Primer on Epilepsy Experimental Models - Revisited (from 2015)
I am an epileptologist and was turned onto AVXL in 2015 when I did my original DD on 2-73, specifically interested in its anti-inflammatory properties. The shift in neurology is happening where people are now starting to agree that AD is not due to buildup of toxic beta-amyloid plaques and the like. The shift towards believing that neuroinflammation is the primary trigger that will result in different varied neurological syndromes (depending on age, genotype, environmental factors, etc) that are seemingly different in presentation.
Given the simple concept that neuroinflammation may be the cause for many different neurological pathologies (and chronic inflammation can cause other non-neurological pathologies) - this is why we are seeing this unbelievable potential for 2-73 to help with all sorts of varied problems. The more we learn, the more we question and ask - what is really going on.
As I have nothing to really talk about until Anavex issues some hard science data and starts trials - I'm copying my original primer on epilepsy experimental models that many on the old YMB found useful when it comes to understanding how epilepsy drugs are developed. Hope you find this helpful.
A Primer on Experimental Epilepsy Models - Due Diligence before Monday (I'm in Philly now - at AES)
So I had most of the day off today as I now am in Philadelphia for the annual AES conference. I’m excited because this year, our company will present a poster presentation describing the preclinical results for Anavex 2-73 in regards to a possible future antiepileptic drug indication. Some of you have asked for more information regarding epilepsy experimental models and so here is my go. (Note that I’m not going to proofread – sorry in advance if I ramble or have grammatical or spelling errors).
As most of you do not have a background in general neurology, let alone, epileptology, a certain fund of knowledge regarding mechanisms of seizures is required in order to fully understand the role of experimental models of epilepsy and how they are used when screening for new antiepileptic drugs (AEDs). I will attempt to simply the concepts as much as possible so that all of you retail longs don’t have false expectations regarding the implication of what the preclinical data means. There still is a long way to go before human clinical trials are performed and before possible FDA approval for an epilepsy indication.
In a prior post about the general aspects of epilepsy, I described that epilepsy is a disorder of the brain where there is a propensity for sudden, recurrent, unprovoked seizures. A seizure, is a behavioral episode caused by abnormal hypersynchronous brain electrical discharged. The clinical manifestation of a seizure is essentially a symptom of disordered brain regulation.
It is important to understand what macroscopic and microscopic structures are involved in seizure formation/propagation. There are different levels of organization to consider and each level, in essence, may be possible targets in terms of current and future antiepileptic drugs. The levels of organization to consider are:
1) Channels and the neuronal cell membrane (most current antiepileptic levels target ion channels)
2) Synaptic Transmission (levetiracetam - a popular antiepileptic medication that targets synaptic transmission is an example)
3) Small networks (there are no antiepileptic medications currently that disrupt epileptogenic networks – possibly brevetiracetam (currently in development) might)
4) Modulatory Networks (there are no drugs that can modulatate neural networks currently – could this be Anavex 2-73?)
5) Propagation pathways
Most antiepileptic drugs target ion channels and Ion channels that are often targeted are: sodium channels (excitatory, rapid), chloride channels (inhibitory), potassium channels (inhibitory) and calcium channels (slow excitatory and also involved in 2nd messenger pathways).
It is important to understand what is involved in the production of an action potential to understand the following discussion about ion channels. I suggest reading up on basic neurophysiology, specifically about the “action potential” if you are interested as this topic is impertinent to an investors discussion. Within a neuron, the result of an simultaneous activation of an aggregation of action potentials can create excitatory postsynaptic potentials and inhibitory postsynaptic potentials. The summation of EPSPs and IPSPs can be measured via the electrocephalogram (EEG). The EEG is the tool that neurologists and epileptologists use to identify hyperexcitable regions within the brain.
The classic electrographic (EEG) hallmark of a hyperexcitable region within the brain is the EEG “spike and slow wave” waveform – it is a graphical representation of a “paroxysmal depolarizing shift” and “burst firing” (look it up if you don’t understand these terms). Paroxysmal depolarization shifts and burst firing are calcium dependent therefore AEDs that act on calcium channels (i.e. ethosuximide, zonisamide) can affect the excitability of neurons.
Sodium channels are voltage gated and result in neuronal depolarization. The blockade of sodium channels results in failure of depolarization under repetitive firing conditions and hence, sodium channel blockers tend to be the vast majority of currently available antiepileptic drugs out there. Some examples of sodium blocking AEDs are phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, etc.
Potassium channels are responsible for after hyperpolarization in a neuron. It is theorized that a breakdown of a potassium gradient by repetitive neuronal firing causes transition to a seizure. By increasing the potassium gradient - neurons may be in a more hyperpolarized state thereby making it much harder for depolarization to threshold ( that would trigger an action potential) to occur. AEDs that act on potassium channels allow neurons to be in a more hyperpolarized state, making it harder for depolarization.
Glutamate is an excitatory neurotransmitter and by decreasing the transmission of glutamate from the presynaptic region into the synaptic cleft, seizure propagation may be stymied. A discussion about different type of glutamate receptors (AMPA, kainite, NMDA, metabotropic) is beyond this discussion.
GABA is an inhibitory neurotransmitter and by increasing transmission of GABA, increased net inhibition will result and seizure propagation may be stymied as well. Further discussion of GABA is beyond this discussion.
Okay, I’m starting to get longwinded so I’m going to stop before I start writing like I’m teaching medical students. Onto the pertinent information for you investors – experimental models in epilepsy.
All of the current AEDs approved for treatment of epilepsy have been identified and developed as a result of their ability to block seizures in rodent seizure and epilepsy models. “A new AED must always demonstrate some degree of efficacy in one or more animal seizure or epilepsy models before it is likely to proceed down the drug development pathway and ultimately validated in well-controlled double blinded randomized clinical trials.” (Wyllie, et. al). An investigative AED will be evaluated by its ability to block seizures in models of generalized and/or focal seizures. This approach essentially provides the necessary proof of concept needed to support funding for further development of a new therapeutic agent. It also provides an indication of the potential therapeutic spectrum of a new AED – broad spectrum (treats generalized and focal seizures) or narrow spectrum (treats either generalized or focal seizures but not both).
It is important to realize that the MES (maximal electroshock) test and the subconvulsive PTZ (subcutaneous pentylenetetrazol) test are two of the most frequently used animal in vivo models of seizures and have been used for some 45 years in the early identification and characterization of AEDs.
The MES test uses an electrical stimulus – AC current delivered subcorneal or subauricular – to induce a convulsive or tonic seizure. As an epilepsy model, it has proven to be quite predictive of a drug’s potential utility against generalized tonic-clonic and focal seizures respectively. Merritt and Putnam identified the anticonvulsant potential of phenytoin (Dilantin) using this MES model. The profile of the MES test supports its utility as a predictive model for human generalized tonic-clonic seizures. A potential agent tested with this model is considered to be effective if it blocks convulsive activity.
Pentylenetetrazole is a GABA antagonist. As increased GABAergic activity yields net inhibition, any decrease in GABAergic activity allows for more excitation. The PTZ test uses subconvulsive doses of this chemical delivered repetitively in order to induce “kindling” that will lead to convulsive activity. The kindling model of epilepsy describes how a subconvulsive electrical or chemical stimulus delivered repeatedly can eventually elicit convulsive responses. Subconvulsive units of PTZ are repeatedly delivered in order to induce convulsive activity in the PTZ test. A potential therapeutic agent is considered efficacious if after it is administered, repeated PTZ administrations fail to kindle convulsive activity.
The fact that Anavex 2-73 showed superb preclinical results in terms of its ability to prevent convulsive activity in the MES and the PTZ models increases the confidence that further development of Anavex 2-73 for an epilepsy indication is a venture worth developing, considering there is an unmet need for more AEDs in the setting of refractory epilepsy and idiopathic generalized epilepsy. As Anavex 2-73 (and the other agents in the pipeline) seems to allow for the reversal or prevention of a complex neuroinflammatory cascade that leads to neurodegeneration, I believe that once the research is completed – there may be utility for using it as a broad spectrum antiepileptic. I will even venture to say that it may potentially disrupt the epileptogenic process, allowing for the brain’s natural healing mechanisms via neuroplasticity to “repair” what was damaged while preventing further neurodegeneration/epileptogenicity.
I am now here in Philadelphia, without my wife and my children. I don’t get much time to write much outside of daily patient charting and EEG report writing so it was a pleasure writing the above to the interested investors. I look forward to the poster presentation on Monday and will try to update as best as I can. Goodnight everyone
