รศ.ดร. จินตนา สัตยาศัยDepartment of PharmacologyFaculty of MedicineDepartment of PharmacologyFaculty of Medicine

19 MAY, 2004

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As we grow older,we may grow wiser.

Memory loss &cognitive slowing

Dementia = dementare (Latin) = to drive mad(a state of serious emotional & mental

deterioration of organic or functional origin)

(Lockhart&Lestage, 2003)

AACD=Age-associated cognitive declineAAMI=Age-associated memory impairmentARCD=Age-related cognitive declineMCI=mild cognitive impairmentAD=Alzheimer’s disease

EC=entorrhinal cortex

Model for information processing inhippocampal area CA1

A mismatch signal update the network

(Moser & Paulsen, 2001)

MemoryWorking memory

Declarative memory

Procedural memory

RAMRAM(cortical phenomenon)

(cerebellum)

(hippocampus isnecessary)

*

Hippocampuscontext

Amygdalaemotion

Thalamusfilter, address

system, attention

Prefrontal cortex

Severestress

(Spedding et al., 2003)

The interaction of the prefrontal cortexwith the amygdala & hippocampus

Stimuli Behavior

Modelbuilding

Acquisitionการไดมาของขอมูล

Consolidationการรวบรวมใหเปนความจํา

Retentionการเก็บ

Retrievalการเรียกความจํา

Performanceการแสดงออก

(Learning & Memory)

Mentalmodel

Dementia Risk Factor Matrix

Very likely Advanced age, family history (AD, PD),apolipoprotein E-4, Down’s syndrome,head trauma, depression, blood flow,stroke, estrogen imbalance.

Likely emotional stress, toxic damage, alcoholabuse, nutrient deficiencies, transmitter deficits, metabolic deficits, underactivity,lower educational level, occupational electromagnetic exposure.

Possible Aluminum exposure, latent viruses, sugarconsumption, olfactory deficit, coronaryartery disease.

(Kidd, 1999)

Cognitive deficit

Neurodegenerative disorders

Neuropsychiatric disorders

Acetylcholine

Dopamine Serotonin

Norepinephrine

Glutamate is widely distributed in the brain

Neurotransmitters involvedin learning & memory

Glutamate Receptors

P PCaMKII

PCa2+

NMDA AMPANa+

Short-term

PostSynapticMembrane

(Abel&Lattel,2001;Johnston et al., 2003;Nguyen&Woo,2003)

GlutamateACh

Serotonin

DopamineNorepinephrine

SerotoninGrowthFactors

PPGRBRas

PLCPKC

AdenylateCyclase

cAMP

PKA

RafMEK

MAPKRSK2

PKC

CaMKIV

Ca2+

Synaptic protein,Neurite outgrowthNeurotransmitter

release,Synaptic plasticity,Neuronal survival& neurogenesis

PPCREB

CBPTICThyr

Reep

Transcription

CRE

Long-term

Trophicfactors

PKA=Protein kinase APKC=Protein kinase CRSK2=Ribosomal S6 kinase-2CaMK=Calcium/calmodulin kinaseCRE=c-AMP-response elementCREB=c-AMP-response elementbinding protein MAPK=mitogen-activated protein kinase (ERK)

Nucleus

Cell birth in adulthood:granule cell layer of dentate

gyrus of hippocampus

[3H]-thymidine-labelled cell

BrdU-labelledcell

BrdU-labelledmitotic figurein anaphase

New neurons:Improved performance onhippocampal-dependent learning tasks

Motility of filopodia

rewiring and strengtheningof neural circuits

CA1

Glutamatereceptor

NMDAAMPAmGluRs

Protein kinase CPKGPAFNOCO

cGMP/PKG

cAMP/PKAsignallingpathway

β-adrenergicD1/D55-HT1AAde.cyclasePKACREB-P

MAP kinaseProtein synthesis

Time (hours) 0 1 2 3 4 5 6 7 8 9

Long-term MemoryShort-term memory

CaM Kinase II

Cognition enhancers -Cholinergic replacement therapy-Muscarinic & nicotinic receptorcompounds

-Glutamatergic systems-Nootropics-Behavioral effects & currenttherapies

-Nutrients & botanicals-Neuroprotection

-selectivity for different monomeric forms of AChE-AChE & BuChE inhibition-molecular interaction with the catalytic site-pharmacokinetic properties

Donopezil Galantamine Rivastigmine

-relatively marginal therapeutic benefit-the lack of improvement in function-the underreported adverse effects

Muscarinic receptor compounds:xanomeline, sabcomeline, talaclidine,melamine, PD-151832

Nicotinic receptor compounds:galantamine, ABT-089, GTS-21

Need more selective compounds

Excitatory synaptic transmission inhippocampal & cortical structures:ionotropic & metabotropic receptors

Memantine = uncompetitive NMDA antagonistcompleted phase III double-blind placebo-controlled clinical trialsin AD a significant improvement in the cognitive function &demonstrate neuroprotective effects

IDRA-21 etc.= AMPA modulatorspreclinical & clinical studies cognitive, attention,anti-depressant, anti-psychotic effects & expression ofneurotrophic factor BDNF

=compounds capable of enhancement of learning& memory with excellent safety & tolerability

Aniracetam: positively modulate AMPA receptors

In general, no regulatory approval forthe use of nootropics in dementia exists

Piracetam = prototype mechanism?

Antidepressants: SSRE -Tianeptinemelatonin antagonist-Agomelatine

Antipsychotics: Haloperidol Antiparkinson: Piribedil (5HT-14 agonist,

D4 agonist, alpha2 antagonist)

Phosphatidylserine=major building block of nerve cellsAcetyl-L-Carnitine=offer major metabolic benefits

to the brain

Vinpocetin= alkaloid from Vinca minormay have clinical utility in themanagement of stroke sequelae (Japan),benefits for retinal microcirculation, & inner ear=highly potent vasodilator, enhance cerebral blood flow

(Kidd,1999)

Ginkgo biloba= PAF antagonist, antioxidant

Glutamate antagonists

Antioxidants

Bioenergentic agentsAntiapoptotic

Ion channel blockers

Neurotrophic factors

Anti-inflammatoryagents

Increase of GABAergic

Possible neuroprotectants

Roles of Cognitive Enhancersin Neurological Disorders

-quality of life of patients-quality of life of caretakers- progression of the diseases-etc.