Cognitive Enhancement- How much justified?

                Enhancement of human abilities is always center of attraction for all since long time. It is not uncommon that in past people used various herbs and searched for special plants which increase their strength, intellectual capabilities and life span. The main difference between past and present is at present this all search are done in specialized laboratories instead of jungles.
               Another widely debated and controversial area is athletic enhancement where athletes take various substances to enhance their athletic performance. But this gives unfair advantage to user of these substance, so no wonder we have long list of doping substances which are prohibited during athletic games.
               21st century life and tough competition in all fields have given rise to another human enhancement area, The Cognitive Enhancement. Cognitive enhancement can increase your work productivity, creativity, memory, smartness. All these factors are valuable in any business or academic field. If you take something that increases your test scores, then It can change your whole life.
               Cognitive Enhancement is same as athletic Enhancement where the person who is taking cognitive enhancers get unfair advantages. He may pop a pill and study for whole day, on other hand person who is not taking them may have to work hard to stay motivated. Unfortunately, there are no doping tests available in this field on human enhancement.
               On other hand, cognitive enhancement can be life saving for person having various neurological disease like alzheimer's disease, ADHD, Dementia, Schizophrenia, TBI. These person already struggle to function at normal levels and if taking cognitive enhancers make them able to perform at normal levels it can be miracle for them. We can't tell that this kind of people are getting unfair advantages.
              Use of cognitive enhancement by scientists is also justified because their main aim is to provide society new technologies and cures for medical conditions. Chances of Cognitively Enhanced scientist to discover something new are higher than normal scientist.
              Field of cognitive enhancement is still a matter of debate and it is not clear who should use these substances and who should not.

Nicotinic receptor subtypes and cognitive function

                         Nicotinic receptor systems are involved in a wide variety of behavioral functions including cognitive function. Nicotinic medications may provide beneficial treatment for cognitive dysfunction such as Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Nicotine has been shown to improve attentional performance in all of these disorders. Better efficacy with fewer side effects might be achieved with novel nicotinic ligands selective for particular nicotinic subtypes. To develop these novel selective nicotinic ligands it is important to use animal models to determine the critical neurobehavioral bases for nicotinic involvement in cognitive function. Nicotine-induced cognitive improvement in rats is most consistently seen in working memory tasks. We have found that both acute and chronic nicotine administration significantly improves working memory performance of rats in the radial-arm maze. The pharmacologic and anatomic mechanisms for this effect have been examined in our laboratory in a series of local drug infusion studies. Both alpha 4 beta 2 and alpha 7 nicotinic receptors in the ventral hippocampus and basolateral amygdala are involved in working memory function. Working memory impairments were caused by local infusion of either alpha 4 beta 2 or alpha 7 antagonists. Ventral hippocampal alpha 4 beta 2 blockade-induced working memory deficits are reversed by chronic systemic nicotine treatment, while ventral hippocampal alpha 7 blockade-induced working memory deficits were not found to be reversed by the same nicotine regimen. Interestingly, alpha 4 beta 2 and alpha 7 induced deficits were not found to be additive in either the ventral hippocampus or the basolateral amygdala. In fact, in the amygdala, alpha 7 antagonist cotreatment actually reversed the working memory impairment caused by alpha 4 beta 2 antagonist administration. These studies of the neural nicotinic mechanisms underlying cognitive function are key for opening avenues for development of safe and effective nicotinic treatments for cognitive dysfunction.

Is caffeine a cognitive enhancer?

              The effects of caffeine on cognition were reviewed based on the large body of literature available on the topic. Caffeine does not usually affect performance in learning and memory tasks, although caffeine may occasionally have facilitatory or inhibitory effects on memory and learning. Caffeine facilitates learning in tasks in which information is presented passively; in tasks in which material is learned intentionally, caffeine has no effect. Caffeine facilitates performance in tasks involving working memory to a limited extent, but hinders performance in tasks that heavily depend on working memory, and caffeine appears to rather improve memory performance under suboptimal alertness conditions. Most studies, however, found improvements in reaction time. The ingestion of caffeine does not seem to affect long-term memory. At low doses, caffeine improves hedonic tone and reduces anxiety, while at high doses, there is an increase in tense arousal, including anxiety, nervousness, jitteriness. The larger improvement of performance in fatigued subjects confirms that caffeine is a mild stimulant. Caffeine has also been reported to prevent cognitive decline in healthy subjects but the results of the studies are heterogeneous, some finding no age-related effect while others reported effects only in one sex and mainly in the oldest population. In conclusion, it appears that caffeine cannot be considered a ;pure' cognitive enhancer. Its indirect action on arousal, mood and concentration contributes in large part to its cognitive enhancing properties.

A molecular link between the active component of marijuana and Alzheimer's disease pathology.

           Alzheimer's disease is the leading cause of dementia among the elderly, and with the ever-increasing size of this population, cases of Alzheimer's disease are expected to triple over the next 50 years. Consequently, the development of treatments that slow or halt the disease progression have become imperative to both improve the quality of life for patients and reduce the health care costs attributable to Alzheimer's disease. Here, we demonstrate that the active component of marijuana, Delta9-tetrahydrocannabinol (THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid beta-peptide (Abeta) aggregation, the key pathological marker of Alzheimer's disease. Computational modeling of the THC-AChE interaction revealed that THC binds in the peripheral anionic site of AChE, the critical region involved in amyloidgenesis. Compared to currently approved drugs prescribed for the treatment of Alzheimer's disease, THC is a considerably superior inhibitor of Abeta aggregation, and this study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease.

Centella asiatica treatment during postnatal period enhances learning and memory in mice.

                 Present investigation was planned to evaluate the nootropic effect of Centella asiatica. Three months old male Swiss albino mice were injected orally with graded doses (200, 500, 700, 1000 mg/kg body weight) of C. asiatica aqueous extract for 15 days to select an effective dose for nootropic studies. Animals were tested in radial arm maze to assess the learning and memory performance. Based on these results, mice were treated orally with 200 mg/kg of C. asiatica for 15 days from day 15 to day 30 post partum (p.p.) and the nootropic effect was evaluated on the 31st day and 6 months p.p. The behavioral (open field, dark/bright arena, hole board and radial arm maze tests), biochemical (acetylcholine esterase activity) and histological studies (dendritic arborization) were carried out. Performance of juvenile and young adult mice was significantly improved in radial arm maze and hole board tests, but locomotor activity did not show any change compared to control. Treatment resulted in increased acetylcholine esterase activity in the hippocampus. Dendritic arborization of hippocampal CA3 neurons was also increased in terms of intersections and branching points, both at one month and 6 months. Results of the present investigation show that treatment during postnatal developmental stage with C. asiatica extract can influence the neuronal morphology and promote the higher brain function of juvenile and young adult mice.

Cognitive enhancement in man with ispronicline

              Cholinergic mechanisms are clearly involved in memory deficits associated with Alzheimer's disease (AD) Recently, there has been growing interest in the nicotinic approach to the treatment of AD; however, compounds have failed in the clinic because of a lack of separation between central and peripheral nicotinic effects. Ispronicline (TC-1734) is an orally active, selective, partial agonist of the central alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR), with high binding affinity to membrane preparations from rat brain or mammalian cells expressing recombinant human alpha4beta2 receptor. Ispronicline has no detectable effects on muscle or ganglionic nAChRs, indicating a marked CNS over PNS selectivity. In animal models ispronicline potently improved cognitive function. A long duration of memory enhancement was displayed in object recognition and radial arm maze tests. Ispronicline pharmacokinetics (half-life of 2 h in rats) contrasts with the long-lasting improvement of working memory (18 h to 2 d).

Clavulanic Acid- Unexpected CNS Effects

   Clavulanic acid which is common beta lactamase inhibitior has been shown to have some unexpected CNS effects.   Clavulanic acid acts as Duel enhancer of Serotonin and Dopamine. It is under clinical trials for its use as antidepressant and nootropic.

   Clinical stage pharma company Rexahn Pharmaceuticals (NYSE Amex: RNN) said Tuesday that a published Drug Development Research article indicates that clavulanic acid, the active ingredient of the company's lead central nervous system drug Seradaxin, protects neurons from brain damage associated with neurodegnerative disease.

In the study, rodents that were exposed to different neurotoxins, were administered with clavulanic acid, which protected neurons in the hippocampus and dopaminergic regions of the brain that are critical in Alzheimer's and Parkinson's disease, respectively.

"The exciting neuronal protective properties of clavulanic acid make it a highly promising treatment for neuronal cell death diseases like Parkinson's and Alzheimer's," said Rexahn CEO Chang Ahn.

Parkinson's disease afflicts five million people worldwide, and with the aging of the baby boom generation, that population is expected to double by 2030.

According to the Alzheimer's Association, by 2050, the number of Americans aged 65 and older with Alzheimer's is projected to reach between 11 million and 16 million, unless medical breakthroughs can prevent or more effectively treat the disease.

Currently, Alzheimer's and Parkinson's therapies only provide symptomatic relief.

"Clavulanic acid has breakthrough potential of shielding the brain cell survival mechanisms, rather than fighting one-by-one the multitude of triggers that can activate the cell death mechanisms common in Alzheimer's and Parkinson's," added Ahn.

Alzheimer's has at least five major triggers, while Parkinson's has three major dysfunctioning mechanisms. Rather than intercepting and fighting each trigger, clavulanic acid has shown to broadly protect brain cell mechanisms.

Rexahn develops and commercializes therapeutics for cancer, CNS disorders, sexual dysfunction and other unmet medical needs. The company currently has three drug candidates in Phase II clinical trials, including Archexin, Serdaxin, and Zoraxel.

Piracetam's Mechanism of Action.

            Piracetam is stand alone drug which has nootropic properties and it has very good safety profile. Even after thousands of studies, Mechanism of action of piracetam is still matter of debate. Different studies has shown different mechanism of action of Piracetam. Some of those mechanism are as follows.
           1. Piracetam is believed to enhance uptake of choline thus increasing synthesis of Acetylcholine and enhancing cholinergic neurotransmitter.
           2. Piracetam is reported to have neither stimulant nor depressant action on CNS. It is believed to stimulated ion channels which is responsible for action potential across CNS neurons.
           3. Piracetam is reported to have action on AMPA type glutamate receptors where it acts as positive allosteric modulator.
           4. Piracetam has been shown to increase density of NMDA type glutamate receptors in CNS which are crucial for memory consolidation and long term potentiation.
           5. Piracetam has been shown to increase GABA levels in brain.
           6. Piracetam is reported to increase communication between two hemisphere of brain which is crucial for creativity.
           7. Piracetam has been shown to increase ATP synthesis and oxygen consumption in brain. Thus, increasing brain activity.

Memantine- a new study pill?

              Although memantine hydrochloride is currently known as the latest treatment for moderate-to-severe Alzheimer disease (AD), we entertain the idea that it might also come to be known as a memory enhancer among healthy high achievers.
              The drug acts by noncompetitively binding to the N-methyl D-aspartate (NMDA) receptors of neurons in brain tissue to prevent overstimulation by glutamate. When this excitatory neurotransmitter overactivates NMDA receptors in a tonic manner, an excessive influx of neurotoxic calcium ions follows. The resultant excitotoxicity may play a role in the impairment of memory and cognition in AD. Because memantine has a low-to-moderate affinity for NMDA receptors, it does not seem to block normal glutamate transmission; rather, it reduces abnormal neurotransmitter-mediated activation of the receptors, thereby potentially reducing excitotoxic neuronal damage. This form of neuroprotection may explain the improved cognition in patients with AD reported in the literature.
             Can transient low-level, nonpathologic, glutamate-mediated neuronal damage occur in the brains of normal individuals? And, if so, could memantine's neuroprotective effect antagonize the damaging effects and enhance memory potential in these individuals? Future research should address these issues.
             Memantine's suggested neuroprotective effect  may also increase brain levels of the neuronal marker, N-acetyl aspartate (NAA). Because NAA is found primarily on neuronal axons in the brain,  perhaps the Neuroprotective effect of Memantine can be measured by quantifying the change in NAA concentrations in brain tissue via magnetic resonance spectroscopy. Magnetic resonance spectroscopy has demonstrated that patients with AD show a decline in NAA relative to normal controls.  The reduction in excitotoxicity via memantine's mechanism of action may allow affected neurons to regain some level of physiologic functioning, such as growth of neuronal processes and synaptogenesis, which is fundamental to learning and memory formation—a process that is damaged in AD.
             Moreover, a direct relationship has been observed between NAA levels in the brain and intelligence. Healthy individuals with high levels of NAA appear to have higher scores on intelligence tests than healthy individuals with lower levels of this marker in brain tissue. It may be possible that the higher levels of NAA indicate an increased presence of neuronal processes and their synapses.
            The effects of drugs that have cognitive-enhancing potential have been studied in healthy individuals. Acetylcholineesterase inhibitors (some of which are used to treat AD), such as donepezil, huperzine A, and physostigmine, have been shown to improve memory and cognitive tasks in normal subjects. Another medication that enhances cognitive performance is methylphenidate, a drug commonly prescribed for attention deficit hyperactivity disorder (ADHD) but increasingly used by healthy university students nationwide as an academic performance–enhancing agent.  A recent national survey reported that ADHD medications have much higher rates of abuse in colleges with higher admission standards.
           In light of all of the mentioned factors and the recent reports regarding the misuse of anabolic-androgenic steroids for the enhancement of athletic performance,  the misuse of memory-enhancing drugs to improve academic performance by some ambitious students may not be a far-fetched conjecture. The purpose of this letter is to raise a medically and ethically relevant question: If transient low-level, nonpathologic, glutamate-mediated neuronal damage can occur in normal brain tissue, and neuroprotection against this occurrence could promote neuroplastic processes such as syneptogenesis, could memantine be misused by students for academic performance-enhancement in the near future?

Ampakines- The memorybooster drugs

           Ampakines are a class of drugs that modulate neurotransmitters in the brain. One of the major neurotransmitters is glutamate, and a reduced level of glutamate-mediated excitatory stimulation has been implicated in Alzheimer’s disease, schizophrenia, and a number of other diseases and disorders.
          Neurotransmitters bind to proteins, called receptors, located on the surface of the receiving neurons. This binding then triggers subsequent cellular events in the receiving neurons. Ampakines influence the receptors. Ampakines enhance the functioning of a receptor, called the AMPA receptor, which plays a key role in memory formation and communication within and between different regions of the brain.
          The hope and promise of ampakines is that they will produce cognitive benefits when used as drugs. There is research interest in memory enhancement, stroke therapy, Alzheimers treatment, sleep deprivation aid, and other theraputic uses of Ampakines. Several of these possibilities have been tested with positive results in preclinical models; preliminary clinical work has also been encouraging. Further, scientists feel that ampakines can change information encoding and organization in the brain.
         Ampalex® has been shown in preclinical trials to be highly promising in improving cognitive function, and has been relatively free of serious side effects. Reseach has suggested that the ampakine CX717 may help protect against respiratory depression in patients under the anesthesia fentanyl. A depressed repiratory system and apnea are threats for people under anesthesia.
                     

Alpha-7 Nicotinic Acetylcholine Receptors New Target For Cognitive Enhancement.

               In Central Nervous System Cholinergic system is very important and vital component for memory and cognitive functions. Disruption of this system is seen in case of Dementia, Alzheimer's Disease.
              Cholinergic system includes neurotransmitter acetylcholine, Muscarinic receptors and Nicotinic receptors. Acetylcholine binds to this receptors and activate them. This receptors are located on cholinergic neurons. Nicotinic receptors are most important for memory, cognition and Higher Intellectual functions.Activation of Nicotinic receptors causes release of other neurotransmitters like dopamine, norepinephrine, serotonin, etc.
              Nicotinic receptors have various subtypes. Among all subtypes Apha-7 subunit is of great importance.Scientists have discovered that Alpha 7 Nicotinic receptors regulate most important Higher Intellectual functions.There is evidence of involvement of Alpha 7 Nicotinic receptors in various Nervous system disorders like schizophrenia, Alzheimer's Disease, Dementia, Learning Disability. Density of Alpha 7 Receptors is reduced in these diseases.
              Agonist of Alpha 7 Nicotinic Receptors causes upregulation of this receptors. Most powerful agonist of these receptors is Nicotine. Nicotine has been found to improve symptoms of above mentioned disease. It has been found to improve working memory, Attention, Cognitive Abilities. But use of Nicotine for this purpose is not recommended as benifits of nicotine are far away from well known health risks. Scientists are discovering molecule that targets Alpha 7 receptors other than Nicotine. Discovery and Developement of Drug targeting Alpha 7 Nicotinic receptors will bring great revolution in field of Human Cognitive Enhancement.

ADHD

ADHD is known as Attention Deficit Hyperactivity Disorder.

Neurological Basis:
 -ADHD has proven neurological basis. It involves our brain's Neurotransmitter systems. Mainly Dopaminergic and Noradrenergic systems.
-Dopamine is involved in Reward, Quality of attention, Motivation, Pleasure, Confidence, Working memory, Social Cognition etc
-Norepinephrine is involved in Energy, Drive, Length of Attention, Interest in Life, Memory etc.
-In person with ADHD there is deficit in noradrenergic and dopaminergic Neurotransmission. This Deficit is not organic in nature nor there is any loss of neurons. There is no degeneration of Any neurons of above mentioned system.
-ADHD results from decreased availability of Dopamine and Norepinephrine in synapse of neuron.
 This may be due to decreased release or due to rapid uptake of these by respective transporter DAT and NET.
-Main function of this transporter is to collect the released neurotransmitter and return it to its storage vesicle again. So it can be released again. In ADHD patients density of these transporters have been found to be very high in number than normal person in MRI and PET scans. This results in rapid washout of neurotransmitter from synapse which results in weak signal transmission. Weak signals of Noradrenergic and Dopaminergic system Gives rise to symptoms of ADHD.

How Medicines Work?
First line drugs for ADHD are stimulants like Methylphenidate, Dextroamphetamine, Dextromethamphetamine. Other includes Modafinil, Atomoxetine, Guanfacine, Tricyclic antidepressants, rarely anticonvulsants.
Stimulants exerts their effects by blocking DAT and NET transporters, thus delaying removal of these neurotransmitters from synapse and strengthens subsequent Neurotransmission. Moreover Amphetamine also causes release of there neurotransmitter by reversing the action of Transporters which results in release of neurotransmitters from storage vesicle into synapse.

Cognitive Enhancement

•       FOR thousands of years, people have sought substances that they hoped would boost their mental powers and their stamina. Leaves, roots and fruit have been chewed, brewed and smoked in a quest to expand the mind. That search continues today, with the difference only that the shamans work in pharmaceutical laboratories rather than forests. If asked why, the shamans reply that they are looking for drugs to treat the effects of Alzheimer's disease, attention-deficit disorder, strokes, and the dementias associated with Parkinson's disease and schizophrenia—and that is the truth. But by creating compounds that benefit the sick, they are offering a mental boost to the healthy, too.
•       Such drugs are known as cognition enhancers. They work on the neural processes that underlie such mental activities as attention, perception, learning, memory, language, planning and decision-making, usually by altering the balance of the chemical neurotransmitters involved in these processes. This week a report* from the Academy of Medical Sciences, a British learned society, says that a large number of such brain-affecting drugs are likely to emerge over the next few decades. Sir Gabriel Horn, a researcher at Cambridge University who chaired the group that produced the report, reckons that scientists are working on more than 600 drugs for neurological disorders.
•       History suggests that most of these will fall by the regulatory wayside, but given their numbers, a fair few are likely to be approved. And although none of the companies working on cognition-enhancing drugs designed to treat illness intends to license them for wider use, that is what is likely to happen—at least going by the growing “off-label” use of existing drugs such as Ritalin (methylphenidate) and Provigil (modafinil) by people who want to pep themselves up.