Ampakine Update: S18986 and Brain Aging

Scientific work continues on the use of Ampakine drugs to treat Alzheimer's and other neurological disorders.

The drug, temporarily designated S18986, interacts with AMPA (short for α- Amino-3-hydroxy-5- methylisoxazole-4- propionic acid, or ampakine) receptors in the brain. These receptors transmit excitatory signals in the brain, and researchers were interested in experimental AMPA-receptor drugs (such as S18986) for their neuroprotective abilities and for the way they temporarily boost memory. But rather than investigating the compound’s short-term effects, Alfred E. Mirsky Professor Bruce McEwen and his lab members...studied the drug’s impacts on middle-aged to elderly rats and found that, when administered daily over four consecutive months, it appeared to improve memory and slow brain aging.

...When compared to control animals that had received only sugar water, the drugged rats were not only more active and better at memory tests, but their brains showed physical signs of slowed aging. Neurons in the forebrain that produce acetylcholine, a neurotransmitter known to play a role in learning and memory, had 37 percent less decline. Dopamine-producing neurons, which are responsible for sustaining activity and motivation levels, slowed their decline by 43 percent. Levels of inflammation in the brain were also significantly lower. “Every marker we chose to look at seemed to indicate there was some preservation of function during aging with chronic treatment,” Hunter says. The drug appears to slow aging’s effects throughout the entire brain.___ScienceDaily__via__FutureScanner

This particular Ampakine appears to have a protective effect on the brains of rats over a significant part of the rat's lifespan.

Ampakines are being researched as potential treatments for Alzheimer's, Depression, and other neuropathological and neuropsychiatric conditions. This research suggests an even broader potential application of Ampakines--as a neuroprotective for those at risk for neuropathology. Broadly speaking, that would be most of us, over our lifespans.

Better Memories, Smarter Minds, Larger Horizons

Drug makers trying to create smart drugs and better memory drugs are approaching the goal from several directions. First of all, the need for an effective anti-Alzheimer's drug is growing critical--with the aging of the western world, Russia, and China. Next, competition in schools and the workplace (including the casino) makes a better memory worth its weight in gold. Effective drug treatments to mitigate disability from mental retardation are also being sought. Finally, society itself is in need of a more intelligent population--to maximise solutions to problems, and to minimise crime and delinquency.

Beyond traditional treatment approaches to Alzheimer's, ADHD, and abnormal drowsiness, some genuinely novel approaches to smart drugs are being tested in several research labs.

AMPAkines
CREB
PDE Inhibitors(4,10)
Nicotinic Alpha-7 agonists
mGluR antagonists
5HT6 antagonists

Frontrunners in the pharmaceutical race for smarter, better memory drugs include Memory Pharmaceuticals, Cortex Pharmaceuticals, Saegis Pharmaceuticals, Helicon, Lilly, Pfizer, Wyeth, Merck, Sention and many others. The precedent of approving drugs for erectile dysfunction (ED)--a lifestyle drug--suggests that smart drugs will eventually be approved for drooping memories as well.

Further Reading:

Molecules for Memory

Future Directions in Neuroscience

Nootropics

Smart Drugs: What Are the Prospects?

Shaping the Brain with Smart Drugs (Gazzaniga)

CREB and Memory (basic neuroscience)

CREB, Synapses, and Memory Disorders

Hat tip Advanced Nano and Kurzweilai.net

On Losing Your Depression Quickly

Conventional antidepressants may require from a few weeks up to a few months to achieve their antidepressant effect, when they are effective. Depression is a very common condition worldwide, very expensive in terms of lost time and lost lives. A quicker way to lose one's depression would be quite useful.

A new study has revealed more about how the medication ketamine, when used experimentally for depression, relieves symptoms of the disorder in hours instead of the weeks or months it takes for current antidepressants to work. While ketamine itself probably won’t come into use as an antidepressant because of its side effects, the new finding moves scientists considerably closer to understanding how to develop faster-acting antidepressant medications – among the priorities of the National Institute of Mental Health (NIMH), part of the National Institutes of Health.

Ketamine blocks a receptor called NMDA on brain cells, an earlier NIMH study in humans had shown, but the new study in mice shows that this is an intermediate step. It turns out that blocking NMDA increases the activity of another receptor, AMPA, and that this boost in AMPA is crucial for ketamine’s rapid antidepressant actions. The study was reported online in Biological Psychiatry on July 23, by NIMH researchers Husseini K. Manji, MD, Guang Chen, MD, PhD, Carlos Zarate, MD, and colleagues.
...Almost 15 million American adults have a depressive disorder. During the long wait to begin feeling the effects of conventional medications, patients may worsen, raising the risk of suicide for some. Depressive disorders also affect children and adolescents.

By aiming new medications at more direct molecular targets, such as NMDA or AMPA, scientists may be able to bypass some of the steps through which current antidepressants indirectly exert their effects – a roundabout route that accounts for the long time it takes for patients to begin feeling better with the conventional medications.

While ketamine appears to achieve this, it is an unlikely candidate to become a new treatment for depression, because of the side effects it can cause in humans, including hallucinations. It is approved as an anesthetic by the Food and Drug Administration at much higher doses than those given in the study, but its use is limited because it may cause hallucinations during recovery from anesthesia.

Source

Of course ketamine would be an absurd choice for routine antidepressant treatment--it is administered by injection, incapacitates an individual for a period of time, and often subjects an individual to horrific nightmares on emergence from the drug.

And yet if scientists and clinical researchers can learn from the effects of ketamine on the brain and on subsequent mental states, why not?

Ampakines are drugs under development by Cortex Pharmaceuticals (Amex: COR) that also affect the AMPA receptors. And like ketamine, some ampakines also have an antidepressant effect.

I suspect that we are due for a breakthrough in therapy for depression, given how long it has been since any significant progress has been made in that area of neuropharmaceutics. Looking at glutamate receptors in that regard can certainly not hurt. If we accidentally stumble across better therapies for Alzheimer's and other neurological conditions in the process, vive le serendipity!
;-)

Getting to Ampakines--How Much Longer?

Brain boosting drugs in the new Ampakine class are back in the news--this time in connection with the problem of respiratory depression from sedative/hypnotic drugs.

Researchers at the University of Alberta (Edmonton, AB) and Cortex Pharmaceuticals (Irvine, CA) believe that AMPAKINE drugs may provide protection from drug-induced respiratory depression, while simultaneously allowing the sedative or analgesic to continue working as it was intended.

The drug tested in this study belongs to a novel class of molecules known as AMPAKINE compounds being developed by Cortex Pharmaceuticals, Inc. located in Irvine, California. AMPAKINE compounds act on the most common excitatory receptor in the brain, the AMPA "Glutamate type receptor," which has been shown in rodent models to boost the brain's own protein for improving age-related deficits in memory mechanisms. In primate models AMPAKINE compounds have replicated the studies in rodents and in adults patients suffering from Attention Deficit Hyperactivity Disorder, significant clinical and statistical improvement in increase attention and decrease hyperactivity have been observed. The U. Alberta research provide evidence that another important AMPAKINE indication is to stimulate primitive areas of the brain called the pre-Botzinger Complex responsible for breathing, without causing side effects. The pre-Botzinger Complex generated respiratory-related oscillations similar to those generated by the whole brainstem in vitro, and neurons with voltage-dependent pacemaker-like properties that have been identified in this brain region.

In a study published in 2006, Dr. John J. Greer of U. Alberta demonstrated that certain AMPAKINE compounds enhance the respiratory drive and breathing rhythm at the brain-stem level containing the pre-Botzinger Complex in laboratory rats whose respiration rates were purposely suppressed by administration of central nervous system depressants.

Dr. Greer found that respiratory depression induced by these agents can be reversed or prevented in test animals with an experimental AMPAKINE drug, without a reduction of pain relief or sedation.

Greer and coworkers treated rats with the opioids analgesic fentanyl or the barbiturate sedative Phenobarbital, both commonly prescribed in the United States. Greer used a technique known as plethysmography, which measures blood flow throughout the body, to determine the level of respiratory distressed caused by the drugs. When drugged rats were treated with the AMPAKINE , the respiratory distress quickly resolved. The drug worked in both newborn and adult rats. Interestingly, the drug on its own did not affect blood flow in animals not treated with the sedative drugs, nor did administration of the drug cause noticeable arousal in the animals.

Greer concluded, in a study published in the September 20, 2006 issue of the American Journal of Respiratory Critical Care Medicine, that CX546, "effectively reverses opioid- and barbiturate-induced respiratory depression without reversing the analgesic response."

"These results open up the real possibility of combining an ampakine compound with commonly prescribed barbiturates or opiates to reduce the likelihood that life-threatening respiratory depression will occur," noted explained Roger G. Stoll, Ph.D., Chairman, President, and CEO of Cortex.

Source

Ampakines hold out a promise for effective palliative treatments for Alzheimer's and other neurodegenerative disease. Currently, the Cortex drug CX717 is being held up by the FDA over toxicity concerns. Consequently the stock price of Cortex is currently quite low--trading below US $3 a share for over a year.

It is easy to see that should Cortex navigate through the labyrinthine bureaucracy of the FDA and reach approval for any of its Ampakines in development, that the stock price could rise rapidly.

Frankly, it is the potential for cognitive enhancement in normal people that fascinates me the most about the Ampakines. But the potential to make a substantial profit on a fairly small investment is also attractive. But do your own research before investing.

Here is more about Cortex' attempt to satisfy the FDA's concerns about possible toxicity of CX717 in animal studies.

Here is a recent report on a study that suggests that Ampakines might benefit Huntington's Disease patients, through their role in releasing BDNF in the brain.

The Next Generation of Cortical Stimulants

Cephalon's drug Modafinil has been a hit with people who wanted to stay awake while remaining alert--pilots, soldiers, medical doctors, swing shift workers, students . . . But Cephalon cannot rest on its laurels and expect to stay on top in this market. Cortex Pharmaceuticals is developing a newer type of cortical stimulant--an ampakine called CX717. CX717 promises to revolutionise treatment of ADHD, age-related cognitive decline, and cognitive deterioration from sleep deprivation.

Cephalon's answer to CX717 is Nuvigil--the single isomer of the racemic drug Modafinil. It isn't clear that Nuvigil will be better in terms of better efficacy or fewer side effects than Modafinil, but it will allow Cephalon to patent a new drug in the same class--just when Modafinil's patent will be running out.

No, it is the new Ampakine that is being anticipated by most neuroscientists and mental health workers. This class of drugs may very well improve the outlook for sufferers of cognitive decline of several types, including Alzheimer's, Parkinson's, even congenital childhood diseases of cognition.

Hat tip gizmag, and Popular Science.

Update: Here's an interesting story on the stock price of Cortex Pharmaceuticals. The FDA recently halted trials of CX717 because of "tissue damage" in some test rats. It may be concluded eventually that the damage was actually caused by formaldehyde--quien sabe?

The interesting thing about this little setback is that the price of Cortex (COR) was recently trading for under US $2 a share, due to the FDA's continuing hold on CX717. If CX717 is finally approved, and proves itself even fractionally as important as many informed observers expect, that $2 price should shoot up very quickly.

Beyond Smart Drugs: Getting Smarter

Aubrey de Grey's SENS approach to gerontology may very well help us to live longer, perhaps much longer. Then what? Humans really do need to become smarter. Present levels of human intelligence are just about good enough to get us all killed. To go beyond what was discussed in the posting Smart Drugs, I would like to look toward longer term prospects for boosting intelligence--permanently.

Returning briefly to neuroscientist Michael Gazzaniga in his Oct 2005 SCIAM articleSmarter On Drugs, we see the real essence of the problem. Smart drugs temporarily augment the brains we have, but they do not make them better. To do that, we have to go further:

We have isolated one gene involved in intelligence, and others will follow. We know which parts of the brain are influenced by particular genes and which parts correlate with high IQ. We also know some of the neurochemicals involved in learning and memory. With such knowledge, we will gain understanding of what needs to be manipulated to increase intelligence in people who were not blessed with brilliance in their genomes or further increase the intelligence of those who were. Gene therapy could insert, delete, turn on or turn off genes that we find to be associated with intelligence.

We know about the Human Genome Project, and we understand that it is the foundation for much bigger things. We have heard about the International Hapmap Project, and we may have a vague idea of the possibilities that will be generated because of it. Diseases and other human attributes possess significant genetic components. We need to know what they are.

But we must think more broadly than mere genes. Genes are only part of the story. The better understanding of proteins, or proteomics, holds many of the keys we are looking for. In addition, non-coding RNA is a critical piece of the puzzle. The entire control structure of each cell is a highly complex internetwork of feedback systems. If you add the feedback systems of neighboring cells and tissues, then take into account signals coming to the cell from the blood, lymph, nerve terminals, and other meta-control systems--and you begin to see the problem.

We were talking about how to become more intelligent, using the genes. But now we understand that it can never be just the genes. It has to include the entire biological environment of the nervous system, and the entire organism.

But, wait. The organism is not hermetically sealed. The organism has inputs from the outside, and outputs to the outside. We know that growing organisms have to be given adequate nutrition, physical exercise, and mental stimuli to develop normally. They also need emotional nurturing. From Intelligence Testing Blog, we learn from Kevin that even video games may contribute to cognitive enhancement in young children. But what about the mature, developed organism--human? Assuming he is getting optimal nutrition, exercise, mental challenge, and emotional support? What else can be done?

OK, I talked about ampakines, donezepil, and modafinil here. If you are living on the edge of your mental capacity, it might be worth it to you, to try to get your hands on some donezepil. Modafinil should be treated gently, since everyone needs ample sleep, and with modafinil the temptation is to skimp on sleep to get more done, potentially abusing the body in the process. Ampakines are not available yet, but will be relatively soon. These are temporary approaches.

While we are waiting for researchers to understand the genetics, proteomics, and epigenetics of intelligence, there may be more permanent actions we can take to augment our mental capacity.

Assuming your nutrition is indeed optimal, your physical activity regular, your mental stimulation productive, and your emotional supports satisfying--what else can you do?

Neurofeedback is a technology that has been largely ignored by the public and news media, but is an approach that holds enormous potential for mental growth, even for mature and normal human mind/brains. It is still experimental in terms of stimulating mental growth for normal brains, but it is safe and non-invasive.

People with phobias, such as math phobia, are preventing themselves from progressing in the direction of their phobia. Such persons can certainly be helped by neurofeedback and other behavioural approaches.

There are many commercial programs, such as this one, that tries to capitalise on the human desire to improve oneself. This is another group that seems to be taking an even more advanced approach to developing mind improving technology. And while Daniel Amen may be rightly criticised by his peers for jumping too quickly into imaging technology to diagnose common everyday conditions, there is no doubt that Amen is at the leading edge of the curve, and may have the last laugh after all.

Taking nutritional supplements may not be a bad idea, either. In addition to the multivitamins, the extra vitamin C and E, and the minerals, taking curcumin, lipoic acid, and precursors for neurotransmitters might be helpful for many, particulary those with depression, fatigue, or ADD. This is not medical advice, but merely a suggestion for something that might be looked into.

Long life and increased intelligence are not the final goal. To reach the final goal, you must also include enlightenment, and wisdom. Using both sides of the brain to the fullest extent. Mysticism and holism are only part of wisdom. Wisdom also includes the ability to look at the details with exquisite clarity, and being able to place them into dynamic context.

We have some distance yet to travel, many things to learn. There is no reason not to use the footstools, ladders, and knotted ropes dangling above us.

Smart Drugs: What are the Prospects?

We begin with an article from Sciam Mind, by Michael Gazzaniga.
Enhancing intelligence is not science fiction. Many "smart" drugs are in clinical trials and could be on the market in less than five years. Some medications currently available to patients with memory disorders may also increase intelligence in the healthy population. Likewise, few people would lament the use of such aids to ameliorate the forgetfulness that aging brings. Drugs that counter these deficits would be adopted gratefully by millions of people.

Drugs designed for psychotherapy can also be used to enhance certain regular mental functions. Just as Ritalin can improve the academic performance of hyperactive children, it can do the same for normal children. It is commonly thought to boost SAT scores by more than 100 points, for both the hyperactive and the normal user. Many healthy young people now use it that way for that purpose, and quite frankly, there is no stopping this abuse.

... consider the following. In July 2002 Jerome Yesavage and his colleagues at Stanford University discovered that donepezil, a drug approved by the FDA to slow the memory loss of Alzheimer's patients, improves the memory of the normal population. The researchers trained pilots in a flight simulator to perform specific maneuvers and to respond to emergencies that developed during their mock flight, after giving half the pilots donepezil and half a placebo. One month later they retested the pilots and found that those who had taken the donepezil remembered their training better, as shown by improved performance. The possibility exists that donepezil could become a Ritalin for college students. I believe nothing can stop this trend, either.

...Recently geneticists have discovered that even such abstract qualities as personality and intelligence are coded for in our genetic blueprint. Studies of the genetic basis of g are just beginning, and because g most likely arises from the influence of many genes, the hunt will be a long one. Yet one study has already found that a gene on chromosome 6 is linked to intelligence.

So-called genetic brain mapping could help the search. Scientists are looking at the structural features (size, volume, and so on) of the brains of many individuals, including twins, familial relatives and unrelated individuals. By scanning all these brains in magnetic resonance imaging machines and looking at the differences, researchers have been able to determine which areas of the brain are most under the control of genes. These studies have emerged only in the past three to four years. Geneticists hope that once they know which brain areas are most affected by heredity, they can figure out which genes are responsible for those regions. With this kind of reverse mapping, the experts should be able to learn more about the genetics of intelligence.

...Whatever happens, we can be sure that cognitive enhancement drugs will be developed and that they will be used and misused. But just as most people do not choose to alter their mood with Prozac and just as we all reorient our lives in the face of unending opportunities to change our sense of normal, our society will absorb new memory drugs according to each individual's underlying philosophy and sense of self. Self-regulation will occur. The few people who desire altered states will find the means, and those who do not want to alter their sense of who they are will ignore the drug potions. The government should stay out of it, letting our own ethical and moral sense guide us through the new enhancement landscape. by Michael Gazzaniga

Next we go to Nootropics.com, a Hedweb site. This review of "Smart Drugs 2" by John Morgenthaler and Steven Fowkes, links to discussions of several potential smart drugs, as well as discussions about the underlying neuroscience and pharmacology involved. Here, we are introduced to modafinil, an increasingly prescribed drug that seems to do what it is supposed to do, with few serious side effects.

Modafinil, or Provigil, is a new stimulant with several different indications, and many more off label uses. Modafinil.org lists 45 uses of modafinil, cognitive enhancement being number 45. Modafinil.com is another Hedweb site, full of links to other pages describing the neuropharmacology of provigil, and the underlying neuroscience involved. Modafinil is becoming very popular with young professionals who never seem to have enough time to get everything done. Militaries use it for special ops troops, helicopter pilots, and pilots on long bombing missions. It works for ADD/ADHD, as an adjunct for depression, for cerebral palsy, and many more dysfunctions. Cephalon is coming out with a single isomer formulation of modafinil called "Nuvigil."

Both donazepil and modafinil are available from physicians, and over the internet. The ethics of internet prescribing are a bit shaky, but expect these drugs to become more available, rather than less, with time.

The last stop on today's smart drug train is the Ampakine station. Ampakines have the potential to not only help normal people think more clearly, as Donazepil and Modafinil seem to do, but to also make them "smarter." Ampakines directly affect the basic learning system of the brain.

New Scientist presented an article last May titled "11 Steps to a Better Brain." Gary Lynch, the inventor of ampakines, was cautious but optimistic:
The drug acts only in the brain, claims Lynch. It has a short half-life of hours. Ampakines have been shown to restore function to severely sleep-deprived monkeys that would otherwise perform poorly. Preliminary studies in humans are just as exciting. You could make an elderly person perform like a much younger person, he says.

While donazepil works on the acetylcholine system, and modafinil works on dopamine receptors, ampakines in contrast affect the glutamate receptors, specifically AMPA receptors. From neurotrasmitter.net, here are a few dozen scientific abstracts dealing with potential ampakines and mechanisms of ampakines--if the wikipedia article did not give you enough information.

That is a lot of information to digest, although if you take these drugs it may not be as difficult as you might think. Perhaps a joke, perhaps not? In time, people who choose not to boost their cognition may be less common than those who choose to do so.

The long term goal is to adjust the genes themselves, to do a better job of improving cognition than any one drug, or symphony of drugs, could possibly do. In the meantime, expect smart drugs to be delivered by pill, injection, skin patch, long term implant, and even injector pumps. The intelligence of a population is serious business, more serious than most people understand. For now.