Dr. Clarke's Website
DR. CLARKE’S PROTOCOL FOR STROKE
Before I get into my stroke protocol, let me tell you a story. Last week I admitted a patient to the rehabilitation hospital who had been seen at one of the hospitals in the medical center in Houston. She is typical of the stroke patients that I see several times a week. She is a youthful 70 year old woman who had been living independently by herself in Galveston, driving and participating in community activities.
She was spending the Christmas holidays with her daughter in Houston when she suddenly had a paralysis in her left arm. This slowly resolved over the space of several hours, and she insisted to her daughter that she was fine. However, this paralysis recurred several hours later. Her daughter, realizing something was indeed wrong, took her to the emergency room where the routine CT scan of her brain and an EKG were performed, both of which were normal. This is usually the case with strokes because, if there is no bleeding in the brain, the CT will be “negative” for the first 2 or 3 days after a stroke. After this time, the CT will show the areas of dead and ischemic brain tissue. The EKG is performed to rule out an arrhythmia of the heart that could have set up intracardiac clots that could have dislodged and been pumped up to the brain. Since both of these were negative and since the paralysis had again resolved, she was told she had not had a stroke and to go home and make an appointment with a neurologist.
When she finally saw the neurologist, she was told that, in fact, she had indeed had a stroke and was sent for Doppler scans of her carotid arteries which showed a 95% stenosis or narrowing of the right carotid artery. However, before she received the report of these results, her left arm paralysis recurred, and this time it did not resolve. At this point she was finally admitted to the hospital with the diagnosis of a stroke.
The unfortunate truth here is that this woman was having an evolving or stuttering stroke when she experienced her first episode of left arm weakness. The other unfortunate truth is that if doctors understood what happens at the cellular and neurochemical and biochemical levels during this early phase of the stroke, there is a good possibility that the whole event could be aborted before paralysis occurs. That’s what my stroke protocol is all about.
But let’s continue with our story. Once admitted to the hospital, a complete workup of her heart ensued. Echocardiograms and angiograms were performed at a cost of tens of thousands of dollars, all of which were also “negative”, and still NOTHING has been done to protect the brain cells that are still starving for oxygen.
As an aside, remember this, every payor such as Medicare and insurance companies readily pay for cardiac procedures and hospitals owe much of their profit margin to this. Cardiologists and heart surgeons are paid the highest billing level for every patient visit they make in the hospital, but I, as a rehabilitation doctor, am not paid at all for 4 out of 7 hospital visits I make on my stroke patients. If I send a bill to medicare, it is denied with the statement, “…seeing the patient too often”. Rehabilitation hospitals are being denied payment by medicare and insurance companies for any care of patients that these payors, in their opinion, think exceeds that which is “medically necessary”, and even more tragic is that many of the Medicare replacement policies advertised to senior citizen to save them money deny rehabilitation benefits altogether in many of these cases. Ok, enough of my complaining. Let’s continue.
The patient was then given aspirin and Aggrenox, which is the old “post-stroke formula” that we were all taught in medical school, but all these do is to slow down the aggregation or clumping together of blood platelets to prevent more clotting. She became nauseated on these medications when the doctors DOUBLED the dose, so it was changed to just aspirin and Plavix which is essentially the same medicine with less aspirin. In the meantime an MRI was performed of the brain that indeed showed, not one stroke, but multiple strokes involving both the occipital lobe (which accounted for her partial vision loss in her left eye of which she had also been complaining) and in the right frontal and parietal lobes of the brain (which accounted for her paralysis). These are the stroke areas of the brain that had been stuttering along for the several days prior to her admission to the hospital.
Since the patient had no cardiac problem and now that the stroke had been visualized by MRI and she had been started on her antiplatelet drugs, she had completed the “usual and customary” treatment for a new stroke. Nothing left to do now except to send her off to rehab and to tell the family and patient, "Yep, it looks like you've had a stroke."
Yes, that's all there is! That's the medical treatment in 2008 for one of the most life-changing and debilitating events that can strike down a human being...and in America.....where we have the "best medicine in the world". Our medical treatment of the stroke patient has not appreciably changed for the past 100 years except that in 2008 we can scan the brain with MRI and see exactly where the stroke is.
Think about this carefully. Much more is done for patients seen in the ER for a heart attack than for a 'brain attack'. Large areas of heart muscle can sustain ischemic damage and the patient can still survive with all their motor, sensory, vision, speech, and cognition intact and they can return to a normal life. However, even a SMALL area of ischemic damage to the brain will ALWAYS have some functional deficit that profoundly affects a patient's life.
It's time to adopt a new emergent treatment plan for strokes that includes:
a. intervening in the chemical cascades that result in neuronal destruction occurring during the evolving ischemia; and
b. maximize local vasodilation to reperfuse this brain tissue; and
c. to bind receptors such as the NMDA receptors which will continue to propagate neuron death even after blood supply is restored; and
d. to reduce the free radicals released in enormous amounts during the stroke which continue to destroy more neurons and glia; and
e. to utilize biochemical mechanisms which minimize the damage resulting from the Ischemia-Reperfusion sequence.
These ongoing processes are the reason that the patient comes in initially with a weak arm and within 24 hours, the entire hemibody is paralysed.
I’ll show you how much more could have been done in an attempt to prevent the ultimate paralysis of this patient. All of these biochemical treatments I am suggesting are noninvasive and have been extensively published in hundreds of neuroscience and neurobiology journals, as I will also demonstrate.
So, if you’re reading this, you are wondering about strokes. Either you, one of your parents or other loved one has had a stroke and you want answers. You may be a doctor and, like me you have been struck with the revelation that in the past 50 years we have made virtually no advances in either the immediate management of stroke victims or any impact on diminishing the long term deficits which so profoundly affect the lives of these patients and their families. Your questions could and, in fact, should include:
“What causes a stroke?”
“What kinds of strokes are there?”
“How can I prevent a stroke?”
“What happens in the Emergency Room when a new stroke patient is admitted?”
“What should be done in the Emergency Room when a new stroke is admitted?”
“What can be done if I or my loved one has a stroke?”
“Is the damage permanent?”
“What can stroke rehabilitation do for a stroke patient?”
And for physicians, “What is the neuropharmacology of a stroke?”
These questions will be answered in great detail in this chapter, perhaps even more detail than the layman might understand. However, in my attempt to change the current dogma and impotent management of this devastating process, I will need to delve into the current neuropharmacology research and this may be more science than the average person wishes to contemplate. As for the physician, our basic science training in medical school is a long time ago for most of us, but I feel certain that memories of these fundaments will quickly be refreshed in these doctors and they will unquestionably be able to understand the data and the merits of my protocols and the science on which it is based.
It is my sincere prayer that this will introduce a new protocol to the acute or emergent management of the stroke patient. It is also my hope that the research presented which is published in highly reputed journals and reviewed prior to its original publication by some of the world’s foremost scientists will be appreciated for its scientific merit and the layman and physician alike will see the potential for its practical application in the care of the stroke patient.
In addition, I would like to see, utilizing information and concepts presented in this book, well-designed scientific studies of biochemical, structural, and functional outcomes in stroke patients. Perhaps we can impact stroke outcomes by implementing these basic biochemical and neuropharmacologic interventions and bring about a long overdue change in the management of stroke.
So let's begin.
Several years ago I read a paper by Dr. Robert Friedlander from Brigham and Women's Hospital, Boston, published in Annals of Neurology, February 2003. What impressed me was that he used a “cocktail” of chemicals to treat a disease process. The disease was Lou Gehrig’s or ALS, amyotrophic lateral sclerosis, a universally fatal degenerative neurologic disease. Once diagnosed the average survival is only 3 to 5 years. The only treatment as of this writing is riluzole which only extends the life of these patients by 3 months. Dr. Friedlander used a species of rats who are genetically engineered to develop this disease. I haven’t seen this multi-chemical or cocktail approach before, except in research papers of yesteryear. The idea, of course, is to help the patient rather than to find “the one drug” that will cure them.
He found that when he administered to these rats a combination or cocktail of minocycline and creatine, (read more about minocycline and how it might work in the Alzheimer’s and the Neurogenesis sections of this website) the onset of the disease was delayed and the rats lived 25% longer. His logic was that if one chemical helped, then two might be additive. He showed that in fact that was the case. It is this approach that I am using to find a NEW PROTOCOL for treatment of strokes. It is known in my local hospitals as Clarke’s protocol, or folly, depending on whom you talk to.
Read on and I’ll explain the logic and the science behind the protocol. Then read the section on Neurogenesis and put it together for your patients with CVA, traumatic brain injury, and spinal cord injury. I know you'll see remarkable improvements in the patient outcomes. Eventually I’ll add sections on similar protocols for multiple sclerosis and other neurodegenerative diseases as well as autoimmune diseases such as rheumatoid arthritis, lupus, and polymyositis. Remember as you’re reading this that ALL CELLS WORK THE SAME WAY. That means that biochemical manipulations that heal neurologic lesions will also heal skin wounds and injured areas in cardiac muscle, and even fractures in bones.
Phase 1: Ischemia In the first phase of a stroke, there is a blockage or occlusion of an artery that feeds a part of the brain. This is called ischemia. This robs the neurons in that part of the brain of its vital oxygen and glucose which are essential to the brain cell survival. If the blood flow is not quickly restored, these neurons will die, just like myocardial cells in a heart attack. Unfortunately, unlike heart muscle, brain cells cannot tolerate ischemia for long. In a heart attack, doctors can restore the blood flow with medications and with angioplasty. However, in the brain we have neither the time nor the ability to get access into the brain arteries to reopen them with angioplasty. We can, however, use drugs and chemicals to dilate these arteries and reestablish blood flow to the brain. So what drugs should we use? First, we need to understand the sequence of the biochemical events that occurs in ischemia in order to know what medications might be useful to counter these events and restore oxygen and glucose to these brain cells. Initially after the artery plugs up, the body tries to make nitric oxide (NO) to dilate it as well as other arteries that might feed the same brain tissue. It uses an amino acid arginine which is acted upon by the enzyme nitric oxide synthetase (NOS) to produce NO. We should, therefore, immediately give stroke patients in the ER high doses of intravenous arginine. (However, this should be done only as I have carefully documented below.) This not only provides the substrate for nitric oxide production, but also blocks the receptors for aspartate and glutamate (NMDA) which are excitatory neurotransmitters that are toxic to brain cells and are released by dying neurons during the stroke. If these transmitters are allowed to bind to receptors on healthy neurons, these neurons will also die, thereby increasing the size of the stroke. I’ll discuss this in more detail later. So arginine accomplishes two goals, the dilation of the arteries and the blocking of the NMDA receptors thereby limiting the number of neurons that will die and consequently the size of the stroke. Arginine should be given in the acute phase of the stroke. Phase 2: Oxidation The same destructive ischemia-reperfusion phenomenon occurs in the brain (Gursoy-Ozdemir, et.al. Stroke 2000 Aug;31(8):1974-80) after a stroke. I explained how promoting the NO production can vasodilate and increase the perfusion of oxygen-starved tissue. However, NO can be toxic, too. (Cowart, et.al. J Med Chem 1998 Jul 2;41(14):2636-42; Spinnewyn, et.al. Cereb Blood Flow Metab 1999 Feb;19(2):139-43; Bredt, Free Radic Res 1999 Dec;31(6):577-96) If NO is acted upon by another enzyme, superoxide dismutase (SOD), it can be converted to peroxylnitrite, a powerful oxidant. In low arginine concentrations, “neuronal NOS” (possibly via the excitatory neurotransmitters glutamate and aspartate, see my discussion below) generates NO and superoxide, favoring the production of the toxin peroxylnitrite. Peroxylnitrite, as with any free radical, then: 1. kills off more neurons by its free radical action; 2. kills off glial cells (the cells that support neurons and produce myelin to “insulate” the nerve fibers that carry the signals from one neuron to another); 3. causes inflammation which causes the release of cytokines such as interleukin-6 (IL6) and tumor necrosis factor alpha (TNFalpha) which kill off more neurons; 4. damages the mitochondria of more neurons via its free radical oxidation; 5. causes the release of aspartate and glutamate which kill off more neurons. In addition to peroxylnitrite, other free radicals are released by tissue ischemia that add to the oxidative destruction of adjacent neurons and contribute to tissue inflammation and cytokine release and platelet activation which, in turn, causes more artery occlusion. The treatment goal should be to block peroxylnitrite production as well as to provide potent antioxidant chemicals to eliminate the free radicals produced by ischemia and reduce the membrane oxidative potentials and to inhibit platelet aggregation. Phase 3: Inflammation This process is mediated by a number of factors in addition to the free radicals mentioned above. In addition to the body’s own cytokine release which promote more inflammation, there is also a release of matrix metalloproteinases which are potent inflammatory agents resulting in even more local cytokine destruction of neuronal tissue and more platelet activation. The treatment goal, then, should be to give medications and chemicals to block the body’s production of these inflammatory cytokines and to inhibit matrix metalloproteinases. Phase 4: Release of Excitotoxic Neurotransmitters The treatment goal, then, should be to block the NMDA receptors on neurons NOT intended to receive these excitatory neurotransmitters. SUMMARY: So this is why a stroke patient comes into the ER with a slight weakness in one arm and 24 hours later, the entire right or left side is paralysed. It is a cascade of events which evolves over a period of time beginning with a small arteriole occlusion but ending with a large area of destroyed neurons. The emergent treatment plan should focus on the following: v Increase Beneficial Tissue Perfusion v Reduce Membrane Oxidative Potential v Decrease Inflammation and Cytokine Production (IL-6, TNF-alpha) v Block NMDA Receptors v Block Platelet Activation Caused by Inflammation The subacute treatment during the rehabilitation phase should include the following: Restore Normal Metabolism & Repair v Increase Intracellular Metabolic Rate and Efficiency v Restore Normal Nutrition and Protein Substrates v Promote Anabolic Functions v Protect Cell Membranes from Hyperglycemia v Initiate Neurogenesis by Activation of Adult Stem Cells It seems intuitive and straightforward, doesn’t it? IT IS…if you understand the mechanisms involved. Let me explain my protocol. Arginine:
The “Ischemia-Reperfusion” sequence produces many species of highly destructive free radicals and is extensively discussed in the cardiovascular literature as it relates to myocardial infarction and cardiac bypass grafting. It is very well known that reducing membrane oxidative potentials by pretreating patients undergoing bypass grafting with various antioxidants will minimize any tissue damage resulting from the ischemia-reperfusion process.
Aspartate and Glutamate are excitatory neurotransmitters that occur normally throughout the brain and function just like other neurotransmitters such as norepinephrine, GABA, serotonin, etc. They are not toxic as long as they remain in their own respective neurons and the receptors intended to receive them. However, if they are released into the tissues and contact other neurons not intended to receive them, they are highly toxic to these cells.
Stop the Cascade
Since we’ve already mentioned this amino acid, let’s begin with this. Arginine is normally obtained from dietary sources and loading the patient is easily accomplished with oral supplements. I would recommend, however, using IV loading in the emergency room for an acute management of a stroke patient. However, arginine should NOT be given without also blocking the NMDA receptors and decreasing inflammatory reactions and administering antioxidants. Otherwise, an overproduction of NO could be produced and actually INCREASE infarct size. See the discussion below. In the rehab or subacute setting, using the oral route to administer about 2 or 3 grams of arginine per day is adequate.
Arginine is, as I’ve already indicated, the substrate for the enzyme nitric oxide synthetase to produce nitric oxide (NO). L-arginine has been shown in numerous studies to reduce the size of cerebral infarcts or be neuroprotective in animals (Sadoshima et.al. Brain Res 1997 Jan 9;744(2):246-52; Kidd et.al. Hypertension 2000 May;35(5):1111-8; Rosenblum, Keio J Med 1998 Sep;47(3):142-9; Morikawa et.al. Stroke 1994 Feb;25(2):429-35; Zhang and Iadecola, Neuroreport 1993 May;4(5):559-62; Dawson, et.al. Neurosci Lett 1992 Aug 17;142(2):151-4).
However, there are a number of studies that demonstrate that inhibition of NOS thereby decreasing NO reduces the size of cerebral infarcts (Zhang, et.al., Stroke 1996 Feb;27(2):317-23; Zhang, et.al. J Cereb Blood Flow Metab 1996 Jul;16(4):599-604; Iadecola et.al. Am J Physiol 1995 Jan;268(1 Pt 2):R286-92). These conflicting data may be the result of thrombotic processes that occur during the ischemic event that override the beneficial effects of L-arginine and NO (Prado, et.al. J Cereb Blood Flow Metab 1996 Jul;16(4):612-22). Such neurotoxic effects of NO could also be the effect of peroxylnitrite rather than the NO itself (Dawson and Dawson, J Chem Neuroanat 1996 Jun;10(3-4):179-90). Dalkara, et.al. at Harvard demonstrated that IV infusion of L-arginine decreased infarct size in a dose dependent fashion, but excessive NO production by “neural mechanisms” facilitated a neurotoxic effect (Neuropharmacology 1994 Nov;33(11):1447-52). This could be an excitotoxic neurotransmitter release of glutamate and aspartate because overactivation of glutamate receptors in response to cerebral ischemia has been shown to produce a massive release of NO (Bredt, Free Radic Res 1999 Dec;31(6):577-96).
There appear to be 2 pools of NO. One is produced by endothelial arginine within the vascular tree and the other by the neuronal release of glutamate and aspartate and perhaps acetylcholine. The former seems to be neuroprotective and vasodilatory and the latter to be neurotoxic. So it appears that NO production by arginine is most probably beneficial in limiting the size of infarcts as long as concurrent blocking of NMDA and free radicals and inflammatory reactions are also accomplished.
By the way, NO is also produced by IGF1 (insulin growth factor 1). IGF1 is the product of human growth hormone which plays a premier role in my stroke protocol as both an anabolic stimulus to increase muscle mass and strength and to induce neurogenesis to convert adult stem cells into neurons and glial cells. Please refer to the section on Neurogenesis for more on this subject.
Oh, and as long as I’m talking about hormones, estradiol (ie. 17-beta estradiol or “bio-identical” estradiol) is also neuroprotective and it may be due to its ability to increase endothelial NOS and therefore NO (McNeill, et.al, Stroke 2002 Jun;33(6):1685-91).
Okay, back to the subject. Once NO is produced from arginine, NO has the following effects in and of itself:
v Functions as an amino acid neurotransmitter and is involved in learning and memory (Piedrafita, et.al., Learn Mem. 2007 Apr 5;14(4):254-8).
v Relaxes smooth muscle, found in the walls of the blood vessels, resulting in vasodilatation of large and small vessels and even capillaries and decreases the size of the infarction .(McCarty, Med Hypotheses 2000 Nov;55(5):386-403; Kidd, et.al. Hypertension 2000 May;35(5):1111-8).
v Inhibits platelet aggregation and therefore prevents further clot formation that might otherwise result from inflammatory reactions (French, et.al. Blood 1997 Jun 15;89(12):4591-9).
v Stimulates bone remodeling, fracture healing, and reverses osteopenia.(Fini, et.al. Pharmacother 2001 May;55(4):213-20; Zhu, et.al.,Miner Res 2001 Mar;16(3):535-40; Fiore, et.al., Pharmacol 2000 Nov 24;408(3):323-6; O’Shaughnessy, et.al., Biophys Res Commun 2000 Nov 2;277(3):604-10; Diwan, et.al, Miner Res 2000 Feb;15(2):342-51; Corbett, et.al., Orthop 1999 Aug;(365):247-53; Kanamaru, et.al., Med Sci 2001 Feb;47(1):1-11).
v Wound Healing (Kane, et.al.,Pharmacol 2001 Apr;132(8):1631-8).
The physiologic effects of arginine are extensive, but the only ones in which we are interested for purposes of this protocol are its NMDA receptor blocking activity, its function as a normal protein substrate for tissue and muscle rebuilding, and its vasodilating effect on vasoconstricted tissue resulting in greater reperfusion. The NMDA receptor blocking effect is achieved via hexapeptides which incorporate arginine resulting in an arginine-rich receptor blocker (Ferrer-Montiel, et. al. Nat Biotechnol 1998 Mar;16(3):286-91).
Arginine is therefore an important component of my stroke protocol, both in the emergent and subacute management.
Melatonin:
Free Radical Scavenger
In my Alzheimer’s section of this website I have presented some of the benefits of melatonin. What I have not discussed is the science behind the neuroprotective effects of melatonin in cerebral ischemia. I have already stated that the generation of free radical species occurs during and after a stroke from both the conversion of the NO by super oxide dismutase to peroxylnitrite and by the ischemia-reperfusion cascade. It should be readily apparent that melatonin would be most efficient at scavenging these free radicals. This is indeed the case.
At the National Institute of Health, in the Cellular Neurobiology Branch, a study was conducted by Borlongan, et.al. (FASEB J 2000 Jul;14(10):1307-17) demonstrating dramatic glial cell survival during experimental middle cerebral artery occlusion with melatonin compared to control animals. This resulted in a reduction in the size of the infarct and an improvement in locomotor deficits.
Kilic, et.al. (J Cereb Blood Flow Metab 1999 May;19(5):511-6) reported similar results with experimental middle cerebral artery occlusion. Injection of melatonin (4 mg/kg) before both ischemia and reperfusion reduced infarct volume by 40% and significantly improved neurologic deficit scores in pinealectomized as well as sham-operated rats subjected to middle cerebral artery occlusion. This indeed demonstrates that physiologic melatonin release as well as exogenously given melatonin has a neuroprotective action in focal cerebral ischemia. In a more recent paper (J Pineal Res. 2008 Feb 14) These authors used a similar paradigm and showed that when melatonin was administered even 24 hours post CVA and dosing was continued for another 29 days, both cell survival AND neurogenesis was significantly improved. This result also translated into both improved motor and coordination functional outcomes. This is one of the first studies that suggests a possible role of melatonin in neurogenesis, although it may be that melatonin is only neuroprotective and the neurogenesis is initiated by other mechanisms discussed in that section on this website.
Kaur and Ling (Curr Neurovasc Res. 2008 Feb;5(1):71-81) have studied the varying permeability of the blood brain barrier in hypoxic injury. These authors discuss the favorable effects of curcurmin, melatonin, and minocycline in decreasing the permeability of this natural barrier when administered following hypoxic conditions. This may represent another protective mechanism of melatonin in CVA.
Zou, et.al. (Conf Proc IEEE Eng Med Biol Soc. 2004;7:4748-50) also demonstrate the same diminished infarct size with melatonin treatment, but also that cyclooxygenase (COX1) anti-inflammatory pathway mediated this melatonin neuroprotection. This is an interesting finding since anti-inflammatory effects of melatonin via inhibition of inflammatory cytokines are well documented.
Cuzzocrea, et.al. (J Pineal Res 2000 Nov;29(4):217-27) also found this neuroprotective effect of melatonin in brain ischemia and noted that both malondialdehyde and myeloperoxidase levels (oxyradicals and peroxylnitrite radical species) in the hippocampus were also reduced as well as post-ischemic brain edema. Neuronal loss was decreased in the pyramidal layer in melatonin treated animals following ischemia. Even more interesting was the finding that the same effects can be achieved whether the melatonin was administered pre, 2 hours, 4 hours, or 6 hours post ischemia. This confirms a potential for a POST STROKE treatment with melatonin which would reduce the size of the infarct and could be implemented in a clinical setting.
In one of my favorite journals for casual reading, Zhongguo Yao Li Xue Bao 1997 Sep;18(5):394-6, Dr. Li, et.al. also found in rats a significant reduction with melatonin treatment in hydroxyl free radicals which are the result of the ischemia-reperfusion cascade.
NMDA Receptor Antagonist
As I have indicated in the above introduction, the “blocking” of the excitotoxic neurotransmitter receptors, N-methyl-D-Aspartate receptors, is paramount in curtailing the extent, size, and deficits resulting from a cerebral infarction. I have also given data in the Alzheimer’s section of this website to show that melatonin is an effective NMDA receptor antagonist. Skaper, et.al. (FASEB J 1998 Jun;12(9):725-31) demonstrate using in vitro cell cultures that, in fact, melatonin administration prevented cell death induced in these neurons by glutamate which stimulates the NMDA receptors. This indicates that melatonin is a specific antagonist for this receptor as well as providing neuroprotection via its free radical scavenger function.
More data comes from Escames, et.al. (J Neuroendocrinol. 2004 Nov;16(11):929-35) who not only showed that melatonin inhibited NMDA and glutamate excitation, but present persuasive evidence that this effect is not by membrane receptor blockade, but by inhibition of neuronal nitric oxide synthetase activity and by targeting the redox site of the NMDA receptor. So melatonin is not an NMDA receptor antagonist in the traditional sense, but indirectly counteracts the excitation of the receptor. The result is, however, essentially the same.
These are not the ONLY mechanisms by which melatonin blocks the excitatory NMDA and glutamate receptors. Louzada, et.al. (FASEB J. 2004 Mar;18(3):511-8) propose that GABA(A) receptors inhibit the excitatory effects of glutamate and that agonists of GABA(A) receptors, Taurine, Phenobarbital, and MELATONIN act similarly to suppress these excitatory responses. This represents an indirect inhibition by melatonin of NMDA and glutamic acid receptors.
By the way, Magnesium and Zinc also block the NMDA receptors by blocking the NMDA calcium channel and a voltage-dependent block of the NMDA receptor itself, respectively (Escames, et.al., J Pineal Res. 1998 Mar;24(2):123-9). When these cations were iontophoresed together with melatonin, additive inhibitory effects were observed on the NMDA receptors. Magnesium and Zinc are also part of my stroke protocol.
Inflammatory Cytokine Blocker
I have indicated that after a stroke or brain injury there is a surge in the production of destructive inflammatory cytokines and matrix metalloproteinases. Melatonin inhibits both. Fascinating, isn’t it? Not only is melatonin one of the most potent reducing (free radical scavenging) agents and an antagonist of excitotoxic neurotransmitters, it is also a potent anti-inflammatory. I’ll show you some fun science.
Dr. Esposito, et.al. (J Pineal Res. 2008 Apr 21) used melatonin to decrease matrix metalloproteinases 9 and 2 in an experimental model of colitis thereby reducing the inflammation thereof. These same authors reported that melatonin decreased inflammation in an experimental spinal cord injury model (J Pineal Res. 2008 Feb 19) and the mechanism by which this was mediated was via reduction in both matrix metalloproteinases 9 and 2 as well as tumor necrosis factor alpha, an inflammatory cytokine.
So melatonin works in the gut AND in the central nervous system. (Remember my basic law of cell biology? ALL CELLS WORK THE SAME) In fact, melatonin is produced in large amounts in the gastrointestinal tract and is protective there as well via the same mechanisms of redox and anti-inflammation. I’ve just gotta share this study with you. Dr. Swarnakar et.al. (J Pineal Res. 2007 Aug;43(1):56-64) showed that melatonin’s ability to prevent and heal ethanol induced gastric ulcers is found in its ability to decrease matrix metalloproteinases 9 and 2 and TNF-alpha.
Melatonin neutralizes ROS (reactive oxygen species), increases antioxidative enzymes activities and glutathione levels, prevents electron leakage from mitochondrial respiratory chain, acts synergistically with vitamins C, E, and glutathione. Melatonin reduces levels of proinflammatory cytokines: IL-6, IL-12, TNF-alpha, IFN-gamma.
This should be more than enough data to demonstrate that including melatonin in my stroke protocol is based on hard science. Let’s summarize all this melatonin data by saying that WITHOUT QUESTION MELATONIN IS A POTENT AND EFFECTIVE NEUROPROTECTIVE NEUROTRANSMITTER IN CEREBRAL ISCHEMIA BY MULTIPLE NEUROCHEMICAL MECHANISMS. A good study to use as a summary of the protective role of melatonin in stroke is that of Macloed, et.al. (J Pineal Res. 2005 Jan;38(1):35-41) who performed a meta-analysis of all the available papers regarding neuroprotective effects of melatonin and confirmed a marked efficacy of melatonin in animal models of focal cerebral ischemia. Melatonin is a critical part of my stroke protocol.
Let’s move on to the next chapter in my stroke protocol.
Stay tuned. I’ve got to dig out more references. There's a whole lot more coming!!
