May 31, 2013
Valium-Like Protein Made Naturally By The Brain
redOrbit Staff & Wire Reports - Your Universe Online
A naturally occurring protein secreted only in discrete areas of the mammalian brain may act as a Valium-like constraint on certain types of epileptic seizures, Stanford University researchers reported on Thursday.
"This is one of the most exciting findings we have had in many years," said John Huguenard, professor of neurology and neurological sciences at Stanford University and the study's senior author.
"Our results show for the first time that a nucleus deep in the middle of the brain generates a small protein product, or peptide, that acts just like benzodiazepines."
This drug class includes the anti-anxiety compound Valium, first marketed in 1965, its predecessor Librium, discovered in 1955, and the more recently developed sleep aid Halcyon.
Valium (generic name diazepam) became a popularly prescribed medicine during the 1970s for the treatment of both anxiety and seizures brought on by epilepsy. However, the drug has fallen out of favor in recent years because its efficacy quickly wears off, it is notoriously addictive, prone to abuse, and dangerous at high doses. It has since been replaced with better anti-epileptic drugs.
DBI has been known for decades by the name ACBP, and is found in every cell of the body, where it is an intracellular transporter of a metabolite called acyl-CoA.
"But in a very specific and very important brain circuit that we've been studying for many years, DBI not only leaves the cells that made it but is — or undergoes further processing to become — a natural anti-epileptic compound," Huguenard explained.
"In this circuit, DBI or one of its peptide fragments acts just like Valium biochemically and produces the same neurological effect."
Other internally produced, or endogenous, substances have been shown to cause effects similar to psychoactive drugs.
In 1974 scientists isolated endogenous proteins called endorphins, which have biochemical activity and painkilling properties similar to that of opiates. A more recently identified set of substances, the endocannabinoids, mimic the memory, appetite and analgesia regulating actions of the psychoactive components of marijuana.
DBI binds to receptors that sit on nerve-cell surfaces and are responsive to a tiny, but important, chemical messenger or neurotransmitter, called GABA. The roughly 20 percent of all nerve cells in the brain that are inhibitory mainly do their job by secreting GABA.
GABA binds to receptors on nearby nerve cells, rendering those cells temporarily unable to fire any electrical signals of their own.
Benzodiazepine drugs enhance GABA-induced inhibition by binding to a different site on GABA receptors than the one to which GABA binds. This changes the receptor's shape, making it hyper-responsive to GABA. However, these receptors come in many different types and subtypes, not all of which are responsive to benzodiazepines.
DBI binds to the same spot to which benzodiazepines bind on benzodiazepine-responsive GABA receptors. But until now, the implications of this have been unclear.
Huguenard, his colleague Catherine Christian and several other Stanford researchers focused on DBI's function in the thalamus, a deep-brain structure that serves as a relay station for sensory information and which previous studies have implicated on the initiation of seizures.
The researchers used single-nerve-cell-recording techniques to show that within a GABA-secreting nerve-cell cluster called the thalamic reticular nucleus, DBI has the same inhibition-boosting effect on benzodiazepine-responsive GABA receptors as do benzodiazepines.
Using bioengineered mice in which those receptors' benzodiazepine-binding site was defective, the researchers showed that DBI lost its effect, which Huguenard and Christian suggested may be responsible for making these mice seizure-prone.
In another seizure-prone mouse strain in which that site was intact but the gene for DBI was missing, the scientists saw diminished inhibitory activity on the part of benzodiazepine-responsive GABA receptors. Re-introducing the DBI gene to the brains of these mice via a sophisticated laboratory technique restored the strength of the GABA-induced inhibition.
In normal mice, a compound known to block the benzodiazepine-binding site weakened these same receptors' inhibitory activity in the thalamic reticular nucleus, even in the absence of any administered benzodiazepines. This suggested that some naturally occurring benzodiazepine-like substance was being displaced from the benzodiazepine-binding site by the drug. In DBI-gene-lacking mice, the blocking agent had no effect at all.
Huguenard and his team also showed that DBI has the same inhibition-enhancing effect on nerve cells in an adjacent thalamic region, but that no DBI is naturally generated in or near this region. But at least in the corticothalamic circuit, DBI appears to be released only in the thalamic reticular nucleus, and the actions of DBI on GABA receptors appear to be tightly controlled so that they occur only in specific brain areas.
Huguenard doesn't know yet whether it is DBI as a whole molecule or simply one of its peptide fragments that is exerting the active inhibitory role. However, by identifying exactly which cells are releasing DBI under what biochemical circumstances, it may someday be possible to develop agents that could stimulate and boost its activity in epileptic patients at the very onset of seizures, effectively nipping them in the bud, he said.
A report of the study was published May 30 in the journal Neuron.