Rick, and others,
This time I will respond. I own other in thread explanation. For one week I will be ignorant to any question.
I am bit surprise that you are asking this questions. I am far away from neurology, simply chemist and on everything I am looking as organic chemist. You, as immunologist/genetic, should have much great knowledge on this mater. I hope you do as, I think, you like SIBI.
Because many followers on this thread do not understand , in many parts also I don't, terminology and complexity of the stroke problem, I will tried by simple words explain some terminology. Also this is how I view stroke.
ISCHEMIC Neuron-cells death: Disturbance in blood-flow (caused by burst or clot) cause initial neuron damage which, by nature of the neurotransmitters, has for consequence that this neurons release glutamate or/and glycine (in controlled amount they are neurotransmitter, in uncontrolled event-progressive increased concentration they are excitotoxins). Glutamate/glycine is NMDA receptors and by this interaction he open Calcium ion channel (calcium enter neurons and if it is in uncontrolled amount it cause cells necrosis/death). Death neurons again release glutamate and....EXPONENTIALLY PROGRESSIVE UNCONTROLLED EVENTS!
NON-ISCHEMIC Neuron-cells injury/death: Slow secret of the excitotoxins (AIDS Dementia, trauma, ...), elevated calcium ion plasma concentration, other neurodegenerative disease, and other neuronal and cell injury. Released glutamate and other exicotoxins are removed from CNS by normal blood flow. Elevated level can cause neuronal damage, and by time slow progressive neuro-damage become neuro-disease. SLOW BUT STEADY EVENTS!
CALCIUM ION CHANNELS: Divided in to human body (cardiovascular disease: angina and hypertension) and CNS. CNS channels (from human brain tissue) is deviled in to: 1. Voltage-gated (N-Type, pain), 2. Excitatory amino acids (NMDA and AMPA; Stroke, TBI, ..) and 3. Nicotinic Acetycoline (Parkinson's, ...).
NMDA Chanels (The name:N-Methyl-D-Aspartate is chosen because It is used for indentification of the receptors): Ionotropic and metabotropic. Several subtype of the Ionotropic, main is heteromeric pentamer to which glutamate bind. Receptor- agonist/ligand to DMNA can be small molecules, peptides, ...Receptor antagonist can be small molecules, peptides, polyamines, redox molecules,....
COMPETITIVE antagonist: Acid which bind to receptors site and block binding of the glutamate.
NON-COMPETITIVE antagonist: After glutamate bind to receptors channel is open. Antagonist "sit" on top of this channel and suppress calcium ions flux in to cells. Binding affinity and selectivity depend on "basic" strain of the amines and structure-compatibility with receptor pocket.
MEMANTINE is: a) anti-Parkinsonian (AGONIST for Nicotinic Acethylcholine calcium channel responsible for dopamine release), b) low affinity and non-selective non-competitive NMDA antagonist, and low affinity N-Type antagonist. Structurally it is primary mono-amin with bulk group. If someone want to applied Memantine as NMDA antagonist for ischemic stroke, large plasma concentration will be needed for therapeutic effects. This will be problem with his anti-parkinsonian property (mediate influx of the calcium ions in to neuro-cells by nicotinic receptor. I think this is the main reasons that Dr. Lipton is calling Memantine (last patent Mart 21, 1997) non-ischemic NMDA antagonist, where steady low concentration are sufficient for neuroprotective effects.
CERESTAT is non-competitive selective (heteromeric glutamate channel) NMDA high affinity (guanidine class, three amino groups) antagonist with therapeutic effects at very low plasma concentration. It is designed for severe ischemic condition like stroke and traumatic brain injury.
Up to date none competitive or non-competitive NMDA antagonist for stroke successfully completed clinical trials. Reasons are : severe side effects, non-selectivity, not clinical relevant positive results.
Will Cerestat be the first one? Will know at the June and end of the year.
mz |
