Cognitive enhancers

In this chapter, we use the term cognitive enhancers to refer to two classes of pharmacological agents used in the treatment of Alzheimer s disease the cholinesterase inhibitors and the A-methyl-D-aspartate (NMDA) receptor antagonists. 

Cholinesterase inhibitors cross the blood-brain barrier and decrease enzymatic hydrolysis of acetylcholine in the synaptic cleft, thereby increasing acetylcholine availability for neurotransmission. The rationale for using cholinergic agents to treat Alzheimer s disease stems from evidence of decreased cerebral choline acetyltrans-ferase (the enzyme responsible for acetylcholine synthesis) and cholinergic neuron loss in the nucleus basalis of Meynert, which correlate with plaque formation and cognitive impairment (Arendt et al. 1985 Davies and Maloney 1976 Etienne et al. 1986 Perry et al. 1978b). 

Drug Trade name Dosing guidelines Formulations 

Tacrine Cognex Administer 10 mg po qid for 4 weeks, dien 20 mg qid for 4 weeks, then 30 mg qid for 4 weeks, and dien 40 mg qid. Titration is based on tolerability and serum transaminase levels. Refer to current product labeling for guidelines on dose adjustments, monitoring, and rechallenging. 10-, 20-, 30-, 40-mg capsules 

Donepezil Aricept Administer 5 mg po qhs (with or widiout a meal) for 4—6 weeks. Some patients then increase to 10 mg/day if tolerated. Target daily dose range 5-10 mg po qhs 5-, 10-mg tablets 5-, 10-mg oral disintegrating tablets (Aricept ODT) 

Influencing cognition by manipulating blood glucose and oxygen levels 

The effects of oxygen breathing on cognition in healthy people has only received limited attention. In the 1970s, Edwards and Hart examined the effects of hyperbaric oxygen administration on healthy elderly outpatients and found substantial 

L-acetylcarnitine is produced naturally in the CNS and indirectly stimulates acetylcholine production, as well as purportedly modulating cerebral metabolism. A study of nearly 500 geriatric patients in Italy provided evidence that L-acetylcarnitine 

Nimodipine is a racemic mixture (i.e., it is a compound in two mirror image forms, one of which is more active than the other). Veng et al. (2003) reported the reversal of 

Increased cerebral metabolism increased cerebral oxygen delivery. 

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The term nootropic has been used to describe a class of compounds defined by the abibty of its members to facibtate learning (36). The compounds are most effective in animals that have had their cognitive abihties compromised in some way. The molecular mechanism undedying the cognitive-enhancing... 

DuP 753 is an orally active AT receptor antagonist and as of this writing is in clinical trials as an antihypertensive (see Cardiovascularagents). AT-11 antagonists affect the brain RAS system to enhance ACh release offering the possibiUty that these agents may function as cognition enhancers. 

However, clinical results with compounds enhancing cholinergic function have not been overly convincing (272). In the case of tacriae, however, the beneficial therapeutic iadex was sufficient to justify regulatory approval ia several countries. Psychostimulants such as pemoline, amphetamine, procaine, and methylphenidate have failed to show cognitive enhancing effects ia patients with dementia, except possibly as iadirect consequences of mood elevation. 

Table 6. Marketed Drugs Used as Cognition Enhancers...

Vasopressin is closely related to oxytocin and both peptides are cyclic in that they contain a disulphide bridge. Although much is known about the peripheral actions of the peptides the extent of our current knowledge of their possible CNS function is that vasopressin appears to act as a cognitive enhancer and has positive effects on learning processes in animals. Vasopressin acts on three receptors, Via and b and a V2 receptor. 

Riedel, W. and Jolles, J., Cognition enhancers in age related cognitive decline. Drugs Aging, 8(4), 245-474, 1996. 

Hsieh MT, Peng WH, Wu CR, Wang WH. The ameliorating effects of the cognitive-enhancing Chinese herbs on scopolamine-induced amnesia in rats. Phytother Res 2000 14 375-377. 

Revell, 1988). These studies were interpreted as showing that nicotine was a cognitive enhancer, boosting alertness through an increase in cholinergic activity (Parrott and Winder, 1989 Revell, 1988 Wesnes and Warburton, 1983 Wesnes and Parrott, 1992). 

Table 14.1. Nootropics the proposed modes of actions for several putative cognitive enhancers. 

The evidence cited here is only a very small sample of the vast quantity of research into putative cognitive enhancers. However, many of these compounds that have demonstrated positive effects are believed to influence cerebral metabolism, whether through increased blood flow, glucose metabolism or other indirect routes, as outlined above. Furthermore, these metabolic effects are hypothesised to be at least partly responsible for the cognitive improvements documented. Indeed, many of the putative cognitive enhancers currently available claim modes of influence (Table 14.1) that would fall in line with a metabolic model of cognitive enhancement. 

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