Introduction to CNS pharmacology Flashcards
Diagram of Chemical Neurotransmission
Diagram of when neurons reach a threshold potential.
What’s notable about the discovery of drugs which treat CNS disorders?
Much of the discovery of drugs to treat CNS disorders has been serendipitous (i.e. based on luck)
Give a few examples of serendipity in CNS drug discovery.
- The first antiepileptic drug (phenobarbital) was prescribed as a sedative but had anticonvulsant properties
- The first antipsychotic drug (Thorazine) was also prescribed as a sedative but stopped hallucinations
- The first antidepressant drug (imipramine) came from a failed attempt to develop a new antipsychotic drug
What are astrocytes?
Astrocytes maintain nutrition and regulate ionic concentrations. They also play a role in neurotransmitter synthesis and metabolism.
What do Oligodendrocytes do?
Oligodendrocytes (& Schwann cells in the periphery) produce myelin (inset) that insulates nerve cell membranes.
What is the function of Microglia?
Microglia act like macrophages, scavenging unwanted materials from the brain. They proliferate in disease states.
What are some of the neurotransmitters in the CNS?
Amines
- Dopamine
- Serotonin
- Noradrenaline
Amino Acids
- Dopamine
- Serotonin
- Noradrenaline
- Histamine
Cholinergic
- Acetylcholine
Purines
- ATP
- Adenosine
Peptides
- Enkephalins & endorphins
- Vasoactive intestinal polypeptide (VIP)
- Substance P
- Cholecystokinin (CCK)
- Opioids
Some neurotransmitters have well-defined roles (e.g. glycine), but many have complex and overlapping functions (e.g. amines in emotion and cognition).
How are neurons defined?
Neurons are largely defined by the neurotransmitter that they release.
List of receptors and the receptors subtypes.
Dopamine: D1, D2, D3, D4, D5
Serotonin: 5HT1A/1B/1D/1e/1F, 5HT2A/2C, 5HT3A/3B/3C/3D/3E, 5HT4, 5HT5A, 5HT6, 5HT7
Noradrenaline: a1A/1B/1D, a2A/2C,b1, b2
Glutamate: AMPA (GluA1-4), NMDA (GluN1, GluN2A-D, GluN3A/3B), kainate (GluK1-5), metabotropic (mGlu1-8)
GABA: GABAA (a1-6, b1-3, g1-3, d, e, q, p, r1-3), GABAB1/B2
Acetylcholine: nicotinic (a2/3/4/5/6/7/9, b2/3/4), muscarinic (mostly M1, M4, M5)
Purines: A1, A2A, A3, P2X1/2/3/7, P2Y1/2/4/6/11/12/13/14
Tachykinins: NK1, NK2, NK3
Opioids: u, k, d, ORL1
Impossible to remember them all but try to remember those that are ligand-gated ion channels and those that are GPCRs.
What are some of the technical issues with neuropharmacology?
Technical issues
- Tissue baths cannot be used, so instead researchers use:
- Electrophysiology
- Lesion studies
- Genetic techniques (KO mice, siRNA, etc.)
- Behavioral effects of selective drugs
- Very few reliable animal models; can’t biopsy tissue
- Outputs are hard to measure both in humans and animal models (although for different reasons)
- Using induced pluripotent stem cells derived neurons to model brain diseases
Most of the techniques above are NOT unique to neuropharmacology (e.g. electrophysiology); the difference mainly lies in what cannot be done in the brain.
Describe the plasticity within the CNS?
- The brain (and its pharmacology) continues to develop into adulthood
- The information the brain stores and processes change constantly
- Continued post-natal migration of cells and development of connections
- Changes in the strength of connections throughout life, e.g. long-term potentiation & depression
- Neurogenesis (in specific brain regions)
What is the Blood-Brain Barrier?
The blood-brain barrier (BBB) is a crucial immunological feature of the human central nervous system (CNS). Composed of many cell types, the BBB is both a structural and functional roadblock to microorganisms, such as bacteria, fungi, viruses, or parasites, that may be circulating in the bloodstream.
Give some of the features of the Blood-Brain Barrier.
- Continuous endothelium
- Tight junctions & basal membrane
- Lack of fenestrations
- Pericytes and astrocytes
- Few pinocytotic vesicles
- High metabolic rate
- Drug transporters
- Drug metabolizing enzymes
- The brain is inaccessible to many drugs (~85%); the drug requires high lipid solubility.
- The BBB is weak at the postrema
- During a brain infection, the Blood-Brain Barrier is compromised.
Types of Dementia
- Alzheimer’s disease (>50% of cases)
- Multiple cerebral infarcts (Vascular dementia) 20%
- Dementia with Lewy bodies (15%)
- Frontotemporal dementia (5%)
What are some causes of dementia?
- Parkinson’s/Huntingdon’s/Pick’s disease
- Prion disease (e.g. CJD)
- Alcoholism (Wernicke-Korsakoff), syphilis, HIV
- Other damage/metabolic or vit B deficiency etc
What’s the most common form of senile dementia in the USA population incidence?
0.1% at 60 (early onset)
Rising to 10% by age 80 (Late-onset)
Rising to over 30% by age 90 (Alzheimer’s Disease)
Alzheimer’s symptoms.
- Onset may be very slow and gradual or rapid
- 4-12 years(7-10 most common)
‘Gradual onset and continuing decline of cognitive function from a previously higher level resulting in impairment of social and occupational function’
- Decrease in the following:
- Memory
- language
- Perceptual abilities
- 1st symptom = loss of recent memory and inability to store recent information in long term memory
Common Symptoms of Alzheimer’s by stage.
The Aetiology of Alzheimer’s
A number of environmental and genetic risk factors may be involved e.g.
- head trauma
- exposure to aluminium
- family history of Down’s syndrome
- cerebrovascular disease
- Increasing age
- Gender-specific? ( 2x at risk thanbut live longer!)
- Genetic mutation/s
Describe the Neuropathology when the brain is in the disease state of Alzheimer’s.
- Neurone degeneration and death occurs in the hippocampus & the amygdala (subcortical limbic system)
- mainly regions of the brain that function in memory and learning.
- Massive cell loss and brain shrinkage
- Atrophy in parts of the cerebral cortex
- Thinned temporal lobes and ventricle size
What is the Limbic System?
The limbic system is the part of the brain involved in our behavioural and emotional responses, especially when it comes to behaviours we need for survival: feeding, reproduction and caring for our young, and fight or flight responses.
What does the limbic system consist of and how is it affected by Alzheimer’s?
The limbic system consists of a number of structures, including the fornix, hippocampus, cingulate gyrus, amygdala, parahippocampal gyrus, and parts of the thalamus. The hippocampus is one of the first areas affected by Alzheimer’s disease. As the disease progresses, the damage extends throughout the lobes.
Diagram of the Gross Anatomical Pathology of Alzheimer’s
What is the pathology of early and late-onset Alzheimer’s?
- 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
What is the amyloid cascade hypothesis?
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.
Stages in the Amyloid Cascade Hypothesis.
What are Amyloid Plaques?
- 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
How is beta-amyloid 42 derived?
- 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
How are Beta-Amyloid Plaques formed?
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.
What does the current Beta Amyloid Hypothesis suggest?
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.
Aβ42 peptide – evidence for………
- 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
What are Neurofibrillary Tangles?
- 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.
Stages of Hyperphosphorylation of tau.
- Hyperphosphorylation of tau
- Tau destabilizes and detaches from microtubules
- Paired helical filaments form neurofibrillary tangles
- Microtubules destabilize leading to disintegration
Apolipoprotein E and its link to Alzheimer’s.
- 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
What are the 3 major Alipoprotein E alleles?
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
How does APOE4 result in an increased risk of developing AD?
- 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
Statistics about Familial ALzheimer’s
- 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
What are some of the neurotransmitter systems affected?
- 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
What are some of the treatments available for AD?
- 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
What is the Synaptic Plasticity and Memory Hypothesis?
What is a contemporary approach to the treatment of AD?
- 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!
Inhibitors of amyloid aggregation.
- 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
SALAs and Alzheimer’s
- Selective amyloid lowering agents
- New class of anti-Ab drugs targeted at mild AD
- e.g. tarenflurbil modifies secretase which lowers Ab42
Why did tarenflurbil fail?
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.
What is Parkinson’s Disease?
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.
What is the Basal Ganglia?
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.
What are the three types of nuclei that the Basal Ganglia consist of?
- Input Nuclei
- Output Nuclei
- Intrinsic Nuclei.
What does the input nuclei in the Basal ganglia consist of?
The Input Nuclei consist of the striatum, which consists of the caudate and the putamen.
What does the Output Nuclei in the basal ganglia consist of?
Output Nuclei
- Globus Pallidus Internal
- Substantia Nigra
- Pars Reticulata
What does the Intrinsic Nuclei in the basal ganglia consist of?
Intrinsic Nuclei
- Subthalamic Nucleus
- Globus Pallidus external
- Substantia Nigra Pars Compacta
Basal Ganglia Circuitry Diagram
Basal Ganglia Motor Loop
Diagram of the stages of Parkinson Disease
What are some of the Dopamine Pathways?
Table of the distribution and functional roles of the D1 and D2 type receptors.
- 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.
What are some of the causes of PD?
- 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?
Flowchart for the treatment of PD
Describe how Levodopa treats PD
- 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.
Diagram of the brain in the epilepsy disease states. From Partial Seizures - Unclassified epileptic seizures.
Pie Chart Demonstrating the Prevalence of Seizure types.
Diagram of Ion Channels in Epileptic Discharges
If epilepsy is caused by a neurotransmitter imbalance between Glutamate and GABA, how would it look?
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.
What are symptomatic/acquired epilepsies usually? And what may they be associated with?
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
Diagram of Networks and Synaptic Connections
What are some theories for hyperexcitable networks in epilepsy?
Who synthesized Phenobarbital?
Synthesized as a sedative by Emil Fischer in 1911. It was marketed by F. Bayer & Co. as “Luminal”.
Describe Voltage-Gated Sodium Channels and what they’re responsible for?
- 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)
Diagram of GABAergic neurotransmission
