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Emerging cognitive enhancing drugs

Dr Dharamraj

FLOW OF PRESENTATION
Introduction Definition Process of memory formation Existing drugs Need for new drugs Emerging drugs various classes Conclusion References

Introduction

Cognition is the physiological process of Perception, attention, reasoning , judgment & memory Cognitive dysfunction, a major health problem in 21st century, one of the most functionally debilitating aspect of many neuropsychiatric and neurodegenerative disorders Affected by number of factors including ageing, stress, depression & various pathological conditions such as dementia related to Parkinsons disease (PD), Alzheimers disease (AD), schizophrenia, cancer and HIV

Cognitive enhancement may be defined as the amplification or extension of core capacities of the mind through improvement or augmentation of processing systems Cognitive functions mainly categorized into memory, attention, creativity and intelligence Ageing play an important role in development of cognitive dysfunction by causing impairment in Long Term Potentiation (LTP) induction and synaptic plasticity

Process of memory formation

During the process of learning and memory formation, brain undergoes a physical and chemical change which is called as synaptic plasticity It shows involvement of various signal transduction pathways, induction of gene expression which results in formation of new synapses between nerve cells

Process of memory formation involves the binding of neurotransmitter to the receptor (NMDA, AMPA) which triggers the cascade of molecular events including activation of CREB and PKC pathways, results in the formation of new proteins Receptors and some structural proteins that cement the synaptic connection between two repeatedly communicating neurons which ultimately results in development of long term memory

Role of cognitive enhancers

Aim to enhance activity of nerves containing specific types of chemicals called neurotransmitters Reinforce or maintain particular pathways of neurons in the brain by strengthening the synapses that connect brain cells Prevent neuronal excitotoxicity Others include vasodilators, designed to increase blood flow in the brain, and drugs intended to protect the brain from damage by oxidation, free radicals or cell death

Existing Drugs

Acetyl choline esterase inhibitors (AchEI) Donepezil Rivastigmine Galantamine Tacrine


NMDA Antagonist : Memantine Miscellaneous drugs Piracetam Pyritinol Piribedil Ginkgo biloba

Medical need

Currently available drugs improve cognitive symptoms temporarily No treatment to reverse, stop or slow neurodegenerative process Initial improvements in cognitive function and other symptoms, there is an inevitable decline in efficacy as the disease progresses Therefore, the search continues for new compounds that have the potential to provide more than symptomatic relief.

Mimopezil

M.O.A- AchE inhibitor Chinese herbal product that has long been a component of homeopathic medications for cognition enhancement Drug is in early clinical testing for a once monthly dosing regimen to help with compliance in Alzheimers disease Promising results in phase 11 Status phase III

Phenserine
M.O.A- AChE inhibitor Phenserine is a derivative of the potent, but short-acting inhibitor physostigmine

Phenserine has demonstrated modest benefit in terms of cognition enhancement in clinical trials of Alzheimers disease

Status phase II

Ladostigil
M.O.A- MAO-B/AChE inhibitor Multi-functional drug

Ladostigil was designed to incorporate the functional moieties of the AChE inhibitor rivastigmine (cognition improvement) and the MAO inhibitor rasagiline (neuroprotection).

Ladostigil is effective in stimulating the expression of the anti-apoptotic (cell survival) genes Status phase II

CX 717 & LY 451395


Positive AMPA receptor modulator Phase I safety and tolerability studies was found to be safe and well tolerated In Phase IIa, was reported to improve alertness, with early indications of positive cognitive responses. Demonstrate a significant effect on cognitive performance

Subsequent study, it was reported that the drug could be useful in the treatment of adult attention deficit disorder. Status phase II

SGS 742

GABA B antagonist Active in several preclinical animal models where the compound exhibited clear cognition-enhancing actions

Clinical experience with this compound revealed a significant improvement in attention and memory
The compound is currently undergoing clinical trials for treating the cognitive impairment associated with schizophrenia Status phase II

MEM 3454

7 Nicotinic receptor agonist Hypothesized the drug may reduce cognitive deficits In addition to its potential as a cognitionenhancing drug, it has been shown to be neuroprotective in preclinical studies Dual actions to improve cognition and to slow the disease process Shown to improve cognition in early clinical trials in schizophrenic subjects Status- phase II

SAM 531

5 HT 6 antagonist Induce release of endogenous Ach & glutamateImprove attention & memory

Tested adjunctive to 4 - 8 mg risperidone to improve cognitive functioning and negative symptoms 12-week, placebo-controlled trial (n=20)

Significant improvement of cognition Visual memory also improved significantly

Status- phase II

Nicergoline

1 Adrenoceptor antagonist Dilates blood vessels of the cerebro vasculature Nicergoline can improve cerebral blood flow and improve the delivery of oxygen to neural cells The result of treatment is improved and clarified thinking and enhanced memory function The ability of the drug to increase nerve growth factor in the brain also is suggestive of a disease modifying action Status- phase III

Dimebolin

Dual action NMDA antagonist & cholinesterase inhibition


Shown to protect neurons from the damaging effects caused by excessive cell stimulation through its blocking action on L-type Ca+ channels Neuroprotective and has the ability to decrease the toxicity induced by amyloid A in rat cortical cell cultures Effect of dimebolin on safety, tolerability and efficacy was assessed in a double-blind placebo-controlled study that enrolled 183 patients with mild to moderate Alzheimers disease Status phase 11

Summary
MOLECULE Mimopezil Nicergoline Phenserine Ladostigil (TV3326) CX 717 & LY 451395 MEM 3454 SAM 531 MECHANISM Ach E inhibitor 1 Adrenoceptor antagonist AChE inhibitor MAO-B/AChE inhibitor Positive AMPA receptor modulator 7 Nicotinic receptor agonist 5-HT6 receptor antagonist STATUS Phase 111 Phase 111 Phase 11 Phase 11 Phase 11 Phase 11 Phase 11

SGS742
Dimebolin

GABA B antagonist
NMDA antagonist & cholinesterase inhibition

Phase 11
Phase 11

Conclusion

Despite of several years of scientific efforts, still there is no satisfactory therapeutic strategy to cure cognitive impairment. Researchers have unveiled many of the new key players of the pathological cascades which lead to cognitive impairment Many of newer compounds targeting these pathways are under preclinical and clinical investigation and can be promising therapies for cognitive impairment

Apart from the pharmacological approaches, other approaches such as dietary supplementation and encouragement of healthy lifestyle which is physically and mentally stimulating are going to have a big impact on cognitive research in future.

References
Expert Opinion Emerging Drugs (2009) 14(4):577-589 Harrisons 17th edition of internal medicine Review Article Cognition Enhancers: Current Strategies and Future Perspectives

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