondrial metabolism of astrocytes to be a key target for pharmacologic intervention, not only because astrocytes play a central role in regulating brain metabolism, but also because they are essential for neuronal health and support. Here we review current literature pertaining to the pathobiology of stroke, along with the role of astrocytes and metabolism in stroke. We also discuss our research, which has revealed that pharmacologic stimulation of metabotropic P2Y1 receptor signaling in astrocytes can increase mitochondrial energy production and also reduce damage after stroke.

*Author contributed equally with all other contributors.

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Abbreviations

2MeSADP:

2 Methylthioadenosine triphosphate

6-NBDG:

6-Deoxy-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-aminoglucose

ANLS:

Astrocyte-neuron lactate shuttle

ANT:

Adenine nucleotide transporter

ApN:

Aminopeptidase N

ATP:

Adenosine triphosphate

BDNF:

Brain-derived neurotrophic factor

CBF:

Cerebral blood flow

DALY:

Disability-adjusted life-years

ER:

Endoplasmic reticulum

FAO:

Fatty acid oxidation

GCL:

Glutamate cysteine ligase

GFAP:

Glial fibrillary acidic protein

GLUT:

Glucose transporter

GPCR:

G protein-coupled receptor

GS:

Glutathione synthetase

GSH:

Glutathione

GSSG:

Glutathione disulfide

GST:

Glutathione S-transferase

IP3:

Inositol triphosphate

MCAO:

Middle cerebral artery occlusion

MCT:

Monocarboxylic acid transporter isoform

MICU:

Mitochondrial EF hand Ca2+ uptake porter

MRP1:

Multidrug resistance protein 1

NMDA:

N-methyl-d-aspartate

NQO1:

NAD(P)H dehydrogenase [quinone] 1

P2X:

Ionotropic purinergic receptor

P2Y:

Metabotropic purinergic receptor

PFKB3:

6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3

PIP2:

Phosphatidylinositol 4,5-bisphosphate

PPP:

Pentose phosphate pathway

RB:

Rose Bengal

ROS:

Reactive oxidative species

RSD:

Recurrent spreading depolarizations

TCA:

Tricarboxylic acid

Thy1:

Tyrosine hydroxylase 1

TMRM:

Tetra-methyl rhodamine methyl ester

tPA:

Recombinant tissue plasminogen activator

VDCC:

Voltage-dependent calcium channels

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    1. Department of Cellular and Structural Biology, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

      Naomi L. Sayre, Yanan Chen, Mikaela Sifuentes, Brian Stoveken & James D. Lechleiter

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      Vladimir Parpura

    2. Faculty of Health and Medical Sciences, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark

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    Sayre, N.L., Chen, Y., Sifuentes, M., Stoveken, B., Lechleiter, J.D. (2014). Purinergic Receptor Stimulation Decreases Ischemic Brain Damage by Energizing Astrocyte Mitochondria. In: Parpura, V., Schousboe, A., Verkhratsky, A. (eds) Glutamate and ATP at the Interface of Metabolism and Signaling in the Brain. Advances in Neurobiology, vol 11. Springer, Cham. https://doi.org/10.1007/978-3-319-08894-5_7

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