Wednesday, November 16, 2011

Cognitive Enhancers In Health and Disease

Cognitive enhancerNeuromodulatory mechanismCognitive functions improvedKnown brain systems most affectedCurrently recommended clinical use
Methylphenidate, amphetamineDopamine and noradrenaline reuptake inhibitorsResponse inhibition, working memory, attention, vigilanceFrontoparietal attentional systems, striatum, default mode networksADHD, wake-promoting agent
CaffeineNon-selective adenosine receptor antagonistVigilance, working memory, incidental learningFrontal lobe attentional systems
NicotineNicotinic cholinergic receptor agonistWorking memory, episodic memory, attentionFronto-parietal attentional systems, medial temporal lobe, default mode networks
ModafinilUnknown, but effects on dopamine, noradrenaline and orexin systems proposedWorking memory, episodic memory, attentionFrontal lobe attentional systemsWake-promoting agent
Atomoxetine, reboxetineNoradrenaline reuptake inhibitorsResponse inhibition, working memory, attentionFrontoparietal attentional systemsADHD, depression
Donepezil, galantamine, rivastigmine (AChEI)Blocks enzymatic breakdown of acetylcholineEpisodic memory, attentionFrontal lobe attentional systemsAlzheimer's disease, PDD, DLB
MemantineNoncompetitive, low-affinity, open channel blocker of the NMDA receptorEpisodic memory, attentionFrontal and parietal lobeAlzheimer's disease
Table Source
The ongoing process of ageing in all advanced societies around the world presents the unhappy prospect of a veritable global epidemic of Alzheimer's and other neurodegenerative conditions. Such an ominous prospect makes the quest for cognitive enhancers somewhat urgent, for all modern nations. We will look at the nature of current cognitive enhancers, and consider the prospects for future enhancers of cognition. The focus will be on long-term enhancement and neuroprotection, rather than the short-term performance enhancers which are popular on college campuses.
It would probably be fair to say that we are still in the first generation of studies to examine the potential for cognitive enhancement in humans. In both healthy individuals and many patient groups, the overall effects of drugs generally seem to be modest. However, there is evidence that there might be more significant effects in subgroups, such as those whose baseline performance is poorest or individuals with a particular genotype. Moreover, new drugs aimed at enhancing the phasic response of neurotransmitter systems, such as direct nicotinic agonists for the cholinergic system [34], might prove to have greater effects than existing modulators that globally increase levels of a neurotransmitter in a tonic fashion. The neurobiology underpinning the effects of cognitive enhancers and the mechanisms that determine responsiveness across individuals promise to be the focus of research in health and brain disorders in the future. _Source
The ongoing study of current cognitive enhancers such as those in the table above, have given us scattered hints as to what future therapies might offer. Here is a short list of possible future targets for cognitive therapies:
Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABAA α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population. _Source
It is important for us, at the outset, to take as realistic a viewpoint toward the possibility of meaningful cognitive enhancement as possible. The Likelihood of Cognitive Enhancement (Lynch et al 2011 PDF) is a useful introduction to many of the practical issues that need to be faced from the very beginning of this enterprise. Cognitive Enhacement: Promises and Perils (Hyman 2011 PDF) is a less technical introduction to the topic, perhaps more accessible to most laymen.

Cognitive Enhancement as a Pharmacotherapy Target for Stimulant Addiction (Sofuoglu 2010) looks at the use of cognitive enhancers as possible treatments for cocaine and methamphetamine addictions. Long term and heavy use of these drugs leads to cognitive deficits which make it even more difficult for a person to stop using these drugs and lead a "normal" life. The restoration of cognitive function is likely to provide a certain amount of "mental fortification" to allow at least some addicts to turn away from the dead end lifestyle. Similarly, restoration of cognitive function in persons suffering from age-related neurodegeneration is more likely to allow the person to participate in normal social interaction, and to undertake some level of responsibility, and perhaps productive activity.

Emerging Pharmacotherapies for Neurodevelopmental Disorders (Wetmore et Garner 2010) looks at the use of cognitive enhancers for persons who suffer from neurodevelopmental disorders such as Down's Syndrome, Fragile X, autism, etc. Given the overlap of mechanisms between some of the cognitive deficits in developmental disorders and ageing-related cognitive deficits, some of the coming developments in this area of pharmacotherapy should also prove quite helpful for treating age-related dementias.
As more is learned about the time-course of dysfunction in NDDs [neurodevelopmental disorders], targeting of therapies to the existing brain state may be improved. Moreover, individuals with NDDs have multiple cognitive and behavioral disabilities, and a particular drug therapy may improve only a subset of cognitive functions. Thus, a combination of complementary drugs may offer the most benefit by addressing deficits in attention, arousal, information processing, or depression.
The NDDs discussed here are phenotypically diverse yet linked by common mechanisms of dysfunction, including abnormal gene dosage, imbalance among neurotransmitter systems, and local protein translation (Fig. 2). A particular NDD can be caused by mutations in multiple genes, underscoring the convergence of dysfunction in key biochemical pathways. _Source
Finally, I would like to append to this entry some material from an earlier Al Fin article, which provides a few hints of future drug targets, as well as links to related material:

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


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



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