In This Issue pubs.acs.org/chemneuro
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STEM CELL ENGINEERING COMES INTO THE LIGHT
Chemogenetic control of neuronal activity is a relatively noninvasive method of manipulating specific populations of neurons. A widely used chemogenetic technique is Designer Receptors Activated by Designer Drugs (DREADD), wherein artificial receptors are genetically inserted into target neurons and modulated selectively and exclusively by exogenous pharmacological agents. Here, Raper et al. (DOI: 10.1021/acschemneuro.7b00079) explore one commonly used DREADD: artificial GPCRs that are activated by clozapine-N-oxide (CNO). The effects of CNO as a chemogenetic agent have been extensively characterized in rodents, but limited studies have been carried out in non-human primates due to the dearth of pharmacokinetic data available for these model systems. In this issue, the authors carry out detailed pharamokinetic analysis of CNO in rhesus monkeys, revealing, notably, that CNO is rapidly metabolized into its psychoactive parent compound, clozapine. These results indicate that, despite early success in rats, CNO metabolism and distribution in higher mammals may limit its DREADD-related clinical applications in humans.
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Nuclear receptor related 1 protein (NURR1) is required for maintenance of the dopaminergic system in the brain. Deficiencies in NURR1 are associated with neurodegenerative disorders such as Parkinson’s disease; consequently, restoration of functional NURR1 expression represents a potentially promising therapeutic pathway for treatment of such dopaminergic dysfunction. Protein expression can be controlled pharmacologically or through genetic engineering methods. Under the right circumstances, it can be controlled using light. Notably, blue LED light induces neuronal differentiation from stem cells, and polarized light can confer chiral control over biochemical reactions occurring inside the cell. In this issue, Patel and co-workers (DOI: 10.1021/ acschemneuro.7b00136) explore the effects of various wavelengths of polarized LED light on stem cell stimulation. In one set of experiments, they exposed stem cells to L- and R-polarized blue LED light for 24 h and examined the mRNA levels of several neuronal biomarkers, including NURR1. They found that NURR1, enhanced specifically with L-polarized blue LED light, was the only protein that was selectively upregulated with such chiro-optical control. This paper establishes the potential use of polarized LED light to engineer stem cells with a specific expression profile and biochemical activity.
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MECHANISMS OF OXYGEN FLOW TO THE BRAIN
The brain requires a considerable amount of energy to carry out its numerous functions, thus requiring a steadily available supply of metabolic substrates such as glucose and oxygen. These substrates are delivered to the brain via cerebral blood flow (CBF), which is coupled with neuronal activity; following excitatory neurotransmission, CBF increases to replenish the brain’s supply of glucose and O2. However, CBF is not exclusively regulated by neuronal activity, as recent studies have shown that CBF increases can occur under hypoxic or hypoglycemic conditions. This suggests that there is a more complex relationship at play between the brain’s activity and the metabolic pathway. Here, Walton and co-workers (DOI: 10.1021/acschemneuro.7b00088) evaluate this relationship using new approaches to monitor both neuronal activity and local changes in oxygen concentrations simultaneously. The authors employed the neurotransmitter glutamate to stimulate both global and localized excitatory neurotransmission, allowing for spatial observation of O2 dynamics. These studies revealed that while most changes in O2 levels corresponded to localized neurotransmission, neuronal firing was at times decoupled from O2 dynamics in the cortex and striatum.
FILLED WITH DREADD: A PHARMACOKINETICS STUDY OF CLOZAPINE-N-OXIDE
Published: July 19, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acschemneuro.7b00241 ACS Chem. Neurosci. 2017, 8, 1431−1431
