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Biotech / Medical : Neurobiological Tech (NTII) -- Ignore unavailable to you. Want to Upgrade?

To: Dr. John M. de Castro who wrote (668)	9/4/1999 1:56:00 PM
From: Dr. John M. de Castro	Respond to of 1494

Some explanation Part II Craig, I thought that it might be useful to expand a bit on the reasons why NMDA antagonists were thought to be so useful for neuroprotection. The cells of the nervous system, neurons, communicate with one another by releasing minute quantities of chemicals (transmitter substance) at the juncture between the two cells (synapse). This transmitter substance effects the receiving neuron by attaching to a site on the receiving neuron (receptor site). Once attached to the receptor site, a cascade of events takes place that results in the entry of charged molecules (ions) into the receiving cell. This movement of ions is what changes the charge (voltage) of the cell and can lead to either stimulation or inhibition of its activities. That in a nut shell is the process of synaptic transmission. The specific chemicals involved in synaptic transmission vary from cell to cell. However, glutamate is the most common neurotransmitter and virtually all neurons in the nervous system respond to glutamate. The NMDA receptor is one of the receptors that respond to glutamate. A very important characteristic of this receptor is that a moderate amount of a activity is good, but, a overly large amount of activity is bad. In fact too much activation of the NMDA receptor results in a large influx of calcium ions that are deadly to the neuron. This is a process called excitotoxicity. As a result of this process, over activation of the NMDA receptor can kill the receiving cell. Widespread overactivation of NMDA receptors can thus produce significant brain damage. After a brain injury, from a concussion (traumatic brain injury) or stroke, there is a primary destruction of cells produced directly by the injury. However, as it turns out, this is only the beginning. The majority of the brain damage occurs later. After the injury, many of the cells in the area surrounding the injury get overstimulated by glutamate, which destroys these cells. This excitotoxicity can actually account for the majority of the brain damage after an injury. Blocking the NMDA receptor can prevent this excitotoxicity from occurring. That is why NMDA receptor antagonists have been long thought to have great neuroprotection potential. As it turns out, the AIDS virus attacks the cells in the central nervous system in a similar fashion. The virus produces an overstimulation of the NMDA receptor which in turn kills the neuron. This in turn results in AIDS dementia complex. Blocking the NMDA receptor can prevent this from occurring. That is why NMDA receptor blockers are thought to be beneficial in preventing AIDS dementia complex. Finally, the NMDA receptor in the spinal cord is involved in pain reception. Blocking the NMDA receptor can prevent pain signals from getting into the brain. That is why NMDA receptor blockers have analgesic effects and why NMDA blockers are thought to be useful for neuropathic pain. More in Part III John de C

To: Dr. John M. de Castro who wrote (668)	9/4/1999 2:18:00 PM
From: Dr. John M. de Castro	Read Replies (1) \| Respond to of 1494

Some explanation Part III The problem with NMDA blockers are side effects. Since glutamate is such a common transmitter and the NMDA receptor is present on all neurons, blocking the NMDA receptor can have widespread effects on the nervous system. A blanket blockade of NMDA receptors would have devastating effects. Many NMDA receptor blockers produce major psychological side effects such as halucinations. In fact the drug of abuse "angel dust" is an NMDA receptor blocker. It is these side effects that have defeated most NMDA receptor blockers in clinical trials. They have either major side effects or, if used in a low enough dose that the side effects don't occur, lack efficacy. The reason that memantine can work where other NMDA blockers have failed is that memantine is an open channel blocker with fast attachment kinetics. Let me translate. Memantine does not block the receptor unless it is already open. In other words, glutamate is still able to affect the NMDA receptor and affect the receiving cell. However, once the NMDA receptor opens the ion channel then memantine can block further activation of the receptor. Memantine can then disrupt overactivation but not normal activation. It allows normal transmission to occur, but stops it from going too far and becoming toxic. In this way it be effective in protecting neurons without affecting their normal operation. The bottom line on all of this is that NTII's memantine has monstrous potential. It can neuroprotect without serious side effects. There are a large number kinds of injuries and diseases of the nervous system. Memantine has the potential to be useful for the treatment of all of them. The size of the market is mind boggling. NTII has chosen to study two possible uses in particular; AIDS dementia complex and neuropathic pain. NTII's partner, Merz, has chosen to study Alzheimers disease and other senile dementias. However, this is only the tip of the iceberg for memantines potential. This is why I am so excited about memantine and NTII. This is a drug that has been shown to be safe and effective and address huge underserved markets. How NTII can sneak by so unnoticed and undervalued is a mystery to me. Memantine has the potential to produce a revenue stream for NTII that can justify a stock value 20 or 30 times its current level. If NTII does nothing else but, market memantine and collect royalties, it will be a cash machine. By early next year, the magnitude of this bonanza should be apparent as the clinical trial results roll out. Needless to say, I'm invested up to my ears in NTII and am expecting to reap a major reward. Best regards John de C