Dementia science Flashcards
how do acetylcholinesterase inhibitors work
inhibits acetylcholinesterase to keep acetylcholine in the synapse for longer
what is the benefit to using galantamine over other AChEIs
also inhibits BuChE - non-specific but can break down ACh
what are NMDA antagonists and how do they work
memantine - Glutamate toxicity is proposed to play a role in neuronal cell death - as cells die glutamate is realised
This can cause excitotoxicity and further cell death - this is stopped by memantine
what are the main roles of acetylcholine in the CNS
- widely distributed
- Cholinergic interneurons in the striatum involved in movement` control
- Also roles in arousal and reward pathways (nicotine addiction)
which pathways in the brain use ACh
- Nucleus basalis projects to cortex
- Septal nuclei project to hippocampus - memory!
- Brainstem to thalamus - motor control
how does ACh cause dementia
- loss of cholinergic neurons in basal forebrain and hippocampus
- ACh decreased
- atrophy of hippocampus and enlarged ventricles
- formation of beta-amyloid plaques and intra-neuronal neurofibrillary tangles
- starts in hippocampus and spreads
what is the beta-amyloid protein
peptide produced from amyloid precursor protein (APP) - cleaved by a (sAPP) and y (b-amyloid) secretases
what is APP
amyloid precursor protein - large transmembrane glycoprotein
- in neuronal and non cells
- transcriptional regulator
- growth factor function
- synaptic transmission
what happens if APP is cleaved by b and y secretases
AB40 and 42 formed - found in plaques - AB42 is the worst
which mutations can cause increased AB42 formation
APP mutations
presenilin mutations can increase y-secretase activity
how does Amyloid B form the plaques associated with AD
combine to oligomer which combine to fibrils and then plaques
what are AD plaques made of
fibrils
cell parts
astrocytes
microglia
apolipoproteins
what are neurofibrillary tangles
formed from hyperphosphorylated tau that aggregates to form paired helical filaments - causes microtubules to depolymerise and causes neuronal cell death
what is the normal action of tau
normally stabilises microtubules
which mutations are responsible for early onset AD
- trisomy 21 - down syndrome (APP on chromosome 21 - 3 copies)
- APP mutations - favours AB42
- presenilin - component of y secretase - favours AB42
- tau - increased phosphorylation
which mutations are responsible for late onset AD
ApoE gene variants
- lipid binding lipoprotein
- involved in lipid transport and found in plaques
- ApoE4 increased risk
- ApoE2 decreased risk
what must acetylcholinesterase inhibitors do
cross BBB
what is the SAR for donepezil
- carbonyl required
- dimethoxy substitution optimal - para most important
- 5 C ring essential
- CH2 bridging optimal
- N in 6C ring essential
- substitution with EDG is good but unsub is preferred
how does donepezil work
AChE selective inhibitor and reversible
SAR for carbamates natural product
- carbamate essential - reacts with catalytic triad
- Amine important for activity - pka 7 50% ionised in body
- benzene hydrophobic good leaving group
how does rivastigmine work
pseudo-irreversible, enzyme inhibition lasts for longer then the drug is in plasma
rivastigmine SAR
same as carbamate SAR
- carbamate essential - catalytic triad
- benzene ring makes good leaving group
- amine
