Marijuana-like chemicals bring hope to epileptics
smoking marijuana, are closer to understanding how the drugs active
ingredients exert its effects, paving the way for drugs that
selectively bind and block subtypes of cannabinoid receptors on one
type of cell but not another.
The research holds promise as it implies there may be one way to harness the medically useful aspect of marijuana without causing the associated brain-altering side effects.
Such research could produce drugs that could be useful in treating epilepsy. A drug that blocks cannabinoid receptors on some types of inhibitory interneurons might allow them to continue quieting the seizure-inducing pyramidal cells during periods of intense activity.
In previous work, other researchers had found that pyramidal cells manufacture and release cannabinoids that bind to a receptor on the membrane of interneurons.
The cortex contains two major types of nerve cells. Pyramidal neurons that excite both local and more distant neighbours, and inhibitory interneurons that act as local dimming switches, shutting down the activity of nearby brain cells. The inhibitory interneurons prevent the brain from taking in and responding to every thought, sight or sound it encounters. They also protect against runaway excitation such as that seen in epilepsy.
Scientists at Stanford University School of Medicine discovered the drug's active ingredients tetrahydrocannabinol and related compounds, called cannabinoids inhibit the group of interneurons that act as information gatekeepers in the brain's major information processing centre, called the cerebral cortex.
These interneurons also release cannabinoids that quiet their own activity. This form of self-inhibition is a novel way for neurons to regulate their own ability to send messages to their neighbours. Tetrahydrocannabinol from marijuana may work its brain-altering magic by binding to these same cells.
The research headed up by David Prince and Irene Thiele Pimley, Professor of Neurology and Neurological Sciences is published in the Sept. 16 issue of Nature.
The class of interneurons, the "LTS cells" of the cerebral cortex, manufacture and release cannabinoids that bind to their own cannabinoid receptors and shut down their ability to signal other neurons. By shutting themselves off, the interneurons block their quieting action on the excitatory pyramidal cells. Without the quieting effect, pyramidal cells signal more intensely, triggering a higher level of activity in circuits of the cortex.
Prince commented: "A loss of inhibition in pyramidal cells could produce changes in perception, in motor function and in everything the cerebral cortex does."
During an epileptic seizure, Pyramidal cells are among those that fire out of control during a seizure. One reason these cells fire so rapidly may be that interneurons get shut down.
With 300,000 people in the UK suffering from epilepsy (40 million people worldwide), the need for specialised but effective anti-epileptic drugs (AED) has never been more called for.
The identification of SV2A as the binding site for AED Keppra provides an innovative and unique drug discovery platform to identify new drugs with improved characteristics. It also provides molecular evidence that Keppra is different from all other anti-epileptic and CNS drugs. No other known anti-epileptic drugs (AED's) bind to SV2A.
