Nootropics/ Cerebro-active drugs/ Cognition enhancers

Definition of Nootropic agents

A drug that selectively improves the efficiency of higher telencephalic integrative activities by:

• Enhancement of learning and memory.
• Facilitation of synaptic transmission.
• Facilitates inter-hemisphere information transfer.
• Prevents the development of memory deficits.
• Increased tonic cortical control on subcortical areas.

Cognition is defined as the processes an organism uses to organize information

Concept of cognition related to reasoning, intelligence, learning.

Cognitive disorders category of mental health disorders that mainly affect learning, memory, perception, and problem solving

It includes,

1. Amnesia
2. Dementia
3. Delirium

Dementia: A syndrome due to disease of the brain, characterized by progressive, global deterioration in intellect including Memory, Learning, Orientation, Language, Comprehension, Judgement

The role of Neurotransmitters in memory

• The role of acetylcholine in cognition and memory formation is well established. In the early stages of AD levels of Acetylcholine are reduced.
• Accumulation of beta-amyloid peptide appears to be central to the degenerative changes seen in the brain in Alzheimer’s disease. It results in the destruction of cholinergic neurons and a fall in acetylcholine concentration.
• Acetylcholinesterase breaks down acetylcholine in the synaptic cleft
• Acetylcholinesterase inhibitors e.g. Donepezil prevent this action, thereby increasing levels of acetylcholine.

• Glutamate -Excitatory neurotransmitter, allows Ca⁺ to enter the cell, exciting the neuron. Excitatory activity, if excessive, leads to neuronal cell death
•  Memantine à a glutamate receptor antagonist which addresses the excitotoxic effects of glutamate by occupying NMDA receptor sites.
• Memantine displaces Mg⁺⁺ from N-Methyl-D-Aspartate (NMDA) receptors, thus moderating the excitatory effect of glutamate

Indications of cognition enhancers

A various neurodegenerative disorder associated with cognitive dysfunction –

1. Alzheimer’s disease
2. Senile dementia
3. Multi-infract dementia
4. Parkinson’s disease
5. Stress-induced dementia
6. Attention deficit disorder
7. TIA, CVA, Stroke
8. Sequalae of head injury

Classification of Cognitive enhancers

Drugs

• Cholinergic activators: Donepezil, Rivastigmine
• Glutamate (NMDA) antagonist: Memantine
• Others: Piracetam, Pyritinol(Pyrithioxine), Dihydroergotoxine (Codergocrine), Citicoline, Piribedil, etc
• Herbs: Brahmi, Gingko biloba, etc.

Cholinergic activators:

MOA:

• Donepezil, galantamine, and rivastigmine are used in the treatment of mild to moderate dementia due to Alzheimer’s disease and may be helpful in the treatment of dementia with Lewy bodies. They enhance cholinergic function in the CNS through reversible inhibition of acetylcholinesterase.
• None of the available drugs prevents Alzheimer’s disease or modifies its pathology.

Rivastigmine

• Carbamate derivative of Physostigmine
• Inhibits both AChE and BuChE-more selective to G1 isoform of AChE which is predominant in brain
• Highly lipid-soluble –CNS penetration
• MOA: Introduces carbamyl residues to AChE and renders inactive which dissociates slowly
• Uses: Useful in mild to moderate Alzheimer`s disease
• Available as 1.5, 3, 4.5, 6 mg caps orally(twice daily)
• Transdermal patch available applied every 24hrs

Donepezil:

• Cerebroselective and reversible anti-AChE
• Improves Ach concentration in cortex especially in projecting neurons from basal ganglia to cortex
• Improvement maintains upto2 years
• A long duration of action (half-life –70 hours) and useful in severe cases of AD –once daily

Galantamine:

Natural alkaloid –selective inhibition of cerebral AChE and also direct agonistic action on Nicotinic receptors –twice daily dose

• Common Adverse Effects Donepezil, Rivastigmine, Galantamine: nausea, vomiting, diarrhea, anorexia, abdominal pain, dyspepsia, headache, insomnia, vivid dreams, depression, fatigue, drowsiness, dizziness, tremor, weight loss, muscle cramps, urinary incontinence, increased sweating, hypertension, syncope
• Infrequent or rare-bradycardia, heart block, seizure, agitation, hallucination, confusion, GI hemorrhage

Memantine

• A different mechanism of action than rivastigmine and others
• It’s a new NMDA receptor antagonist and related to amantadine
• Known for slowing down of the process of dementia in moderate to severe dementia
• MOA: Blocks the excitotoxic glutamate neurotransmitter competitively
• Better tolerated than anti-ChEs
• ADRs: constipation, tiredness, headache, and drowsiness, etc.

Piracetam

• Cyclic GABA derivative
• The drug selectively improves the efficiency of higher telencephalic integrative activity
• Piracetam taken with choline -synergistic effect that causes a greater improvement in memory

1.Enhanced efficacy of AMPA induced Ca2+ influx in brain cell
2.Increases the maximal density of AMPA receptors in synaptic membranes from rat cortex
3.Enhancement of learning and memory.
4.Facilitation of synaptic transmission & inter-hemisphere information transfer.
5.Potentiates potassium-induced release of glutamate from rat hippocampal nerves

 Not approved by US-FDA.

 It is used in Europe, Asia & South America.

Citicoline

• Chemically identical to CDP-choline, the natural precursor of the major cell membrane phospholipid phosphatidylcholine
• enter the brain separately &are used to resynthesize CDP-choline inside a brain cell

Pyritinol(Pyrithioxine):-

1. Improve regional blood flow
2. activate cerebral metabolism by selectively increasing glucose transport.

Dihydroergotoxine (Codergocrine):-

Alpha-adrenergic blocker leading to increase cerebral blood flow

• Evidence is poor for other approaches, including anti-amyloid therapies, antioxidants, estrogens and Ginkgo biloba, Brahmi, Ashwagandha

Ginkgo biloba à MOA:

1. Restores impaired mitochondrial function & improves neuronal energy supply
2. Improves compromised hippocampal neurogenesis & neuroplasticity
3. Improves neurotransmission and increases dopamine levels in the prefrontal cortex (working memory & executive control)
4. Inhibits aggregation &toxicity of Aβ protein, anti-inflammatory effects
5. Decreases blood viscosity & enhances micro-perfusion, increasing cerebral blood flow

• HuperzineA (HupA)
  • AChE inhibitor & NMDA receptor antagonist extracted from Huperzia serrata, a firmoss.
  • HupA used clinically to improve cognition and memory in AD and other forms of dementia in China.
  • Currently marketed as a memory-enhancing dietary supplement in the US.
  • In clinical trials, HupA demonstrable cognition-improving capacity in AD patients

• Pioglitazone
  • Insulin sensitizer: thiazolidinedione -> Peroxisome-Proliferator Activated Receptor γ (PPARγ) agonists.
  • It binds to PPARγ, affecting gene transcription and reducing inflammation
  • animal studies -> a role in neuroinflammatory processes in AD and other neurodegenerative disorders
  • Phase II study à evaluated the safety and tolerability of pioglitazone in patients with AD  

• Genetic Modifications
  • Genes in humans found that whose variations account for up to 5% of memory performance
  • Genes for NMDA receptor &adenylyl cyclase, genes involved in stages of the synaptic signal cascade
  • These obvious targets for enhancement
  • It has been proved in preclinical studies of rats and mice