How to adjust the volume on misfiring neural pathways. Our continuing coverage of SfN

The work of pharmaceutical developers would probably be a lot easier if they could turn certain cell functions on or off like a radio. But fighting diseases often requires a balanced approach.

For instance, in designing a vaccine to prevent HIV an ongoing challenge has been finding candidates that induce potent, long-lasting immune responses without inducing too many T cells that might act as additional targets for the virus and therefore potentially increase the risk of HIV infection.

The human brain presents the same kind of conundrum. Our central nervous system contains 100 billion neurons—with 100 trillion connections—surrounded by structural support cells closely packed together. It is a highly complicated, exquisitely tuned organ that dictates how we think, perform and react. When you bite into an apple, take a midterm exam, or respond to bad news, your brain uses excitatory pathways called synapses to relay the information and inhibitory pathways to restrict it. This allows us to process a lot of different information at one time without getting confused.

In certain CNS diseases, such as epilepsy, the circuitry becomes horribly twisted, upsetting the balance of these neural pathways. Drug developers have tried attacking the problem by designing drugs that seek out and bind to receptors on some of these malfunctioning neurotransmitters. The idea is to use the chemicals, called agonists, to unlock the receptor like a key in order to activate or block an associated function. But because these drugs are binding directly to the same part of the receptors that the body’s own natural occurring proteins attach to, they also must compete with those endogenous proteins, which in turn limits the potential effects of the drug.

Another way drug developers are trying to correct the balance of the excitatory and inhibitory pathways that occur in CNS disease is to use allosteric modulators, which bind to different parts of the receptor at one time. Rather than turn the receptor on and off like a radio, they adjust the volume of the signal being sent. Two years ago, Massachusetts-based Sage Therapeutics discovered an innate mechanism to allosterically modulate the N-methyl-D-aspartate

The (NMDA) receptor, which works by regulating the activity of glutamate, is an important neurotransmitter in the brain involved in learning and memory. NMDA could be key in treating a wide range of neuropsychiatric disorders, including Alzheimer’s, schizophrenia, autism and depression. Sage’s drug discovery platform is now focused on developing drugs that use allosteric modulation of NMDA receptors (which cause brain cell firing) and GABAA receptors (which inhibit brain cells) in order to treat the neurological balances that occur during epilepsy or other movement disorders.

At a nanosymposium today (Nov. 14) at the Society for Neuroscience (SfN) meeting in San Diego, Nikolai Fedorov, an electrophysiologist with Charles River Laboratories in Cleveland, presented work on a high-throughput assay that Sage Therapeutics is using to characterize the NMDA receptor on a patch-clamp platform. Patch-clamp is a laboratory technique that allows the study of single or multiple ion channels in cells. It is useful in the study of “excitable” cells such as neurons.

The assay allows the screening of large compound libraries for modulations that are highly specific to subunits of NMDA receptors, says Fedorov. What that means, he says, is that you increase your chances of success in the clinic. “Any successful drug discovery program would demand selectivity of compounds for selective receptors,” he said.

Game Day

Maybe it’s me, but this year’s SfN seems to be more focused on fun ‘n games. Eight different booths in the giant Exhibitor’s Hall at SfN participated in Rodents on the Loose. Find your way to all of them and you not only accumulate a charming collection of refrigerator magnets, you get entered in a drawing for an iPad. Another Exhibitor’s booth beckoned visitors with a Carnival Wheel and a free fist bump or stress toy. There was a daily quiz question making the rounds for the science trivia fans. And traffic was really heavy at Bioss Antibodies, where people were playing a “What’s My Line”-style game called Scientific Journeys Guess Who.

Me, I stuck to the chocolates that were ubiquitous on the Exhibit floor.

How to Cite:

McEnery, Regina. The Balanced Approach in Treating Epilepsy. Eureka blog. Nov. 14, 2016.: