Cognition enhancing or neuroprotective compounds for the treatment of cognitive disorders: why when

1
Cognition enhancing or neuroprotective compounds
for the treatment of cognitive disorders why?
when? which?

• Lockhart BP, Lestage PJ.
• January 2003

2
Prevalence of Alzheimer's and other dementias in
the U.S.A.

• Alzheimer's 65-70 of dementias (1.1 4.5
  million affected individuals)
• Parkinson's 8-10
• Lewy-Body 13-15
• Other cerebrovascular dementias 5-10

3

• Symptomatic treatment of AD is currently based to
  a large degree on the cholinergic hypothesis,
  suggesting that many of the cognitive, functional
  and behavioral symptoms of AD derive in part from
  reductions in acetylcholine (ACh) synthesis via
  choline acetyltransferase and reduced choline
  uptake.

4

• Much effort aimed at reversing cholinergic
  deficit based in increasing ACh neurotransmitter
  levels by stimulating release or blocking
  degredation
• Basis of approved AD drugs
• Donepezil (Aricept)
• Rivastigmine (Exelon)
• Galanthamine (Reminyl)
• Tacrine (Cognex)

5

• These drugs give similar, moderate improvement in
  randomized, controlled trials within the first 6
  months of treatment.
• Slower decline of cognitive function observed in
  longer trials.
• No data has shown that these drugs reduce the
  underlying cause(s) of AD.
• Most of the studies recruited patients lt 75 years
  with mild symptoms.
• Note Recent studies question efficacy.

6
Glutamatergic systems as targets for drugs

• Modest efficacy of ACh drugs in AD patients
  suggests that hypofunction of the cholinergic
  system may not necessarily be the primordial or
  key event in the cognitive deficits in AD and
  other dementias.
• Possible principal factor behind these findings
  may be that fast excitatory synaptic transmission
  in hippocampal and cortical structures is
  mediated by the excitatory amino acid glutamate.

7

• The glutamate receptors include the NMDA family
  and AMPA family. Drug strategy has focused on
  NMDA and AMPA.
• The NMDA antagonist memantine completed phase III
  trials in AD and showed a significant improvement
  in the cognitive function of AD patients with
  reduced adverse effects compared to ACh drugs.
• Modulators of the AMPA receptor have been
  evaluated in clinical trials for cognitive
  function, with promising results. Clinical trials
  are ongoing.

8
The amyloid beta hypothesis

• amyloid beta protein forms senile plaques in
  the brain that are diagnostic of AD
• Considerable evidence, both genetic and
  biochemical, that amyloid beta causes or
  contributes to development and progression of AD.
• amyloid beta is a generator of free radicals, and
  induces oxidative stress damage to neurons in
  vitro.
• Potential target for drugs to treat AD
• Evidence that free radicals play a role in
  neurodegeneration