PBL 1- Mutliple Sclerosis Flashcards

1
Q

Different Types of Inheritance patterns

A

Mendelian traits:
controlled by a single locus and show simple patterns of inheritance
Also have a dominant/recessive relationship

Incomplete Dominance:
Phenotype is intermediate between the two homozygous phenotype eg dark purple and white become Light purple
Incomplete Penetrnace: Not all genotype express the expected Phenotype

Co-Dominance:
The phenotype of a heterozygote shows the phenotype of BOTH the two homozygotes eg: AB blood group (A and B are co-dominant)

Lethal Alleles:
Cause 100% mortality, If recessive then will be non viable if homozygous. Heterozygotes can be carriers. Dominant lethal alleles are very rare Eg: Huntingtons

Gene Interactions:
The effect of a gene at one locus depends on the effect at another locus

Multifactorial Genetic conditions:
Can be preventable if certain environments are avoided ie Xeroderma pigmentosum should avoid sunlight however huntingtons is unavoidable

Variable expressivity:
not all genotype show phenotype to same level- can be more/ less severe

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2
Q

What is the difference between Qualitative and Quantitative traits?

A

Qualitative Traits:
Involve discontinuous variables having only a few possible values (red/yellow)= these are typically analysed using basic Mendelian principles

Quantitative traits:
traits that vary continuously along a scale ie height, blood pressure
- Can have overlapping phenotype – usually cannot tell genotype by phenotype

Each must be described with a quantitative measure

1 Are polygenic- ie influenced by many genes
2 Arise when environmental factors modify the effects of a gene (a single genotype can then give rise to a range of phenotype)
Ie except for extreme phenotype it is impossible to infer the genotype from the phenotype

Most are both polygenic AND influenced by environment therefore are multifactorial
= many genes and many environmental factors

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3
Q

What are single gene versus multifactorial disorders?

What are gene- gene interactions?

A

Single Gene Disorders:
usually autosomal dominant, recessive, sex-linked or related patterns

Polygenic, complex, Multifactorial:
depend on gene-gene interactions, gene-environment interaction, inheritance often complex and/or uncertain- may be unclear if it occurred spontaneously or if it was inherited
- Strongly influence by effects of other genes or the environment (gene gene interactions or environment interactions)
- Depending on other genetic or environmental factors having a mutation does not always result in disease (incomplete penetrance)
- Inheritance patterns often obscured by variation in lifestyle and environmental factors
- Diet, Drugs, Other

Gene-Gene Interactions:
traits not controlled by a. Single gene, usually polygenic- influenced by genes at multiple locus. Alleles of each gene interact not only with each other but with alleles of genes at other loci.

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4
Q

What is familial inheritance?

How can you determine non-mendelian Inheritance

A

Familial Inheritance

  • Family history is a clear risk factor
  • Mutant genes are usually rare in the general population
  • Usually have a single gene mutation which has strong effects that over-ride other factors
  • Having mutation is associated with high disease risk(high penetrance)
  • Gene Environment interactions usually relatively unimportant due to strong effect of mutant gene

Determining if a non-mendelian characteristic is Genetic
o Twin
o Family
o Adoption studies

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5
Q

What is:

  • Complementary gene action?
  • Duplicate Gene Action?
  • Epistasis?
A

Complementary gene action: Functional copies of two genes are required to produce a dominant phenotype . A defect in either of the two genes results in a mutant phenotype eg Hb

Duplicate Gene Action:
A functional copy of either one of two genes is required to produce a dominant phenotype
- A defect in one of the genes does not result in a mutant phenotype
- A defect in both genes will result in a mutant phenotype’
- The genes have similar functions

Epistasis:
alleles of one gene block the phenotypic expression of a second gene
- Not the same as dominance: dominant alleles mask expression of recessive allele of the same gene
- In Epistasis alleles of one gene effect the alleles of a different gene

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6
Q

What are environmental interactions?

What are mulifactorial diseases?

A

Environment interactions:

  • Environment influences each individuals phenotype, individuals with the same genes may look different
  • Genes can influence the individuals susceptibility to environmental factors: different genes can respond differently to the same environmental conditions

Multi-factorial disorders

  • Most human diseases
  • Influences by the effect of other genes and the environment
  • Depending on the environment or other genes the mutation does not always result in disease
  • Inheritance patterns are often obscure with variation depending on lifestyle
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7
Q
What is:
Autoimmunity?
Tolerance?
Self Tolerance?
Self reactivity?

What factors influence tolerance?

A

Autoimmunity

  • Misdirected immune response that occurs when the immune system attacks itself
  • Is present to some extent in everyone and is usually harmless (ie RBCs)
  • Associated with breakdown in immune tolerance

Tolerance:
State of unresponsiveness that is specific for a particular antigen (protects against autoimmunity)

Self Tolerance:
mechanisms by which the body is prevented from mounting an immune response against its own tissues

Self reactivity:
prevented by processes during development rather than being programmed

Factors influencing tolerance:

  • Molecule structure, stage of differentiation when lymphocyte first encounter the epitopes
  • The site of the encounter
    The nature of the cell presenting the epitopes and the number of responding lymphocytes
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8
Q

What are immunologically privelleged sites
What cells are involved?
What cytokines are involved?

A

Immunologically privileged sites (Antigen segregation)

  • Sites in the body where foreign antigens or tissue grafts do not elicit immune response
  • These antigens do interact with T cells but instead of destructive Immune response they induce tolerance or a response innocent to the tissue
  • Immunosuppressive cytokines such as TGF-beta seem to be responsible for the response

Sites include:
Brain, eye, testis, uterus

  • The sites have specific barrier exclude the immune system (BBB)
  • Extracellular fluid does not pass through conventional lymphatics
  • Surrounded by tissue barriers that exclude naïve T cells
  • Cytokines (TGF-beta) are produced and leave the site together with antigens = tolerance

Expression of apoptosis inducing ligands on tissue cells lead to (FAS-L) induction of apoptosis in FAS expressing auto-reactive t cells

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9
Q

What is ignorance of self antigens?

What is “release of sequestered antigen?”

A

Ignorance of self Antigens is a
Passive form of immunological tolerance that occurs when:

  • T cells can not contact with self-antigens
  • If self antigen is present in too low an amount to be detected
  • If it is present on cells with few or no MHC molecules
  • If there are not enough T cells to respond
  • If there is the absence of co-stimulation

Release of Sequestered Antigen
o Trauma or infection can allow the immune system to access these tissues resulting in autoimmune disease
Trauma can cause compromise of the barrier that usually protects the system from auto-immune response

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10
Q

What are the features of Central tolerance?

A
  • Occurs during lymphocyte development
  • Occurs in the thymus (T cells) and bone marrow (b cells)
  • The immune system generates a large amount of TCRs
  • T cells are effector and regulator cells that become “educated” in the thymus
  • They become dependent on self MHC for survival
    Non-self T cell selection in the thymus (90% of t cells die in the thymus due to errors)
  • T cells are positively and negatively selected in the thymus
  • Positive= selects for t cells capable of interacting with MHC
    Negative = removes thymocytes that are capable of strongly binding with SELF MHC
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11
Q

Peripheral tolerance:

What are the aspects of it?

A

Peripheral Anergy”
is the lack of reaction by the immune system to foreign substances a- direct induction of peripheral lymphocyte tolerance. Immune system is unable to mount a normal immune response against a specific antigen

Regulatory T cells:

  • T suppressor cells suppress the immune response through cytokines and intercellular signals. (IL 10 and TGF-B)
  • They Recognize self-antigens and inhibit activation of CD + tcells in the lymph notes that recognize the same self antigen

Clonal Deletion:
During B cell development the complete antigen receptor IgM is first expressed on immature B cells.
If those cells encounter their target antigen in a form which can cross link their IgM then those cells are programmed to die.
The requirement for crosslinking means that the antigen is polyvalent.
Ie if activated by self antigen then they apoptose.

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12
Q

What is X-Linked Immunodeficiency Syndrome

A
Multiple autoimmune diseases such as
o	Type 1 Diabetes
o	Thyroiditis
o	IBD
o	Atopic dermatitis
 Can cause Fatal infections in infancy
Caused by a mutation in the human FOXP3 gene – controls T-Reg cell function
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13
Q

What are T- Regulatory Cells?

A

o Suppress autoreactive T Cells
o Mediated by specialized T cells that develop in the thymus
o Secrete IL-10 and TGF-Beta when encountering antigen
o Suppress all surrounding autoreactive T –Cells regardless of their antigen specificity

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14
Q

What are the mechanisms for breakdown in Self Tolerance?

A

o Failure to present peripheral antigens in the thymus
o Failure to delete autoreactive lymphocytes (clonal deletion apoptosis)
o Release of sequestered antigen (ie damage to the privellaged areas that results in the self antigen not being recognised by the rest of the immune system
o Cross-reactive antigens
o Abnormal antigen presentation
o Reduced suppressor activity (T-Regs, TH2)
o TH1 and TH17 cells are crucial in the effector pahse of autoimmune disease

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15
Q

Summary of the layers of self tolerance

A

Central tolerance:
deletion and editing in the thymus or bone marrow

Antigen segregation:
physical barrier such as BBB- no lymphoid access in peripheral orgeans

Peripheral anergy:
cellular inactivation by weak signaling without co-stimulation- occurs in secondary lymphoid tissue

Regulatory cells:
suppression by cytokines, intercellular signals in secondary lymphoid tissue and sites of inflammation

Clonal deviation:
apoptosis post activation of cells- secondary lymphoid tissue and sites of inflammation

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16
Q

Types of Hypersensitivity

A
  1. Anaphylaxis- Allergy (IgE)
  2. Antibody mediated (IgG)
  3. Immune complex (IgG)
    ( The antibody reacts with antigen, complex is so small it does not get cleared and hangs around in the vascular system, Causes more and more antibodies bind to it)
  4. Cell mediated- (cytotoxic T cell) or delayed sensitivity (Th1 and Th2 cell mediated)
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17
Q

Pathophysiology of MS- autoimmunity

A

o T cell mediated
Destructive immune response against brain antigens (usually an immune privellaged zone)
o Unknown trigger sets up initial focus of inflammation in brain (possible infection producing cross reactivity when there is a secondary traumatic event)
o Blood brain barrier becomes locally permeable to leukocytes and blood proteins
o T- cells specific for CNS antigen and activated in peripheral tissues reencounter antigen presented on microglia or dendritic cells in the brain
o Inflammatory reaction in brain due to:
• mast cell-activation
• complement activation
• cytokines
Demyelination of neurons = no more insulation = short circuiting = abnormal neuronal response

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18
Q

What is involved in Abnormal Antigen Presentation?

A
  • IN normal people only Macrophages, dendritic cells and B cells can express MHC II antigens
  • In some diabetic patients MHC II molecules are expressed on pancreatic islet cells
  • MHC expressing pancreatic cells can reactivate microbe specific helper t cells
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19
Q

Polymyositis

A
Neurological features:
-	Weakness
-	Muscle wasting
-	Muscle tenderness- moderate
Laboratory Findings:
-	Creatine Kinase elevation
-	ESR elevation
-	EMG- characteristic myopathic pain
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20
Q

Myasthenia Gravis

A

Myasthenia Gravis- Cardinal Features

Neurological Features

  • Fatiguable weakness ie may see ptosis
  • Circadian pattern of weakness
  • NO muscle wasting

Laboratory Features

  • EMG response- decremental
  • Tensilon (edrophonim) test is positive
  • Anti-Acetylcholine receptor AB positive

Pathophysiology:
In Myasthenia Gravis: the AcH receptors are blocked by ach antibody or internalized and degraded. This results in impaired muscle contraction

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21
Q

What is the Neuromuscular Junction?

Also How do you test its function?

A

Neuromuscular junction:

  • The area that a motor neuron transmits a signal to a muscle fibre causing contraction
  • Vesicles near the border contain AcH- the neurotransmitter that sends the signal that activates muscle contraction
  • When nerve is stimulated the vesicles attach to the plasma membrane
  • Release the NT into the synaptic cleft (narrow point between peripheral nerve and muscle)
  • AcH activates receptors on the muscle side of the neuromuscular junction
  • Activation causes Sodium influx and Potassium Efflux- resulting in an Action Potential

Tests for Neuromuscular junction: Repetitive nerve stimulation. In MG= there is a lesser and lesser response to repetitive stimulus

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22
Q

Signs of peripheral Neuropahty

Motor and sensory

A
Motor Features:
-	Weakness (distal> proximal)
If weakness was more proximal you should suspect a myopathic cause
-	Atrophy
-	HypOreflexia
Sensory Features
-	Hypaesthesia/anaesthesia
-	Hyporeflexia/Areflexia
-       Sensory Ataxia/Imbalance
     Will have feet wide apart to 
     balance
-    Trophic Changes 
      Skin atrophy, lose hair growth, dry and fragile skin
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23
Q

Features of Guillain-Barre Syndrome

A

Autoimmune disorder that Causes peripheral nervous system demyelination
Sometimes causes long term neurodegenerative changes

Features:

  • Predominantly a motor neuropathy
  • Sub acute ascending paralysis (onset is days to weeks)
  • Hyporeflexia/Areflexia

Autonomic Features

  • Cardiac arrhythmias
  • CP instability

Sensory features (uncommon)

  • Parasthesiae
  • Back pain
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24
Q

Diagnositic features of Guillain-Barre Syndrome

A

Guillain-Barre Diagnostic features

  • Cerebrospinal fluid = Cyto-albuminemic dissociation
    (rise in protein but not in
    cells in the CSF)
  • Nerve conduction studies = Motor conduction slowing

Causative organism = campylobacter jejuni (50% of people)

Immune response causes Mimicry to myelin

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25
Q

Features of Myelopathy (Pathology of the spinal cord)

A
Motor Features
-	Weakness : LMN and UMR characteristics
-	Below the lesion: 
o	Spasticity
o	hypER reflexia 
o	Bladder/sexual function disinhibition

Sensory Features
- Hypaesthesia/anaesthesia

Autonomic Features
- Disinhibited/uncontrolled reactivity

26
Q

Brain Stem Encephalopathy

- cardinal features

A
Brainstem Encephalopathy 
Cardinal Features
-	Cranial nerve dysfunction 
o	Oculomotor dysfunction 
o	Facial sensory loss
o	Facial weakness
o	Dysphagia 
o	Neck, Shoulder Weakness
  • Ataxia/incoordination

Spinal cord features

27
Q

Encephalopathy- Cardinal Features

A
  • Disordered higher function
    o Drowsiness
    o Impaired attention
    o Impaired control of thinking
  • Cognitive dysfunction
    o Dysphagia
    o Dyspraxia
    o Spatial Disorientation
28
Q

What is MS and what are the amin features?

A

Auto-immune disorder which causes Central Nervous System Demyelination
May result in long term neurodegenerative changes
Cardinal Clinical Features
o Brain Dysfunction – various cognitive disturbances
o Cranial Nerve Dysfunction
• Optic Neuritis (often first presentation 40%)
o Brainstem dysfunction
• Oculomotor dysfunction and ataxia (20%)
o Spinal Cord Dysfunction (30%)
• Urinary Incontinence (rarely the first symptom), Sexual Dysfunction
• Weakness, Sensory Loss
o Other symptoms (10%)
Paroxysmal stiffness, spasm, bladder, cognitions, trigeminal neuralgia

29
Q

What are the cardinal DIAGNOSTIC SIGNS

A
Compatible history
•	Multiple episodes at multiple sites
Cerebrospinal fluid (LP)
•	Evidence of Ab formation in the CNS
•	Elevated IgG ratio/index
•	Oligoclonal bands (not specific)
•	=/- Lymphocytosis
•	Myelin Basic Protein > 4 ng/ml
Evoked Potentials
•	Slowing of central conduction (visual, auditory, somatosensory)
Brain Imaging
•	Inflammation
Neuronal loss
30
Q

What is the McDonald Criteria>

A

( > 2 attacks and clinical evidence of > 2 lesions)
- Requires 2 attacks separated by at least 30 days
OR
- MRI evidence of lesions at 2 classical differing MS locations
o Periventricular (fingers sign)
o Juxtacortical
o Infratentorial
o Spinal Cord
Investigations: Gold standard = MRI
Additional: Visual evoked potentials, lumbar puncture, blood tests to exclude other causes

31
Q

Types of MS

A

Relapsing Remitting (most common)

  • Good response to steroids
  • Can have Full recovery between episodes

Primary Progressive (15-20% of people)

  • Progressive deterioration without relapses or remissions
  • Does not respond to current treatments

Secondary Progressive (90% after 25 years)

  • Begins as relapsing remitting
  • Deterioration with or without relapses
32
Q

MS Pathophysiology and Pathology

A

Multiple Sclerosis Pathophysiology
- Not well understood however there may be a role of EBV in activating the self reactive T- Cells
- Initiated by CD4+ T cells that react against self myelin antigens and secrete cytokines
- Macrophages and leucocytes are activated
- The demyelination is caused by the activated cells against the antigens
- The Infiltrate in plaques and surrounding regions of the brain consists of T cells (mainly CD 4 and some CD 8) and macrophages
Pathology
- Variable and changes over the course of the disease
- In early stages pathology is focal areas of inflammatory demyelination and nerve fibre loss
New plaques are usually asymptomatic in parts of the brain with no symptoms

33
Q

MS Histology

A

Multiple Sclerosis HISTOpathology

  • Preivenous mononuclear inflammation
    (Lymphocytes, plasma cells and macrophages)
  • Loss of myelin and variable loss of oligodendrocytes
  • Relative preservation of axons
    Reactive astrogliosis (sclerosis)
34
Q

Drug Treatment for MS

A
  • Depends on the phase and clinical activity of the disease, individual patient considerations, the practicalities of drug administration including the cost
    Acute symptoms/flare ups
  • High dose IV corticosteroids
  • Plasmopharesis- rarely used for disease unresponsive to steroids
    Prevent relapse/slow disease progression
  • Immune-modulators are seen as first line treatment- Beta Interferons 1b and 1a
    Immuno-suppressants are considered as second line agents
35
Q

Interferon Beta Ia and 1b

A

o Indicated for relapsing remitting MS
o Now may also be used for first demyelinating event
o Reduces the frequency of relapses and slow the progression of disability, unsafe in pregnancy
o Given by injection
o Reduces inflammation by:
• Reducing the production of TNFa and T cells
• Switching cytokine production from proinflammatory cells to anti-inflammatory cells
• Decreasing antigen presentation and thereby reducing the attack on myelin
• Reducing the ability of immune cells to cross the blood brain barrier

36
Q

What causes optic Neuritis?

A

Autoimmunity targeting Aquaporin 4- this is a protein associated with the astrocytic feet of the blood brain barrier

37
Q
What are the similarities between hormones and Neurotransmitters 
eg onset
duration
site of action
receptors
A

What is similar between Hormones and NT?

  • Both hormone and NT are chemical signals that the body uses to control function or send signals
  • They are both very diverse

What is different?

-Onset =
Hormones are SLOW Nerves = RAPID

Duration=
Hormones are PROLONGED
Nerves = BRIEF (as long as the neural discharge)

Site of Action =
Hormones are GENERALISED Nerve = Limited to area of INNERVATION

o Hormones = transported by blood to distant site = endocrine
o Neurons= communicate to adjacent cells = paracrine

Receptors :

o NT : on the membrane and linked to intracellular second messengers

o Hormones: on the membrane or INSIDE target cell. Linked to 2nd messengers

38
Q

Where are hormone secreting cells located?

A

Hormone secreting cells:

  • Clusters of specialized cells in specialized endocrine glands
    EG thyroid gland
  • Clusters of specialized cells embedded within other organs and tissues
    EG Gastrin cells in the stomach
39
Q

What travels faster?
myelinated or non myelinated?
Larger diameter or smaller?

A

Myelinated and larger diameter

40
Q

How are water soluble versus fat soluble hormones transported?

A

Water soluable hormones
- Travel in solution in plasma

Non water soluble hormones

  • Are bound to plasma proteins.
  • Small amounts are free.
  • The free form is the biologically active form
41
Q

Adrenocorticotrophic hormone

- how is it released and what does it do?

A

Adrenocorticotrophic hormone

  • Hypothalamus releases corticotropin releasing factor
  • Picked up by portal system and transported to anterior hypophysis
  • ATCH is released
  • This is released into blood and travels to adrenal gland
  • Stimulates release of cortico-steroids- particularly cortisol
  • Uses of cortisol

o Metabolism of glucose, fats and proteins
o Anti-inflammatory
Na/K excretion in the kidney

42
Q

Thyroid stimulating hormone

how is it released and what does it do?

A
  • Hypothalamus releases thyroid releasing hormone
  • Binds to TRH receptor on Thyrotroph cell in the anterior pituitary
  • Causes release of thyroid stimulating hormone into portal vein
  • Acts on thyroid gland to Cause release of Thyroxine (T4) and tri-iodthyronine (T3)
    (Synthesised from the amino acid-thyrosine)
  • Transported in the blood freely or protein bound
  • Uses:

o Increases basal metabolic rate
o Act in multiple organs at multiple cell types via selective receptors in nucleus
o Control growth, protein, fat and carb metabolism
o Involved in maturation of CNS in childhood

  • Negative feedback occurs when TSH is released (feedback to hypothalamus to stop TRH)
    When T3 or T4 released they inhibit hypothalamus and also pituitary secretion of TSH
43
Q

Growth Hormone

where is it released and what does it do?

A

Growth Hormone

  • Hypothalamus releases growth hormone releasing hormone
  • Causes release of GH
  • Acts on bones and muscles
  • Uses: facilitates anabolic growth
44
Q

Prolactin- where is it released and what does it do?

A
Prolactin hormone
-	Hypothalamus releases Dopamine 
-	Prolactin is then stimulated 
-	Acts on mammary gland 
Used for lactation
45
Q

FSH and LH

how are they released and what do they do?

A
  • Hypothalamus releases Gonadotropin releasing hormone

-FSH
o Acts on ovaries
o Maturation of follicles

-	LH
o	Acts on both ovaries and 
testes
o	Ovulation 
o	Levels of testosterone
46
Q

Melatonin Stimulating hormone

- where is it released and what are its uses?

A
Melatonin stimulating hormone
-	Hypothalamus releases Melanocyte hormone releasing factor
-	Acts on skin and hair
-	Uses
o	Synthesis and release of melanin
47
Q
Melatonin stimulating hormone
-	Hypothalamus releases Melanocyte hormone releasing factor
-	Acts on skin and hair
-	Uses
o	Synthesis and release of melanin
A

• Receives sensory infomraiton from peripheral sites
• Receives afferent information from other palces in the CNS
• Can register the temperature of the blood
• Detects chemical changes in the blood including:
o Blood glucose level
o Blood osmolarity
o Leptin levels

48
Q

Difference between and examples of Fast and slow neurotransmitters

A

Neurotransmitters are released by presynaptic terminals and produce rapid or inhibitory responses in the post synaptic neurons

Fast
o Operate through ligand gated ion channels
o Eg GABA and Glutamate

Slow / neuromodulators
o G-protein coupled receptors
Eg Dopamine, neuropeptides

49
Q

life cycle of a neurotransmitter

A
  1. Uptake of precursor
  2. Synthesis of transmitter
  3. Storage of transmitter in a vesicle
  4. Degradation of any surplus transmitter
  5. Depolarisation by propagated action potential
  6. Influx of calcium in response to depolarisation
  7. Release of transmitter by exocytosis
  8. Diffusion to postsynaptic membrane
  9. Interaction with postsynaptic receptors
  10. Inactivation of transmitter
  11. Reuptake of transmitter or degradation products
  12. Uptake of transmitter by non neuronal cells
    Interaction with presynaptic receptors
50
Q

What is the Action of Glutamate?

what are the glutamate receptors?

A

o Major excitatory amino acid in the CNS
o Widely and uniformly distributed in the CNS
o it has a modulatory influence on the CNS systems neuronal connections
o facilitation of learning and memory
o synaptic plasticity (long term potentiation or LTP)
o The brain is vulnerable to glutamate mediated over excitation
o This results in excitotoxicity and death of neurons
o Implicated in the development of epilepsy
Glutamate receptors
- NMDA (N-Methyl- D aspartate)
- AMPA (alpha- amino-3-hydroxy-5-methyl-isoxazole)
- Kainate
GPCR or metabotropic

51
Q

Drugs acting on Glutamate receptors?

what is a limitation to using NMDR antagonists?

A

NMDR antagonists

  • Ketamine (analgesia, anaesthesia)
  • Memantine (alzeimers disease)

Serious limitation to using the NMDR antagonists = psychosis
NMDAR implicated in schizophrenia

52
Q

What is the function of GABA?

What are the types of GABA receptors?

A
  • Present in all areas of the CNS
  • The most Important INHIBITORY Neurotransmitter
  • Glycine is also important in the spinal cord and brainstem
  • Formed from glutamate by the action of the glutamic acid decarboxylase (GAD)
  • Action is terminated by REUPTAKE into neurons and glia

Receptors =
GABA A, GABA b, GABA c

o GABA A = chloride ion channel
o GABA B = GPCR
GABA C = Ligand gated ion changes

53
Q

GABA A rececptors:

  • what is the structure?
  • what are the binding sites?
  • What are the examples for agonists and antagonists?
A
  • GABA a receptors are pentomers composed of 5 subunits associated with a chloride channel
  • Several Binding sites:

o The GABA binding site
o Benzodiazepine binding site
o Barbituate binding site

  • Activation of the benzo or barbiturate binding site enhances the GABA mediated inhibition in the CNS
  • Agonists of the benzodiazepine site (for anxiety, insomnia, muscle spasm and epilepsy)
    o Diazepam
  • Antagonists
    o Flumazenil
54
Q

What kind of GABA drugs do we use for seizures?

A
  • Benzodiazepines
  • Valproate
    o Increases glutamic acid decarboxylase which incrase synthesis of GABA
    o Inhibits activity of enzymes that degrade GABA
  • Gabapentin
    o Enghances Gaba release
  • Vigabatrin
    o Inhibits GABA transaminase which degrades GABA
  • Tiagabine
    o Gaba uptake inhibitor
  • Topiramate
    Blocks NA channels and blocks reuptake so enhances GABA activity
55
Q

What effect does GABA have on other neuro systems?

A
  • Inhibition of dopamine system
    = Muscle relaxation and decreased movements
  • Inhibition of 5 HT system
    = Decreased Anxiety
  • Inhibition of Noradrenergic system
    = Decreased anxiety
56
Q

Amine Transmitters- Noradrenaline

What kind of receptors does it use?

What is the NT important for?

What are some drugs that effect Noradrenaline and how to they work?

A

Receptors: alpha and beta receptors ( GPCR)

Important for :

  • Arousal
  • Blood pressure regulation
  • Control of mood

Antidepressants and cocaine act by : blocking noradrenaline reuptake

Amphetamines cause noradrenaline release from vescicles

Noradrenaline antidepressants

  • Tricyclic antidepressants
  • Monoamine oxidase inhibitors (enzyme that breaks down NA)
  • Noradrenaline serotonin reuptake inhibitors
  • Selective Serotonin reuptake inhibitors
57
Q

Amine Transmitters- Acetylcholine

What kind of receptors does it use?

What is the NT important for?

What are some drugs that effect NAcH and how to they work?

A

Receptors: Mainly Excitatory

  • Nicotinic = ligand gated ion channels (presynaptic and facilitate release of other NT)
  • Muscarinic = GPCR M1-M5. M1 is main one in brain
Important for : 
-	Arousal
-	Learning and short term memory 
-	Motor control
Druga that affect ACH:
-	Muscarinic antagonists = used to treat tremors in Parkinson’s (Benztropine)
-	Anticholinesterases = used in Alzheimer’s disease to assist with memory
Hyoscine- M1 receptor
58
Q

Amine Transmitter - Serotonin 5HT

What kind of receptors does it use?

What is the NT important for?

What are some drugs that effect Serotonin and how to they work?

A

Receptors: 14 subtypes

All are GPCR except 5HT3 which is ION channel

  • Main receptors are : 5HT1a, 5HT1b, 5HT2, 5HT3

Important for:

  • Control of mood and emotion
  • Sensory function
  • Behaviours and vomiting
    Drugs that affect serotonin
  • Nausea and vomiting = ondansetron = 5HT3 antagonist
  • Anxiety – SSRI and Buspiron (5HT1a agonists)
  • Migrane – Triptans = agonist for vascular 5HT1D, 5HT1B and 1F
    Schizophrenia – atypical antipsychotics: 5HT2 antagonists and D2 dopamine antagonist
59
Q

Amine Transmitter - Dopamine

What kind of receptors does it use?

What is the NT important for?

What are some drugs that effect Dopamine and how to they work?

A

Receptors: ALL GPCR
- D1 (D1 and D5)
- D2 (D2-4)
Functional Pathways
- Nigrostriatal = motor control
- Mesolimbic/mesocortical = emotional and drug reward systems
- Tuberohypophyseal = regulation of prolactin release
Drugs that effect Dopamine
- Schizophrenia = haloperidol and clozapine are D2 Antagonists
- Vomiting = dopamine acts on chemoreceptor trigger zone to cause vomiting ( metaclopromide is a D2 antagonist)
Parkinsons = associated with deficiency of dopaminergic neurons – levodopa is a receptor agonist

60
Q

Is the metabolic rate of neurons high or low?

why?

A

Neurons have a relatively high metabolic rate

Require high ATP due to lack of glucose storage

61
Q

If blood pressure changed drastically ie more than 80mmhg, what would happen to the CSF?
why?

A
  • Autoregulation means that CBF stays regular even with a marked change in blood pressure