Emerging cognitive enhancing drugs

Buccafusco, Jerry J.

doi:10.1517/14728210903257796

Cited by 14 publications

(9 citation statements)

References 76 publications

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“…While cognitive dysfunction is a prominent feature of all neurodegenerative and neuropsychiatric diseases [1], the nature of the dysfunction and its cause is disease specific. In autism and schizophrenia, for example, cognitive dysfunction arises from defects early or late in brain development.…”

Section: Introduction/cyclic Nucleotide Phosphodiesterases (Pdes) mentioning

confidence: 99%

PDE4 as a target for cognition enhancement

Richter

Menniti

Zhang

et al. 2013

Expert Opinion on Therapeutic Targets

121

105

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Introduction The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs. Areas covered PDE4 is the largest of the eleven mammalian PDE families. This review covers the properties and functions of the PDE4 family, highlighting procognitive and memory-enhancing effects associated with their inactivation. Expert opinion PAN-selective PDE4 inhibitors exert a number of memory- and cognition-enhancing effects and have neuroprotective and neuroregenerative properties in preclinical models. The major hurdle for their clinical application is to target inhibitors to specific PDE4 isoforms relevant to particular cognitive disorders to realize the therapeutic potential while avoiding side effects, in particular emesis and nausea. The PDE4 family comprises four genes, PDE4A-D, each expressed as multiple variants. Progress to date stems from characterization of rodent models with selective ablation of individual PDE4 subtypes, revealing that individual subtypes exert unique and non-redundant functions in the brain. Thus, targeting specific PDE4 subtypes, as well as splicing variants or conformational states, represents a promising strategy to separate the therapeutic benefits from the side effects of PAN-PDE4 inhibitors.

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Section: Introduction/cyclic Nucleotide Phosphodiesterases (Pdes) mentioning

confidence: 99%

PDE4 as a target for cognition enhancement

Richter

Menniti

Zhang

et al. 2013

Expert Opinion on Therapeutic Targets

121

105

View full text Add to dashboard Cite

show abstract

“…The obvious advantages would be enhanced cognition (and improved day to day quality of life) while at the same time delaying or preventing the progression of the illness (properties not observed in the currently available therapies). One potential advantage of a multifunctional compound over a disease-modifying agent that has no acute pro-cognitive actions pertain to the design and length of clinical trials (reviewed, Buccafusco, 2009). Clinical trials of disease modifying agents (by definition) require long evaluation periods which are often cost-prohibitive.…”

Section: Multiple Drug Targets and Multifunctional Compoundsmentioning

confidence: 99%

“…Unfortunately, a full overview of these targets is beyond the scope of the present review and we refer the reader to additional articles (Gallagher et al, 1985; Minzenberg and Carter, 2008; Buccafusco, 2009; Lynch et al, 2011;) that discuss examples such as glycine transporter related drugs, mGluR2/3 agonists, somatostatin receptor ligands, estrogen receptor ligands, D2 agonists, calcium channel modulators (e.g., MEM 1003, nimodipine), adrenergic compounds (e.g., nicergoline), opioid antagonists (e.g., naloxone) and GABA-related compounds.…”

Section: Other Targetsmentioning

confidence: 99%

Alzheimer's disease and age-related memory decline (preclinical)

Terry

Callahan

Hall

et al. 2011

Pharmacology Biochemistry and Behavior

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An unfortunate result of the rapid rise in geriatric populations worldwide is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that is characterized by a profound impairment of cognitive function, marked physical disability, and an enormous economic burden on the afflicted individual, caregivers, and society in general. The rise in elderly populations is also resulting in an increase in individuals with related (potentially treatable) conditions such as "Mild Cognitive Impairment" (MCI) which is characterized by a less severe (but abnormal) level of cognitive impairment and a high-risk for developing dementia. Even in the absence of a diagnosable disorder of cognition (e.g., AD, MCI), the perception of increased forgetfulness and declining mental function is a clear source of apprehension in the elderly. This is a valid concern given that even a modest impairment of cognitive function is likely to be associated with significant disability in a rapidly evolving, technology-based society. Unfortunately, the currently available therapies designed to improve cognition (i.e., for AD and other forms of dementia) are limited by modest efficacy, adverse side effects, and their effects on cognitive function are not sustained over time. Accordingly, it is incumbent on the scientific community to develop safer and more effective therapies that improve and/or sustain cognitive function in the elderly allowing them to remain mentally active and productive for as long as possible. As diagnostic criteria for memory disorders evolve, the demand for pro-cognitive therapeutic agents is likely to surpass AD and dementia to include MCI and potentially even less severe forms of memory decline. The purpose of this review is to provide an overview of the contemporary therapeutic targets and preclinical pharmacologic approaches (with representative drug examples) designed to enhance memory function.

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“…Aside from motor impairment, reduced cognition is the major debilitating symptom of many neurodegenerative disorders [293][294][295][296]. There are few drugs approved to treat this disease aspect, which are at best only partially effective [297]. The finding that HDAC inhibition may positively impact cognition may thus be applied as a favorable therapeutic strategy.…”

Section: Procognitive Effects Of Hdac Inhibitionmentioning

confidence: 99%

The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

Bürli¹,

Thomas²,

Beaumont

2010

Topics in Medicinal Chemistry

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Neurodegenerative disorders are devastating for patients and their social environment. Their etiology is poorly understood and complex. As a result, there is clearly an urgent need for therapeutic agents that slow down disease progress and alleviate symptoms. In this respect, interference with expression and function of multiple gene products at the epigenetic level has offered much promise, and histone deacetylases play a crucial role in these processes. This review presents an overview of the biological pathways in which these enzymes are involved and illustrates the complex network of proteins that governs their activity. An overview of small molecules that interfere with histone deacetylase function is provided.

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Emerging cognitive enhancing drugs

Abstract: Compounds that act on allosteric sites on neurotransmitter receptors are expected to lead the field with new levels of specificity and reduced side effects. New multi-functional compounds can be designed that can both improve cognition and slow the process of disease.

Cited by 14 publications

References 76 publications

PDE4 as a target for cognition enhancement

PDE4 as a target for cognition enhancement

Alzheimer's disease and age-related memory decline (preclinical)

The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

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