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'Support Cells' Star in Lack of Sleep's Antidepressant Effects

By Anette Breindl
Science Editor

"For much of the 1900s, we studied neurons" to understand brain function, Philip Haydon told BioWorld Today. "And the reasons were purely technical. . . . We could listen to neurons, and we could talk to them." Neurons communicate electrically, and electrical recording and stimulation techniques made them amenable to studying. But in terms of what goes on in the brain, looking only at neurons is bound to deliver a minority report.

"Ninety percent of the volume of the human brain is glial," Haydon said. Some of those glia have support functions – oligodendrocytes, for example, form an insulating sheath around neurons to enable high-speed communication. But others, it is becoming clear, process information and affect mental states and behavior in their own right, although unlike neurons, they do not do so via electrical communication.

In the Jan. 15, 2013, issue of Translational Psychiatry, Haydon, who is at Tufts University School of Medicine, and his team showed that the signaling actions of one type of glial cell, astrocytes, may be the missing link between sleep deprivation and depression.

Antidepressant pills – newer selective serotonin reuptake inhibitors (SSRI) as well as older monoamine oxidase inhibitors – take weeks to have an effect. The reasons for this time lag are still not fully understood. And indeed, although none of them make good long-term antidepressant treatments, several interventions exist that can lift the mood of depressed patients much quicker than an SSRI can.

One of those interventions is sleep deprivation. Keep a depressed patient up for a night, and they have a better than even chance of being in a better mood the next morning. In their work, Haydon and his team showed that this mood boost appears to be due to changes in astrocyte signaling.

Though their signaling occurs on a much slower timescale – seconds compared to neuronal milliseconds – astrocytes, like neurons, release chemical neurotransmitters – among others, adenosine.

In their studies, Haydon and his colleagues showed that the antidepressive effects of sleep deprivation depend on such adenosine release by astrocytes, and that they could pharmacologically mimic the antidepressant effect of sleep deprivation by treating animals with adenosine receptor agonists. Injecting such agonists directly into the brain increased adenosine signaling and decreased depression-like behaviors in several different tests.

Haydon said that the effects his team observed did not overlap with those of the tricyclic antidepressant Tofranil (imipramine, Novartis AG). They also appeared to be independent of the effects of another rapidly acting antidepressant – ketamine. (See BioWorld Today, July 6, 2011.)

Adenosine receptor signaling also has effects in the periphery, including on the heart. By targeting glia to modulate adenosine signaling specifically from glia to neurons, Haydon and his team hope that it will be possible to develop drugs whose activity is specifically antidepressive. "We have [glial] targets," he said, "and some small molecules that hit those targets."

Haydon is the co-founder and president of start-up GliaCure Inc., which has licensed pending patent applications based on the work. GliaCure was founded in 2011 with the goal of treating neurological and neurodegenerative diseases by targeting glia.

GliaCure has its sights on Alzheimer's disease and sleep disorders as well as depression, and according to the company, "targeting glia has the potential to impact many other diseases of the central nervous system including traumatic brain injury, Down syndrome, Parkinson's disease, glioblastoma, neuropathic pain, epilepsy, [and] psychiatric . . . disorders."

For now, GliaCure is focused on its Alzheimer's program, where the company is targeting another type of glial cell, microglia.

During a talk at the 2012 BioPharm America meeting, Haydon explained the company's approach. "During Alzheimer's disease, there is an inflammatory process which shuts down basic functions in the brain," including the clearance of A-beta, the protein whose faulty processing appears to underlie Alzheimer's disease. GliaCure's approach is to reactivate that clearance.

The company plans to start investigational new drug application-enabling studies in its Alzheimer's disease program within the next few months. Though Haydon is enthusiastic about the potential for developing rapid-acting antidepressants, he said, for now the company is focusing its resources on Alzheimer's disease. GliaCure received Angel funding in early 2012, and "we are trying to invest our initial funding wisely to advance this one program."