Activating the Caretakers
Astrocytes are considered the natural caretakers of the brain and are the most abundant cell type in the human brain 1,2. Astrocytes provide metabolic and trophic support to neurons and they modulate synaptic activity 3. After brain injury, astrocytes play pivotal roles in restoring ion balance, controling edema and removing toxic neurotransmitters 4-6. These neuroprotective activites are highly energy-dependent and require astrocyte mitochondria 7,8. Notably, neurons are permanently injured after ischemia only if astrocyte mitochondrial function fails 9,10. Inhibition of astrocyte mitochondria increases cell swelling and induces cell death11. Excitotoxicity, due to high extracellular glutamate, is also principally controled by astrocytes and requires membrane polarization – the energy-dependent maintenance of the Na+ ion gradient12-14.
Astrocytes are ‘activated’ when the production of inositol (1,4,5) triphosphate (IP3) triggers intracellular Ca2+ release from thapsigargin-sensitive stores in the endoplasmic reticulum (ER), which can be initiated by multiple G-protein coupled receptors including our target receptor 15-18. During astrocyte activation, mitochondria, in turn, sequester some of the released Ca2+ and utilize it to activate Ca2+ sensitive dehydrogenases in the tricarboxylic citric acid cycle (TCA). This signaling cascade thereby increases oxidative phosphorylation and ultimately, significant production of ATP19-21.
Results from our laboratory in mouse models of stroke and blunt trauma TBI show that treatment with a novel purinergic agonist, significantly reduces early brain damage 17,18,22. These agonists selectively enhance mitochondrial ATP production in astrocytes by stimulating IP3-mediated Ca2+ release, which, in turn, enhance their energy-dependent neuroprotective functions. Pharmacological and genetic manipulation show that receptor activation not only increases neuronal and astrocyte survival but also partially reverses neuronal and glial damage. Our data also show that the protective pathway activated by our purinergic agonists is conserved in ex vivo human brain tissue experiments (unpublished), emphasizing the potential for this novel approach to be an effective therapy for human brain injuries.
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