Levetiracetam (“Keppra”) and SV2A

Levetiracetam (LEV) is a unique drug.

LEV has shown promise for epileptics. It also has shown promise for those suffering from other neurological diseases such as Social Anxiety Disorder, Autism, mood disorders, and Alzheimer’s Disease.

While it was intended to treat status epilepticus (SE), LEV is now used as a maintenance treatment for partial and generalized seizures. Pubchem quotes MeSH with this description of LEV: “May selectively prevent hypersynchronization of epileptiform burst-firing and propagation of seizure”. The hyperactivity of parts of the brain, that contribute to seizure occurrence, is stunted by LEV. Over time, it was seen to have a particular efficacy for epileptics with retractable or drug resistant epilepsy.

Epilepsy is stubborn. In that, epilepsy may develop a resistance to its treatment. One drug that was quite effective in sustaining remission of seizures, may become less effective and this opens the door for refractory symptoms. As is the case of many anti-epileptic drugs (AED), they share common biological targets and mechanisms of action (MOA). That is, most AED’s act on neuronal Na+-channels, Ca2+-channels, or GABAergic transmission.

When speaking about changes in the “wiring” of the brain, such change is referred to as “plasticity” or “neuroplasticity”.  Plasticity is reason you are able to make memories, learn, adapt, experience emotion, etc in response to your environment.  Thus, taking a drug over a long period of time, despite its MOA, causes neuronal changes or adaptations. For instance, a Na+-channel blocker, may result in the upregulation (increased production) of Na+-channels; GABAergic medications may result in increased production of excitatory neurotransmitters or their receptors. Said physiological adaptations contribute to the decreased efficacy of that drug.

Levetiracetam showed a novelty of little drug resistance. In looking closer into the reason behind this phenomenon, researchers discovered LEV targeted a subtype of neuronally ubiquitous protein called “synaptic vesicle glycoprotein 2A” (SV2A). While it seems that not enough is known about this class of proteins, the very fact that a drug acted in such a novel means, helped inspire the search for further novel drug targets.

SV2A has been shown to influence the release of synaptic vesicles, carrying neurotransmitters into the synaptic cleft. In other words, SV2A affects neuronal activity by modulating the release of chemicals from neurons that influence such activity. Furthermore, SV2A is thought to be associated with every form of epileptiform activity (activity in the brain that contributes to seizure development).

Studies have shown LEV to, among other things, a) decrease the reuptake of the inhibitory neurotransmitter, GABA, and act as a low affinity agonist of GABA-A receptors, b) to decrease excitatory amino acid Taurine, and, perhaps most importantly, c) have an inhibitory effect on Ca2+-induced neurotransmitters (excitatory neurotransmitter glutamate).

Ca2+ “secondary neurotransmitter”, as another means of cell-to-cell communication. Specifically, it is an ion that contributes to neuronal excitation and plasticity (rearrangement of neurons that occurs during processes like learning and memorization). The body normally keeps Ca2+ concentrations in a strict homeostasis. Thus when disturbances in Ca2+ concentrations occur, it may be bad news for the epileptic.

What’s curious to me, about Levetiracetam…

As the name implies, Levetiracetam is chemically related to a class of drugs referred to as “racetams”. Racetams are known nootropics, drugs that have been used to enhance cognitive performance and memory, and as anxiolytics. Racetams are related as such, as they share what’s called a 2-pyrrolidone group (a pyrrolidine ring with an oxygen atom doubly-bonded to the second carbon of the ring).

Chemical structure aside, racetams generally act as stimulants. Stimulants are typically contraindicated for an epileptic. Stimulants increase neuronal activity; they are excitatory, by acting on cholinergic and glutamatergic mechanisms.

So, if a racetam is generally considered to have excitatory effects, it’s bemusing to see levetiracetam as having such efficacy as an AED!

(Below-left: levetiracetam, below-right: piracetam)


512px-Levetiracetam.svg274px-Piracetam.svg

Side note:

The development of new drugs and the process of attaining governmental approval for widespread use, is lengthy and costly for pharmaceutical companies. A cost patients may bear, as Big Pharma recoups its expenditure and gains its profits. (In the United States, the sale of generics is illegal for a number of years after a novel drug hits pharmacy shelves. This so, in order allow companies to recoup expenditure and gain some profit. A boon to patients, whose medical insurance won’t pay for anything but generics.) Given the process of drug development is so costly, drug companies are reluctant to attempt such development. This results in a stagnation of new pharmaceutical treatments and offsets the attainability of potentially life-giving AED treatment.

So, for a drug like LEV to come around and spur research and inspire confidence for the pockets of Big Pharma, is a pleasant thing.

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