A naturally occurring protein, secreted by the human brain, may have a
Valium-like effect in calming down epileptic seizures, researchers from
the Stanford University School of Medicine claim.The protein is known as diazepam binding inhibitor, or DBI. It calms the
rhythms of a key brain circuit and so could prove valuable in
developing novel, less side-effect-prone therapies not only for epilepsy
but possibly for anxiety and sleep disorders, too. The researchers'
discoveries will be published May 30 in Neuron. "This is one of the most exciting findings we have had in many years,"
said John Huguenard, PhD, professor of neurology and neurological
sciences 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 not only the anti-anxiety compound Valium (generic
name diazepam), first marketed in 1965, but its predecessor Librium,
discovered in 1955, and the more recently developed sleep aid Halcyon. Valium, which is notoriously addictive, prone to abuse and dangerous at
high doses, was an early drug treatment for epilepsy, but it has fallen
out of use for this purpose because its efficacy quickly wears off and
because newer, better anti-epileptic drugs have come along. For decades, DBI has also been known to researchers under a different
name: ACBP. In fact, it 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 said. "In this circuit, DBI or one of its peptide
fragments acts just like Valium biochemically and produces the same
neurological effect." Other endogenous (internally produced) substances have been shown to
cause effects similar to psychoactive drugs. In 1974, endogenous
proteins called endorphins, with biochemical activity and painkilling
properties similar to that of opiates, were isolated. A more recently
identified set of substances, the endocannabinoids, mimic the memory-,
appetite- and analgesia-regulating actions of the psychoactive
components of cannabis, or 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 one-fifth of all nerve cells
in the brain that are inhibitory mainly do their job by secreting GABA,
which 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 from the one GABA binds to. That
changes the receptor's shape, making it hyper-responsive to GABA. 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, exactly what this means has remained unclear. Huguenard, along with postdoctoral scholar and lead author Catherine
Christian, PhD, and several Stanford colleagues zeroed in on DBI's
function in the thalamus, a deep-brain structure that serves as a relay
station for sensory information, and which previous studies in the
Huguenard lab 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, they showed that DBI lost its effect, which Huguenard
and Christian suggested makes these mice seizure-prone. In another seizure-prone mouse strain in which that site is intact but
the gene for DBI is 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's team also showed that DBI has the same inhibition-enhancing
effect on nerve cells in an adjacent thalamic region — but also that,
importantly, no DBI is naturally generated in or near this region; in
the corticothalamic circuit, at least, DBI appears to be released only
in the thalamic reticular nucleus. So, the actions of DBI on GABA
receptors appear to be tightly controlled to occur only in specific
brain areas. Huguenard doesn't know yet whether it is DBI per se, or one of its
peptide fragments (and if so which one), that is exerting the active
inhibitory role. But, he said, by finding out exactly which cells are
releasing DBI under what biochemical circumstances, it may someday be
possible to develop agents that could jump-start and boost its activity
in epileptic patients at the very onset of seizures, effectively nipping
them in the bud.
Source: Neuron
Source: Neuron
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