Introduction to CNS pharmacology Flashcards

Question

What is the pathology of early and late-onset Alzheimer's?

Answer 1

* Senile or amyloid plaques in the brain * deficits in amyloid processing * Presence of neurofibrillary tangles in the cerebral cortex * Amyloid microangiopathy * Glial inflammation and toxicity * Leading to the Amyloid Cascade Hypothesis

Answer 2

The amyloid cascade hypothesis postulates that the neurodegeneration in AD is caused by the abnormal accumulation of amyloid-beta (Aβ) plaques in various areas of the brain. “deposition of amyloid β protein (AβP), the main component of the plaques, is the causative agent of Alzheimer’s pathology and that the neurofibrillary tangles, cell loss, vascular damage, and dementia follow as a direct result of this deposition” Research into various approaches and therapies has centered around this cascade theory – unfortunately with little success to date.

Answer 3

* The amyloid plaques contain an insoluble 42-residue peptide called Ab42 (beta-amyloid 42) in core * surrounded by axons/dendrites (neurites) & microglia & astrocytes * structural abnormalities include enlarged mitochondria, liposomes & impaired filaments * It May take decades for plaques to ‘mature’ * Contain glial cells- microglia, astrocytes * N.B these plaques are not specific for AD but more prevalent

Answer 4

* 42 amino acid’s long * (In a healthy brain 90% of the Ab peptide is in the Ab40 form) * Derived by cleavage of the much larger protein encoded by chromosome 21 * Amyloid precursor protein (beta-APP) * Normally cleaved by enzyme (secretase)à Ab40 form

Answer 5

The amyloid precursor protein (APP) is a transmembrane protein that can undergo a series of proteolytic cleavages by secretase enzymes. When it is cleaved by α-secretase in the middle of the β-amyloid domain (Aβ), it is not amyloidogenic. However, when APP is cleaved by β-and γ-secretase enzymes, neurotoxic Aβ peptides are released, which can accumulate into oligomer aggregate. Mutations in the APP gene tend to inhibit cleavage by α-secretase and consequently enable preferential cleavage by β-secretase. Mutations in the presenilin-1 and presenilin-2 genes (PSEN1 and PSEN2), which are components of the γ-secretase complex, increase cleavage by γ-secretase at this site. In both situations, the result is excess Aβ peptide production.

Answer 6

The current Aβ hypothesis suggests that the soluble oligomers can impair synaptic function between neurons. Simultaneously, the oligomers may aggregate into insoluble β-sheet amyloid fibrils, which can trigger a local inflammatory response. 22 Over time, the subsequent oxidative stress and biochemical changes ultimately lead to neuronal death and the development of neuritic plaques typical of Alzheimer's disease.

Answer 7

* detrimental memory formation * initiation of Tau phosphorylation * associated with demyelination * tangle formation * oxidative damage * inflammatory responses (microglia) * deficits in NT’s (excess glutamate) * apoptotic cell death

Answer 8

* Dense bundles of fibres in cytoplasm of neurones * Neurofibrillary tangles contain a highly polymerised form of a cytoskeletal protein called tau in cytoplasm * Occur in many chronic brain diseases * Many people who live to late 70’s will have both senile plaques and neurofibrillary tangles * Hippocampus & parieto-temporal regions of cerebral cortex particularly susceptible. Microtubules are tracks that transport nutrition and other molecules. Tau-proteins act as “ties” that stabilize the structure of the microtubules. In AD, tau proteins become hyperphosphorylated and tangled, destabilizing the structure of the microtubule. Loss of axonal transport results in cell death.

Answer 9

* Hyperphosphorylation of tau * Tau destabilizes and detaches from microtubules * Paired helical filaments form neurofibrillary tangles * Microtubules destabilize leading to disintegration

Answer 10

* Apolipoprotein E -neuronal repair and growth (cholesterol transport) * Common amino acid variations are also shown to be associated with a predisposition to Alzheimer's disease * However, also detected in both senile plaques and neurofibrillary tangles * in vitro, it has an affinity to Ab42 peptide- * increases formation * interferes with removal

Answer 11

_Three major APOE alleles_ * APO\*E2 (approx 6% of population) * Protection from Alzheimers * APO\*E3 (approx 78% of population) * APO\*E4 (approx 16% of population) * increases risk of Alzheimer's in a dose dependent fashion. * the alleles differ by just two amino acids

Answer 12

* Apolipoprotein E gene on Ch 19 is required for normal cholesterol transport necessary for removal of β amyloid protein from CNS * So APOE4à accumulation of β amyloid + binding of APOE protein to τ protein of neurofibrillary tangles * Heterozygous APOE4à 2 x risk of AD * Homozygous APOE4à 5 x risk of AD

Answer 13

* 5% of families clearly show autosomal dominant form of inheritance * Most of these families early onset * However, only 30% of early-onset cases show autosomal dominant inheritance * 34% of overall risk of Alzheimer’s is probably due to hereditary factors

Answer 14

* Acetylcholine * Synthesised by the basal forebrain cholinergic complex (BFCC) axons project to the hippocampus & the cerebral cortex * 40-90% ¯ChAT (acetylcholine transferase) * Glutamate * b amyloid protein accumulates in neuronesà increased release of glutamate * High levels disrupt learning and memory (NMDA receptors) * Excitotoxicity * Catecholamines, somatostatin, corticotrophin etc

Answer 15

* Target Ach & glutamate (memory) & help disability * Block Ach breakdown by inhibiting Acetylcholine esterase (AChE) * e.g. tacrine (Cognex),Doneprezil,Aricept * Memantine (NMDAR antagonist N-methyl-d-aspartate) shown to reduce clinical symptoms with moderate to severe AD Inconsistent & treating symptoms rather than cause

Answer 16

* Reduce activity of b amyloid * b-site APP cleaving enzyme (BACE) inhibitors (block b secretase) & g-secretase inhibitors * Problem: g-secretase is not specific for amyloid cleavage * Disrupts lymphocyte development * Affects intestinal structures * BACE inhibition is not associated with toxic side effects but can’t cross BBB!

Answer 17

* Inhibition of Aβ production and aggregation, acceleration of Aβ clearance as well as reduction of tau hyperphosphorylation. * GAGS sulfated glycosaminoglycans bind A b in solutionà plaques * GAG mimetics block aggregation process * Ovine colostrinin (O-CLN)-improves learning in AD in animal models

Answer 18

* Selective amyloid lowering agents * New class of anti-Ab drugs targeted at mild AD * e.g. tarenflurbil modifies secretase which lowers Ab42

Answer 19

What are the reasons for this setback after the previous apparently encouraging results in a Phase II study? A straightforward explanation of this failure is that the γ-secretase is not the right target for therapy or that, in general, blocking Aβ does not produce clinical benefits in AD. If one still accepts the physiopathological role of Aβ in AD, tarenflurbil could not be the right compound because of its weak pharmacological activity as an Aβ1-42 lowering agent and its poor brain penetration.

Answer 20

A progressive disease of the nervous system marked by tremor, muscular rigidity, and slow, imprecise movement, chiefly affecting middle-aged and elderly people. It is associated with degeneration of the basal ganglia of the brain and a deficiency of the neurotransmitter dopamine.

Answer 21

The “basal ganglia” refers to a group of subcortical nuclei responsible primarily for motor control, as well as other roles such as motor learning, executive functions and behaviors, and emotions. ... Disruption of the basal ganglia network forms the basis for several movement disorders.

Answer 22

1. Input Nuclei 2. Output Nuclei 3. Intrinsic Nuclei.

Answer 23

The Input Nuclei consist of the striatum, which consists of the caudate and the putamen.

Answer 24

_Output Nuclei_ * Globus Pallidus Internal * Substantia Nigra * Pars Reticulata

Answer 25

_Intrinsic Nuclei_ * Subthalamic Nucleus * Globus Pallidus external * Substantia Nigra Pars Compacta

Answer 26

* Damage to any basal ganglia structure may cause slowness of voluntary movement, involuntary movements, involuntary postures, or a combination. * Damage to the striatum causes voluntary movements to be slow and may produce involuntary movements. * Damage to the STN causes large-amplitude involuntary movements. * Damage to the GP causes slowness of movement, abnormal postures, difficulty relaxing muscles. * Damage to SNpc causes tremor at rest, slowness of movement, rigidity and postural instability.

Answer 27

* Parkinson’s disease affects 1% of people over 65. * Second most common neurodegenerative disease after Alzheimer’s disease.

Answer 28

Increased prevalence in men.

Answer 29

Environmental and genetic factors contribute to onset. In most cases idiopathic.

Answer 30

* Characteristic symptoms/signs occurring unilaterally then bilaterally: * Tremor – occurs in 75% of PD patients * Bradykinesia * Muscular rigidity * Impairment of postural reflexes

Answer 31

* Motor impairments are a result of the depletion of dopaminergic neurons within the substantia nigra pars compacta (SNpc). * 60% of nigral neurons are lost before motor impairments appear. * Delay accounted for by: 1. a) increased dopamine production by surviving neurons 2. b) upregulation of dopamine receptors in target striatal neurons. * Nigrostriatal tract degenerates leading to less than 20% dopamine levels in basal ganglia.

Answer 32

_Motor control_ Cell bodies within the substantia nigra, axons project to the striatum. Accounts for 75% of dopamine in the brain.

Answer 33

* Emotional behaviour * Cell bodies within the midbrain ventral tegmental area (adjacent to substantia nigra), project to the nucleus accumbens and amygdala.

Answer 34

* Emotional behavior * Cell bodies within the ventral tegmental area, axons project to the frontal cortex.

Answer 35

* Endocrine control * A group of neurones projecting from the ventral hypothalamus to the pituitary to regulate pituitary secretions.

Answer 36

There's the D1 type and the D2 type. The D1 type consists of the D1 and D5 receptors. The D2 type consists of the D2, D3, and D4 receptors.

Answer 37

* Five different dopamine receptors were identified. * All belong to the family of G-protein coupled transmembrane. * D receptors are expressed in distinct but overlapping brain areas. * Dopamine acts pre- and post-synaptically. * D receptors also mediate effects peripherally: renal vasodilation and increased myocardial contractility.

Answer 38

* In 1912 Friedrich Lewy discovered ‘spherical neuronal inclusions’ during postmortem. * Lewy bodies are defining feature of PD. * Lewy bodies are neuronal intracytoplasmic inclusions comprising numerous proteins, including α–synuclein. * Lewy bodies found in cytoplasm of surviving neurones.

Answer 39

The main constituent of Lewy Bodies is α–synuclein. α–synuclein is a synaptic protein present in presynaptic terminals. Possible involvement in neurotransmitter storage and release, vesicle recycling, and synaptic plasticity. Mutations in synuclein gene identified in familial forms of PD.

Answer 40

* Proposed that Lewy bodies deposited first in the olfactory bulb and lower brainstem, then in SN, progressing to the cortex. * Explains loss of smell and REM sleep disorder onset before motor impairments.

Answer 41

_Mitochondrial dysfunction_ * Mitochondrial complex 1 defect in brain confined to substantia nigra. * Identified in sporadic PD * Linked with oxidative stress and elevated brain iron levels.

Answer 42

_Microgliosis_ * Postmortem evidence of inflammation * Change in cytokine levels in substantia nigra and CSF. * Glial cell activation but is this triggering cell death or a response to cell death?

Answer 43

* Age: possible increased vulnerability of dopaminergic neurones to toxic insult because of age-related failure of physiological and biochemical processes. * Several gene mutations have been identified in familial and sporadic PD. * Environmental risk factors likely contribute but no specific agent has been identified as causative. * Industrialisation, pesticides, rural environment, bacterial, viral?

Answer 44

* The first line of treatment. * Dopamine does not cross BBB so precursor Levodopa is given. * Levodopa converted to dopamine in dopaminergic neurones. * Plasma half life is short – 2 hours. * Given with a peripherally acting dopa decarboxylase inhibitor (e.g. carbidopa) to reduce peripheral side effects. * Decarboxylase inhibitors do not cross BBB so decarboxylation occurs rapidly in the brain.

Answer 45

Levodopa effectiveness decreases as PD advances. Reducing ‘off time’ and dyskinesias (involuntary movements). Require more continuous dopaminergic stimulation to a more constant physiological level.

Answer 46

_Dopamine agonists_ * Effective in controlling symptoms of PD, usefulness is limited by side effects: nausea, vomiting, somnolence, fibrotic reactions in lungs and pericardium. * Do not show fluctuations in efficacy associated with levodopa. * May cause somnolence, hallucinations and predisposition to compulsive behaviour e.g., excessive gambling.

Answer 47

_MAO-B inhibitors_ * Inhibit breakdown of extraneuronal dopamine in the brain. * Lack unwanted side effects of non-selective MAO inhibitors used to treat depression. * Clinical trials show the combination of MAO-B inhibitor Selegiline and levodopa is more effective than levodopa alone.

Answer 48

_Neural transplantation_ * PD first neurodegenerative disease for attempted neural transplantation. * Injection of foetal neuroblasts directly into the striatum. * Some transplants relatively successful – functional dopaminergic connections. * Development of serious dyskinesias. * Five or more foetuses are required for one transplant.

Answer 49

_Gene therapy_ * Aimed at increasing the synthesis of neurotransmitters and neurotrophic factors. * Dopamine in the striatum by expressing tyrosine hydroxylase or dopa decarboxylase. * GABA in the subthalamic nucleus by overexpression of glutamic acid decarboxylase (to reduce excitatory input to SN).

Answer 50

_Deep brain stimulation_ * Treats PD symptoms. * Not a cure * Side effect: depression * Not for everyone. * Used in patients with motor complications – frequent ‘off periods’ while taking levodopa. * Electrodes implanted during awake surgery into the subthalamic nucleus or globus pallidus.

Answer 51

An episodic disorder of the nervous system arising from the excessively synchronous and sustained discharge of a group of neurons. These discharges produce "seizures" that vary from one person to another in frequency and form.

Answer 52

A seizure may manifest as: * a brief stare * a change of awareness * a convulsion A seizure may last a few seconds or a few minutes.

Answer 53

The clinical manifestation of an abnormal and excessive excitation of a population of cortical neurons.

Answer 54

A broad category of symptom complexes arising from … recurrent paroxysmal episodes of brain dysfunction manifested by stereotyped alterations in behavior.

Answer 55

disorder of the brain characterized by enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition More than 50 different epilepsies are recognized

Answer 56

There are: 1. Partial Seizures 2. Generalized Seizures 3. Unclassified Epileptic Seizures

Answer 57

* Simple Partial Seizures - awareness is not impaired * Complex Partial Seizures - awareness is impaired * Partial Seizures evolving to Secondarily Generalized Seizures.

Answer 58

* Absence Seizures * Myoclonic Seizures * Clonic Seizures * Tonic Seizures * Tonic-Clonic Seizures * Atonic Seizures

Answer 59

Epilepsy affects more than 50 million people worldwide, and more than 500,000 people in UK.

Answer 60

The lifetime risk of a single unprovoked seizure is 2% - 5%.

Answer 61

The prevalence of active epilepsy is 0.4% - 1.0%. The prevalence of active epilepsy increases with age.

Answer 62

* Around 40% of all epilepsies are presumed to be genetic\* * minority (2-5%) show monogenic inheritance (single gene defect) * the majority (\>90%) assumed to have polygenic inheritance (multiple gene defects) * an increasing number (2-5%) have de novo mutations (not inherited)

Answer 63

* Another 30% of epilepsy cases are associated with an antecedent brain injury * birth trauma (e.g. peri-natal hypoxia) * aftermath of infection (e.g. meningitis) * head trauma (e.g. car accident, sports injury, etc.) * cerebrovascular malformation * brain tumour * stroke

Answer 64

30% of epilepsy cases are idiopathic.

Answer 65

The simple answer is that we don't know. It probably involves: * Ion channel dysfunction * Neurotransmitter imbalance * Other things as yet unknown They may be caused by: * Genetic Mutations * Damage to the brain * Other things as yet unknown

Answer 66

Neurons are arranged in complex networks; 10¹¹ cells forming 10¹⁵ synapses.

Answer 67

Cell to cell signaling requires the release of neurotransmitters from nerve terminals

Answer 68

NTs act on receptors in pre- and post-synaptic membranes.

Answer 69

Neurotransmitter receptors contribute to excitability in neuronal networks.

Answer 70

The two main NTs in epilepsy are: Glutamate and GABA. _Glutamate_ * Glutamate is the principal excitatory NT in the mammalian brain. * It acts on AMPA, KA, and NMDA receptors, leading to Na⁺ and Ca²⁺ influx. * Generates excitatory post-synaptic potentials (EPSPs) _GABA_ * GABA is the principal inhibitory NT in the mammalian brain * Acts on GABA_A(and GABA_B) receptors, leads to Cl^- influx * Generates inhibitory post-synaptic potentials (IPSPs).

Answer 71

Dopamine, Serotonin and Acetylcholine.

Answer 72

In the normal brain, there is an equal balance between Glutamate and GABA. It is possible that epilepsy can be caused by an excess of Glutamate compared to the concentration of GABA.

Answer 73

* SMEI is a form of monogenic epilepsy, which stands for Severe Myoclonic Epilepsy of Infancy (aka Dravet syndrome). * Children present at ~6 months with generalised clonic seizures;myoclonic, absence and focal seizures may develop later (1-4 years). * The seizures are typically unresponsive to antiepileptic drugs; children develop cognitive, behavioral, and motor impairments.

Answer 74

Mutations in SCN1A gene - the Na_v1.1 subunit of the voltage-gated sodium channel. * 100s of mutations (often de novo) are now described in the SCN1A gene. * 70-80% of SMEI cases carry an SCN1A mutation These mutations eventually lead to the loss of function (unlike GEFS+).

Answer 75

* Loss of NaV1.1 leads to compensatory up-regulation of other sodium channels? * NaV1.1 predominantly expressed in inhibitory interneurons; loss of inhibitory control? * Sodium channel blocking drugs make SMEI worse; block residual channel function?

Answer 76

Savannah Dixon-Salazar * No family history of epilepsy * Developed Lennox-Gastaut syndrome at 2 years * All drugs ineffective - 300 seizures per month * Mum (Tracy) did BSc in Neuroscience, PhD in Genetics * Exome-sequenced Savannah’s DNA * Identified 25 novel calcium ion channel variants * Treated with Ca2+ blocker verapamil (anti-arrhythmic drug) * Seizures down to 20/month; now only at night Intellectual development hugely improved

Answer 77

Acquired or symptomatic epilepsies are often focal seizure disorders. Discernable abnormality is often ID'd on MRI scan. May be associated with previous: * perinatal hypoxia * complex febrile seizures * brain infection * status epilepticus

Answer 78

* Remains subject to considerable stigma * Uncontrolled seizures in one-third of patients * Cognitive decline in some patients, depression, anxiety * Loss of driving license, loss of job, loss of social life? * In general - lower educational attainment, less likely to marry * Dependent behavior – impact on families and carers * Risk of injury * Mortality: 3x higher than the general population, 9x in uncontrolled epilepsy

Answer 79

Synthesized as a sedative by Emil Fischer in 1911. It was marketed by F. Bayer & Co. as "Luminal".

Answer 80

When administered to patients with epilepsy, they had become seizure-free.

Answer 81

First synthesized in 1882 by Burton but there was no known use. It is liquid at room temperature so was used as a lipophilic vehicle for water-insoluble compounds.

Answer 82

* Pierre Eymard (Grenoble, France) used VPA to dissolve khelline derivatives for Ph.D. studies in 1962 * Vehicle (i.e. VPA) but not khelline derivatives showed efficacy against PTZ seizures in mice & rabbits * Earliest clinical trials in 1964, marketed for the treatment of epilepsy in France in 1967

Answer 83

* Apart of the super-family of voltage-gated channels; form ion-selective pores in the membrane * Responsible for depolarisation of the nerve cell membrane and conduction of action potentials across the surface of neuronal cells * Expressed throughout the neuronal membrane, on dendrites, soma, axons, and nerve terminals; expression is highest in the axon initial segment (AIS)

Answer 84

Phenytoin and carbamazepine are classical sodium channel blockers. They show preferential binding to inactivated state of the channel. They exert a '**use-and frequency-dependent** block of channel function. The block is enabled by the use (i.e. activation) and enhanced by the frequency of use. So high-frequency action potential firing is preferentially reduced (i.e. during a seizure). Low-frequency firing and single action potentials are largely unaffected. Other Anti-epileptic Drugs have similar effects - subtle differences only.

Answer 85

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian brain. It is released at 40% of all synapses.

Answer 86

* GABA_A receptor – fast inhibition * GABA_B receptor – slower inhibition

Answer 87

The reuptake of GABA is facilitated by GAT (GABA transporter) on the Glial cell back into the pre-synaptic cell as Glutamine and converted into GABA again.

Answer 88

GABA transaminase converts it into Glutamate which then gets converted into Glutamine.

Introduction to CNS pharmacology Flashcards

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