Block 1 Combo set_3rd one
Give an overview of neuronal regeneration (4).
-Axonal sprouting can occur within 24 hours of injury -All sprouts are unmyelinated to begin with -If the sprouts manage to make distal connections then nerve fibre maturation occurs, with an increase in axon and myelin thickness -Neurites which fail to make distant connections die back and are lost to the regenerative process
Describe the etiology of peripheral nerve injuries (3).
-Can be due to metabolic, collagen disease, malignancy, toxins, thermal or mechanical injury -Mechanical causes producing primary injury include compression, laceration, fracture, fracture manipulation, gunshot wound -Secondary injury can be due to infection, scarring, callus, vascular complications, eg. aneurysm, ischemia
What are the limiting factors of neuronal regeneration?
-Capacity of neurons and Schwann cells to support regeneration declines with time and distance -The critical gap width over which this does not occur is 2mm
Describe the timeline and process of Wallerian degeneration (8).
-Commences two to three days after injury -The distal segment begins to fragment -Activation of Schwann cells close to the injury site: De-differentiation, down regulation of myelin genes, up-regulation of regeneration associated genes (RAGs) -By three days macrophages infiltrate the distal nerve stump to remove the majority of myelin debris; they remain for about one month -By seven days the Schwann cells are mitosing and phagocytosing cellular and myelin debris -By 25 to 30 days the axonal debris is cleared -Schwann cells surround the empty endoneurial tubes forming the 'bands of von Bungner' -The bands guide and support axons which regenerate from the proximal nerve stump into and through the endoneurial tubes of the distal nerve stumps to promote regeneration.
How does the structure of the neurons in the CNS factor into the lack of regeneration of injured neurons in the CNS (2)?
-Connective tissue structures such as endoneural, perineural and epineural sheaths are not present in CNS to provide guidance to target -Denervated oligodendrocytes do not dedifferentiate and fail to form Bands of Bungner
What are the chromatolytic changes seen in the cell body of a neuron whose axon has been damaged (3)?
-Dispersion of Nissl bodies to the outer side of the nuclear membrane and to the perimeter of the cytoplasm -Movement of the nucleus to an eccentric position within the cell body -Often a swollen appearance to the cell body
Neurons rely on chemical signals from their targets for continued existence. What is the significance of these signals (3)?
-Growth factors released by target normally bind to receptors on nerve terminal, get internalized and transported retrogradely to nucleus. -Following axotomy, this signal is not present, and gene transcription in the nucleus is altered -Responses of mature neurons to injury are similar in many ways to the growth of neurons during development
How do CNS injuries compare to PNS injuries (3)?
-Neuronal regeneration is minimal in the CNS -CNS axons undergo Wallerian degeneration at the same rate as PNS -CNS neurons DO NOT usually up-regulate RAGs (regeneration associated genes) to support regeneration: Many CNS neurons have long collateral branches which may still be in contact with targets
List the oligodendrocyte-derived myelin-associated inhibitors (3).
-Nogo -Myelin-associated glycoprotein (MAG) -Oligodendrocyte-myelin glycoprotein (OMgp)
Image of the steps in neuronal regeneration.
-Panel one shows the neuron before injury -Panel two shows the injury to the axon -Panel three depicts the chromatolysis in the cell body of the neuron, neurites sprouting from the severed axon and the denervation of the effector -Panel four depicts neurites who have failed to make a connection degenerating and the axon regenerating -Panel five depicts the intact neuron, with re-innervation of the effector and the disappearance of chromatolysis
What are the three things that happen after an axon is cut?
-Retraction -Inflammation: Expression of cytokines -Degeneration
What are the changes seen in the cell body during retrograde degeneration (3)?
-Swelling -Migration of nucleus to periphery of soma -Chromatolysis (basophilia): Reorganization of chromatin in nucleus; thought to be the basis for changes in mRNA synthesis concurrent with conversion of neuron from "transmitting" to "growth" mode
Give Symptoms of Parkinsons.
5 Stages, ranging from Unilateral blanks face and semi-flexed arm with tremor to stage 5 complete Invalidism.
Parkinson's Drug Class: Entacapone
A COMT inhibitor.
Parkinson's Drug Class: Tolcapone
A COMT inhibitor.
Parkinson's Drug Class: Carbidopa.
A Dopa decarboxylase inhibitor. Given synergistically with Levodopa.
Parkinson's Drug Class: Levodopa.
A Dopamine Prodrug. Gold Standard, particulary with Carbodopa. This is rapidly converted to Dopamine by Dopa Decarboxylase. (important)
What is Mesenchyme?
A general purpose scaffolding tissue, which performs many functions. It is constantly forming through embryology.
Sum up the derivatives of the Pharyngeal Arches.
A good study guide.
What is the endoneurium of a peripheral nerve?
A layer of delicate connective tissue that encloses the myelin sheath of a nerve fiber within a fasciculus.
Drug Class: Riluzole
ALS Disease.
Parkinson's Drug Class: Benztropine
Acetylcholine Inhibitors.
Parkinson's Drug Class: Biperiden
Acetylcholine Inhibitors.
Parkinson's Drug Class: Orphenadrine
Acetylcholine Inhibitors.
Parkinson's Drug Class: Procyclidine
Acetylcholine Inhibitors.
Parkinson's Drug Class: Trihexyphenidyl
Acetylcholine Inhibitors.
Give some Key Points about ALS.
Amyotrophic Lateral Sclerosis is also known as Lou Gehrig's disease, and has unknown cause. Only 10% of patients survive 10 years. Riluzole is the only treatment, which prolongs survival by several months.
Give some Side effects for L-Dopa, which are generally reduced by Carbidopa.
Anorexia, vomiting, nausea. Dyskinesias, Tachycardia, A-Fib, Postural Hypertension. Behavioral Effects: Depression, Anxiety, Insomnia, Confusion
What is the fate of the part of the axon distal to a lesion?
Any part of a neuron detached from its nucleus degenerates. The resulting mess is cleaned up by phagocytosis.
What are Neural Crest Cells?
Appearing at the end of Neurulation, the Neural Crest Cells form from Neurectoderm and can later become Neural Crest Mesenchyme.
Give some Key Points about Huntington's Disease.
Autosomal Dominant caused by repeating sequence, primarily adult onset. The Striatum and Cortex are most affected causing Chorea, Cognitive Impairment, and Metabolic Abnormalities. There is no real cure, but some symptoms can be mitigated.
What is COMT?
Catechol-o-methyltransferase is the enzyme that degrades Dopamine. Inhibiting it increases dopamine, making it a decent drug for Parkinsons. MAO-B also degrades dopamine.
What are the two components of the Striatum?
Caudate Nucleus and Globus Pallidus.
What are Craniosyntosis?
Congenital Defects caused by premature closure of sutures.
What is Wallerian (or secondary) degeneration?
Degeneration distal to the point of injury. The fundamental concept of Wallerian degeneration is that survival of nerve fibres occurs only if they remain connected to the cell body.
How is neuronal degeneration in the CNS different from in the PNS?
Degeneration of oligodendrocyte myelin takes much longer than for Schwann cells. Myelin is associated with inhibitors of axonal regeneration and promotes the proliferation of astrocytes, which produces a "glial scar," which creates further physical and chemical barriers.
What is retrograde (or primary or traumatic) degeneration?
Degeneration proximal to the point of detachment.
Parkinson's Drug Class: Bromocriptine
Direct Dopamine agonists, Ergot Derived.
Parkinson's Drug Class: Pergolide
Direct Dopamine agonists, Ergot Derived.
Parkinson's Drug Class: Pramipexole
Direct Dopamine agonists, Non-Ergot.
Parkinson's Drug Class: Ropinirole
Direct Dopamine agonists, Non-Ergot.
Parkinson's Drug Class: Apomorphine
Direct Dopamine agonists.
Huntington's Disease Drug Class: Butyrophenones
Dopamine Receptor Antagonists.
Huntington's Disease Drug Class: Phenothiazines
Dopamine Receptor Antagonists.
When does the Pharyngeal Apparatus region first become identifiable?
During Embryonic Folding. It is located near the Head Fold.
Describe the Second Part of Palatogenesis.
Good Study aid.
Where is dopamine produced in the brain?
In the Pars Compacta of the Substania Nigra.
Parkinson's Drug Class: Amantadine
Indirect Dopamine agonist. Unknown mechanism to increase release and reduce reuptake.
Contrast the Direct and Indirect Pathways.
Indirect pathway is significantly slower, because it has a detour through the Globus Pallidus Externa and the Subthalamic Nucleus. Indirect pathway produces inhibition of the Motor Cortex, while the Direct Pathway is excitatory.
Give some key points about L-Dopa.
It can cross the BBB, unlike Dopamine, and is then converted to Dopamine by Dopa-Decarboxylase. Given orally, with a half like of about 2 hours, this is the Gold Standard for Parkinson's. Only 1-3% goes to brain. HVA and DOPAC are the metabolites, found in the urine. 1/3 of people respond well, but tolerance develops.
What is the purpose of Carbidopa?
It prevents the action of Dopa-Decarboxylase in the systemic circulation, allowing more unconverted L-Dopa to cross the BBB. Carbidopa itself cannot cross the BBB.
What is a mnemonic to differentiate MAO-A from MAO-B?
MAO-A breaks down Adrenaline (Norepinephrine). MAO-B breaks down Dopamine.
Parkinson's Drug Class: Rasagiline
MAOI.
Parkinson's Drug Class: Selegiline
MAOI.
Describe the neuronal organization of fine motor control (e.g., hands,eyes).
Many motor neurons with only a few branches each, reaching a small number of muscle fibers allows for fine gradations in force.
Contrast Meckels Cartilage and Reichert Cartilage.
Meckel Cartilage is from the first arch and forms the Malleus and Incus. Reichert Cartilage is from the second arches
Huntington's Disease Drug Class: Reserpine
Monoamine Depleters.
Huntington's Disease Drug Class: Tetrabenazine
Monoamine Depleters.
What is important to note about motor neurons and their targets?
Motor neurons branch only at the end of the myelin sheath, near their target muscle.
What are some complications of damage to motor neurons (3)?
Motor neurons may: -Grow back to the wrong target -Branch to innervate opposing targets -Regenerated axons may become myelinated, smaller in diameter and more numerous
What are some contraindications for L-dopa?
do not give to psychotic patients, patients with angle closure glaucoma (increases intraocular pressure), or patients with active peptic ulcers. Never give with MAOI.
How far does retrograde degeneration reach?
Only as far as the next proximal Node of Ranvier.
Which Drugs can cause Parkinson's?
Reserpine, Tetrabenazine, Haloperidol, Phenothiazine, and MPTP. Basically the Huntington's drugs.
Which drugs should not be given with MAOIs?
Should not be taken with patients on Meperidine, Tricyclic agents or Serotonin Reuptake inhibitors or in combination with nonspecific MAO inhibitors. Patient can die.
Give some Side effects for Ergot Derived Direct Dopa Antagonists.
Similar to L-Dopa. these are D2 agonists that cause Ergot Symptoms: Seizures and Dry Gangrene.
What does PP1 make? PP2? PP3?
The IAM. PP2 forms the Tonsillar sinus and Sinus epithelium. PP3 forms the Thymus. PP3 and PP4 make the Parathyroid Glands.
What Prominences does the First Pharyngeal Arch grow at about 32 days?
The Maxillary and Mandibular Prominences.
Describe Palatogenesis.
The Medial Palatine process grows from the Median Intermaxillary Process which grows from the fusion of Median Nasal processes. The Lateral Palatine process goes inward from the Internal Maxillary Prominence. These fuse to form the Median Palatine Raphe.
What is the most important and well described loop that is controlled within the Basal Ganglia?
The Motor Loop, which pertains to coordination and learning of motor skills. Outputs from the Basal Ganglia arrive at the Cortex via the Thalamus. It is a loop because the Cortex can excite the Striatum.
What are the first Arch muscles.
The Muscles of Mastication are derived from the first arch (Orange). Red is the 2nd arch.
Contrast Pharyngeal Grooves and Pouches, when they first appear in the 4-week embryo.
The Pharyngeal Grooves run between the Pharyngeal Arches in the lumen of the mouth, while the Pharyngeal Pouches jut toward the grooves but from the inside. PM is the Pharyngeal Membrane.
What are the two components of the Lenticulate Nucleus?
The Putamen and Globus Pallidus. It looks lens shaped and that is what lentiform means.
What is the only excitatory neuron in the Direct and Indirect pathway?
The Subthalamic Nucleus is inhibitory to the Globus Pallidus Interna and Substantia Nigra. This is on the Indirect pathway. All neurons of the Direct pathway are excitatory.
What is the consequence of damage to the dendrites?
The cell may recover, but it depends on the extent of the damage.
What is the consequence of damage to the soma?
The cell will die due to the influx of sodium and calcium.
What is the consequence of damage to the axon?
The cell will probably recover, but the axon may or may not re-innervate the same target.
Contrast Direct Dopamine Agonists with L-Dopa.
The do not need enzymatic conversion, and cross the BBB without competing with Amino Acids.
When do the four Pharyngeal Arches from?
The first Arch is made on the 24th day and the fourth on the 28th.
What does PG1 become? PM1?
The first Pharyngeal groove becomes the EAM. The first Pharyngeal Membrane becomes the Tympanic Membrane
What is Neurulation?
The formation of the Neural Groove which becomes the Neural Tub, from the Ectoderm.
What determines the success of neuronal regeneration?
The perineurium: -If the perineurium is not disrupted then the axons will be guided along their original pathway (1-3 mm/day) -If the perineurium is disrupted there are neurotrophic substances (NGF - nerve growth factor) from fibroblasts and Schwann cells in distal nerve stump which attract the neurites to distal tissue
What is Gastrulation?
The process by which three layers are formed.
Describe the neuronal organization of coarse motor control (e.g., quadruceps).
There are fewer motor neurons innervating more muscle fibers, which allows for greater coordinated force.
How does retrograde degeneration compare histologically with Wallerian degeneration?
They are identical.
What are neuromas?
They form when neurites migrate aimlessly across a large gap. They can be stump neuromas or neuromas in continuity.
Why are peripheral motor and sensory neurons so susceptible to damage by compression or transection?
They have long axons.
During regeneration, not all axons reach their target. What is the consequence of this?
Those which do regenerate must branch more extensively to innervate all muscle fibers. Fine motor control is lost or reduced.
Drug Class: Fluphenazine
Tourette's Disease Drug.
Drug Class: Haloperidol
Tourette's Disease Drug.
Drug Class: Pimozide
Tourette's Disease Drug.
What Cranial Nerves are formed from Pharyngeal arches?
V2,V3, VII, IX, and X.
What does the prospect of recovery from a peripheral nerve injury depend on?
Where the damage occurred. The more proximal the lesion, the more incomplete the recovery.
Is there Endoderm in the Pharyngeal Apparatus?
Yes. Mesoderm forms the connective tissue of the head. Neural Crest cells, a type of Ectoderm, form the Cranial Nerves and Ganglia. The Neural Tube, also Ectoderm, gives rise to the Pharyngeal Arch cartilages. Endoderm gives rise to the Pharyngeal Pouches, which become the Pharynx.
Give representative examples of Hyperkinetic and Hypokinetic Disorders.
Hyperkinetic Disorders include Hemiballism and Huntington's Disease. Hypokinetic Disorders include Parkinsons.
Contrast Huntington's Disease and Parkinson's disease cause.
In Parkinsons, dopaminergic neurons are not functioning so inhibition of the GABAergic neurons is lost. In Huntington's the GABA neurons are themselves lost.
What can lead to good functional recovery after a peripheral nerve injury?
In a peripheral nerve with many fascicles (i.e. separate bundles of axons ensheathed in perineurium), good functional recovery is more likely when the lesion does not disrupt the perineurium and epineurium. If those layers are disrupted - for example if the nerve is severed - recovery is better if the fascicles proximal and distal to the cut are correctly aligned when the nerve is repaired surgically.
