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Cognitive Enhancers: Classification and Mechanisms of Action
- 2. Cognition & cognitive enhancers For improving cognition Classification and Mech. of action In health & disease Treating –vs- Doping
- 3. Mental process involved in gaining knowledge and comprehension THINKING REMEMBERING JUDGING KNOWING In simple terms: brain process of acquiring and exploiting knowledge Cognition & cognitive enhancers
- 4. COGNITIVE A neuro-active substance that elevates individual’s cognitive abilities in a meaningful & sustained way mind bend
- 5. For improving cognition Increasing blood flow Enhancing neurotransmission Increased neuronal metabolism: stimulation of hormones and enzymes Increased nerve growth factor Improvement of cerebral functions - memory
- 6. Neuroscience Learning Memory of & Explicit memory Implicit memory Knowledge of facts - what we know about places, things and people–and the meaning of these facts Involves information about how to perform something, it’s recalled unconsciously Long term potentiation Habituation Sensitization
- 7. Neurobiology Learning Memory of & Hippocampus Encoding new information Strio-frontal cortex Decision making Frontal lobe Archiving & retrieval
- 8. process formation Memoryof Brain undergoes a physical and chemical change which is called - Synaptic Plasticity lasts for seconds or minutes lasts for days to weeks once stored, can be recalled up to years or even for a lifetime
- 9. synapse-specific structural changes process formation Memoryof Mitogen-activated protein kinases cAMP response element-binding protein
- 10. Cellular mechanisms Neuro-degenerationof Mis-folded, aggregated proteins Oxidative stress Excito-toxicity α – synuclein → Parkins Amyloid β and Tau → Alzheimers Huntingtin – HD SOD, TDP43 → ALS Age related decline in ability to clear misfolded proteins } Neuronal injury resulting from excessive glutamate activity in the brain Destructive effects mediated by NMDA r MoA – acute stroke and head trauma Aging – impaired capacity of neurons to handle oxidative stress ROS – DNA damage, peroxidation of membrane lipids and neuronal death
- 11. Classification and Mech. of action Racetams Neuropeptide Cholinergics AChE inhibitors AMPAkines Smart drugs GABAergics Seretonergics Dopaminergics Cognitive metabolic enhancers Nootropic vitamins Nootropic nutirents Nerve growth promoters Neuroprotectives Natural nootropics Neuro-hormones Drugs with nootropic properties Xanthines
- 13. ↑ ACh activity in the brain ↑ glutamate activity via AMPA and NMDA receptors ~ improve membrane permeability of neurons → enhances overall neuronal function off-label ADHD treatment PIRACETAM
- 14. derivative of Piracetam 5x more potent also stimulates AMPA receptor: learning & memory encoding processes activate D2 and D3 Dopamine receptors & 5-HT(2a) receptor involved in Serotonin processing effective as an anti- anxiety and anti- depression treatment Aniracetam
- 15. Piracetam analogue (30x) influences both Glutamate and ACh receptors ↑ reuptake at ACh receptor sites as well as increasing the efficiency of nerve impulse channels in the hippocampus → central role in memory formation as well as recall mental clarity and concentration also improving critical thinking skills speed of information processing Pramiracetam
- 16. Not racetam, but similar MoA 1000 X high affinity for ACh, AMPA and NDMA receptors: relate to short- term and long-term memory also activates D2 an D3 receptors & selective Serotonin receptors ↑ Nerve Growth Factor - maintenance and repair of healthy brain cells investigated as a possible treatment for Alzheimer’s disease Age-Related Memory Loss depression & anxiety Noopept
- 17. Potentiates excitatory neurotransmission → prolonging the opening of calcium channels binds to N-ACh r: ↑ communication in GABAergc, Cholinergic, monoaminergic and glutamatergic neuronal systems highly cytoprotective treat apathy and improve motivation in post-stroke patients Anti-amnesia effects powerful anxiolytic successful in the treatment of clinical depression Nefiracetam
- 19. ACh is an excitatory NT attention, synaptic plasticity, wakefulness and the reward system ↑ cholinergic activity: improve focus, working memory, alertness, mental clarity and performance 1928: Chavany recovery of cortical function with cholinergics (hemiplegia) at first attributed to cerebral vasodilatation
- 20. water-soluble essential nutrient structural integrity and signaling roles for cell membranes ↑ cholinergic neurotransmission (ACh synthesis) treat apathy and improve motivation in post-stroke patients Anti-amnesia effects powerful anxiolytic successful in the treatment of clinical depression Choline
- 21. occurs naturally in the brain, human breast milk (associated with ↑IQ in breast fed babies) highest bio-availability of Choline readily crosses the blood-brain barrier Alpha - GPC (Alpha Glycerylphosphorylcholine)
- 22. intermediary in the conversion of choline into phosphatidylcholine in the liver ↑ availability of choline in the brain by freeing up quantities of choline preservation of cardiolipin and sphingomyelin Citicoline decreases phospholipase stimulation → less hydroxyl radicals citicoline approved for treatment in cases of head trauma, stroke neurodegenerative diseases
- 23. Centrally acting anticholinesterases tacrine rivastigmine galantamine donepezil Huperzine A approved for the treatment of Alzheimer's disease mild to moderate vascular dementia and Alzheimer's mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson's disease approved for the treatment of Alzheimer's disease
- 25. activate glutamatergic AMPA r: promote alertness, ↑ attention span and memory ↑ synaptic communication: promote growth of neurons and the formation of long term memories potential treatment: Alzheimer's disease, Parkinson's disease, schizophrenia, treatment-resistant depression, neurological disorders such as Attention Deficit Hyperactivity Disorder (ADHD)
- 26. Sunifiram activates AMPA- mediated neurotransmission It enhances LTP improves cognitive deficits via CaM kinase II and protein kinase C activation ↑ release of ACh in the cerebral cortex Sunifiram alleviate symptoms of ADHD
- 28. Smart drugs: interact with natural neurochemicals, such as hormones, enzymes and neurotransmitters benefit in cognitive disorders like ADHD, anxiety, Alzheimer’s and Parkinson’s. In healthy: substantial boost to normal thinking, learning, memory, and focus. considered separately – they may use stimulatory mechanisms of action and may carry a greater risk of side effects
- 29. Eugeroic: wakefulness promoting agent Stimulates the release histamine in CNS to promote wakefulness ~ α1-adrenergic receptor agonist treatment of narcolepsy ADHD Shift work sleep disorder obstructive sleep apnea potentially useful: depression, bipolar, opiate and cocaine dependence, Parkinson's, schizophrenia and disease- related fatigue seasonal affective disorder Modafinil
- 30. Modafinil “Modafinil improves some aspects of working memory, such as digit span, digit manipulation and pattern recognition memory, but the results related to spatial memory, executive function and attention are equivocal” Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ (2003). "Cognitive enhancing effects of modafinil in healthy volunteers". Psychopharmacology (Berl.) 165 (3): 260–9. doi:10.1007/s00213-002-1250-8. PMID 12417966. -
- 31. Prodrug of modafinil Narcolepsy Adrafinil
- 32. Armodafinil (R)-enantiomer of the racemic modafinil Indirect dopamine r agonist: inhibits reuptake narcolepsy and shift work sleep disorder adjuvant therapy for obstructive sleep apnea Schizophrenia (neg sym) BPAD Jet lag
- 33. Methylphenidate Prevents re-uptake of dopamine & NE Also a 5HT1A receptor agonist Enhances the function of neurons in the prefrontal cortex: impulse control, motivation, and mental clarity ADHD Off-label: treatment-resistant lethargy, BPAD, major depressive disorder
- 34. any compounds which interact with GABAergic neurons in the brain GABA: natural inhibitory effect on stress responses in the central nervous system
- 35. Phenibut derivative of GABA GABA cannot cross BBB Phenibut: fully bioavailable Directly stimulate both GABA-A and B receptors non-selectively post-traumatic stress disorder, anxiety, and insomnia (β-phenyl-γ-aminobutyric acid)
- 37. Regulate metabolism and synthesis of dopamine are often direct pre-cursors to dopamine used to treat severe dopamine deficiency disorders like Parkinson’s disease, schizophrenia, and bipolar disorder May also be effective treatments against symptoms of ADHD, anxiety, and depression
- 38. Sulbutiamine Synthetic derivative of thiamine Crosses BBB > thiamine increases the levels of thiamine and thiamine phosphate esters in the brain improves memory: potentiation of cholinergic, dopaminergic, and glutamatergic transmission Asthenia: chronic fatigue of cerebral origin improves memory in schizophrenics and AD
- 39. Rasagiline Irreversible inhibitor of monoamine oxidase →↑Dopamine neuro-protective and neuro-rescuing property: effect on the mitochondria → interferes with and blocks apoptosis in neurodegenerative disorders Monotherapy in Early PD Adjunct Therapy in Advanced PD ~ treatment of Restless Legs Syndrome, AD
- 40. Rasagiline Irreversible inhibitor of monoamine oxidase →↑D neuro-protective and neuro- rescuing property: effect on the mitochondria – interferes with and blocks apoptosis in neurodegenerative disorders Monotherapy in Early PD Adjunct Therapy in Advanced PD ~ treatment of Restless Legs Syndrome, AD Selegiline
- 41. Acetyl L-Carnitine Alpha Lipoic Acid Creatine Pyritinol Vincamine Vinpocetine
- 42. Improved circulation to the brain ↑ oxygen consumption of cells → boost metabolism and energy production
- 43. Acetyl L-Carnitine Crosses BBB Converted into Acetyl-COA, which binds with choline = acetylcholine
- 44. Vincamine Derived from the Vinca Minor (Periwinkle) plant ↑ blood flow to the brain improve memory capability in Alzheimer’s disease
- 45. Vitamin B1 (Thiamine) Vitamin B3 (Niacin) Vitamin B5 (Pantothetic Acid) Vitamin B6 (Pyrodoxine) Inositol Vitamin B12 (Cobalamin) Low levels: fatigue, depression, and poor memory deficiency can potentially cause severe and irreversible damage to the brain and nervous system.
- 46. Artichoke Extract Ashwagandha Bacopa Monnieri Forskolin Grape Seed Extract Ginseng Hordenine Kava Kava Kratom Pterostilbene Rhodiola Rosea St John’s Wort
- 48. class of hormones manufactured by neuroendocrine cells stimulation of cellular growth, stress responses, fight or flight responses, emotional balancing etc.
- 49. DHEA (Dehydro-epiandrosterone) neurohormone produced in human adrenal glands commonly used by athletes as a performance enhancer reduce the visible signs of aging, and prevents neuronal dysfunction
- 50. Vasopressin exerts several nootropic benefits: better short term memory heightened metal acuity deeper memory imprinting used as a treatment for memory issues relating to age, dementia or Alzheimer’s disease popular with students
- 51. Pregnenolone Neurosteroid which is derived from cholesterol in the adrenal glands, liver, brain, skin, and sex organs affects synaptic functioning, neuroprotective, and enhance myelinization Improve cognitive and memory functioning ~ Pregnenolone is also being considered as a potential treatment for schizophrenia
- 52. In health & disease Alzheimer's Dementia (senile/vascular) TIA, CVA MR and ADHD in children Head injury Schizophrenia OCD Phobias Depression Exam going students High stressful jobs which need complete focus: neurosurgeons, pilots, military personnel Artists Athletes
- 53. Treating –vs– Doping Unfair advantage? Where to draw the line? Promotes laziness and shortcuts? Long term effects? US army 2012 Afghanistan incident Trans-humanism?
- 55. References Ingole, S. R., Rajput, S. K., & Sharma, S. S. (2008). Cognition enhancers: Current strategies and future perspectives. CRIPS, 9(3), 42-48. Bostrom, N., & Sandberg, A. (2009). Cognitive enhancement: methods, ethics, regulatory challenges. Science and Engineering Ethics, 15(3), 311-341. Lippincott., Cognitive Enhancers and Neuroprotectants. ln: Gualtieri,T., Brain Injury & Mental Retardation: Neuropsychiatry & psychopharmacology, 2004; 2nd ed. NY. Wolters Kluer. P: 1-37 Insel T., Krystal J., Ehlers M. (2013a). New drug development for cognitive enhancement in mental health: challenges and opportunities. Neuropharmacology 64 2–7 Greely, H., Sahakian, B., Harris, J., Kessler, R. C., Gazzaniga, M., Campbell, P., & Farah, M. J. (2008). Towards responsible use of cognitive-enhancing drugs by the healthy. Nature, 456(7223), P: 702-705.
- 56. References www.nootriment.com [last accessed on 25.02.2015] Swerdlow, N. R. (2012). Beyond antipsychotics: pharmacologically-augmented cognitive therapies (PACTs) for Schizophrenia Neuropsychopharmacology, 37(1), P: 310. Lanni, C., Lenzken, S. C., Pascale, A., Del Vecchio, I., Racchi, M., Pistoia, F., & Govoni, S. (2008). Cognition enhancers between treating and doping the mind. Pharmacological Research, 57(3), P: 196-213. Ressler, K. J., Rothbaum, B. O., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E & Davis, M. (2004). Cognitive enhancers as adjuncts to psychotherapy: Use of D-cycloserine in phobic individuals to facilitate extinctionof fear. Archives of general psychiatry, 61(11), P: 1136-1144. Stip, E., Chouinard, S., & Boulay, L. J. (2005). On the trail of a cognitive enhancer for the treatment of schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 29(2), P: 219-232.