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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.