Injury/regeneration and brain cell death Flashcards
2 types of injury to nerve cells
- Axon damage
- Neuron loss
when axotomy occurs where is function lost?
distal to the cut => toward the axon terminal
what happens with Schwann cells when axonomy occurs?
the cells will start to chew up the myelin they made and incorporate macrophages
what happens with oligodendrocytes when axotomy occurs?
they will more slowly break up and astrocytes will help w/ this ⇒ end seals
what happens with ions when axotomy occurs?
K+ leaks out of cell and Na+/Ca++ leaks into cell within seconds
how long does it take for proximal and distal axon segments to reseal away from cut ends?
2 hours
spinal cord injury (SCI)
loss of sensation + muscle paralysis below the level of injury
- Can be partial or complete
- Probably wont die
Peripheral nerve injury (PNI)
loss of sensation and paralysis in region served by injured nerve
- Nerve may die
what is another name for anterograde effects?
wallerian degeneration
what end is anterograde?
axon terminal end
what are anterograde effects? (5)
- Axon swells ⇒ w/in 2 hours
- Axonal membrane fragments ⇒ w/in 3 days
- Myelin fragments over the dead axon ⇒ w/in 1 week
- Astrocytes (CNS) or schwann cells (PNS) proliferate ⇒ 1-4 weeks
- Glia and microglia phagocytose debris ⇒ 1 month PNS and 3 months CNS
transneural effects
without innervation downstream neurons die
- the effect is reduced by presence of other connections and increased age
- Muscle atrophy if their innervation is lost
as motor axons degenerate what happens spontaneously?
spontaneous action potentials lead to muscle contractions for the following 1-2 hours
- denervation atrophy of muscle
what is muscle denervation?
loss of LMNs and their axons which leads to muscle atrophy
how fast doest LMN denervation occur?
very rapidly and severely
how fast does UMN loss occur?
slow and mild atrophy
disuse atrophy
stopping exercising
how fast does disuse atrophy occur?
Slowest and least severe atrophy
what are some retrograde effects of axotomy? (3)
- neurotrophic supply from the target cell is lost (such as brain derived neurotrophic factor)
- changes in the soma (2-3 days)
- distance between injury and soma is important alongside age
do younger or older animals have more severe responses to axotomy?
younger animals and the longer the distance between target the more effects there are
chromatolysis; how does it try to solve the problem?
dissolving of color and is a loss of RER, soma swells, nucleus moves off center
- Occurs within 3 days ⇒ the metabolism of the cell is profoundly changed
- It tries to recreate the axon and grow back to its target
- the cell down regulates expression of molecules required for neuronal communication (neurotransmitters) and up regulates synthesis of molecules needed for axon growth so the axon will regrow in 1-2 weeks
how fast do axons travel
2-4 mm/day (1.5 mm/day used)
how do axons follow their old path?
- Axons growth within the connective tissue sheath along channels formed by Schwann cells
- Optimal regeneration requires the nerve sheath to be intact
Note: ends of a cut nerve can be connected surgically with sutures in the connective tissue sheath
neuroma
axons that grow outside of the sheat are very painful
where do regenerating axons form synapses?
at or close to their original synaptic sites
Sensory axons
will reinnervate their original territory and may displace axons that have invaded their territory
- Synapses ⇒ neurotrophins (TF) ⇒ gene expression switches to that for neurochemical communication instead of growing still
- The myelin sheath is eventually re-established by Schwann cells
why is regeneration not perfect? (4)
- Less strength and dexterity
- Less sensory discrimination
- Motor units are larger
- Conduction velocity is down 20%
how long does it take for CNS axon growth to fail?
axons may sprout after axonal damage
- Axon growth fails after 1 month
- Spinal cord injury and other CNS injuries due to axotomy don’t resolve
what are injury hypotheses? (3)
- Glial scars
- myelin inhibitory molecules
- Intrinsic inability of mature CNS neurons to grow axons
glial scars
increased density and alignment of glial processes leads to thick, parallel astrocytic processes (proliferation) ⇒ interferes with axon regrowth
Myelin inhibitory molecules
- NOGO
- MAG
Note: MAG and NOGO both interfere with axon extension
how do PNS and CNS axons regenerate?
through a peripheral nerve if they are given a path
- This does not occur through the optic nerve so adult CNS myelin appears to include molecules that inhibit axon growth
what are the myelin cells for the CNS and PNS?
- CNS is oligodendrocytes
- PNS is Schwann cells
what happens when you cut the optic nerve and either graft a peripheral nerve or not?
- cut optic nerve and do nothing further result in no sign of regeneration of axons
- Cut optic nerve and transplant peripheral nerve to bridge between optic nerve head and superior colliculus and find regeneration and function
what is NOGO? What does blocking do?
neurite out-growth inhibitor
- Blocking nogo promotes CNS regeneration by allowing corticospinal axons to regenerate 9 mm beyond injury sites
- Unfortunately there are few axons and they don’t go very far
what is MAG
Myelin associated glycoprotein
- does the same thing as NOGO
what do mature CNS cells express as far as intrinsic inability to grow axons?
KLF4 protein
KLF4; knocked out?
a transcription factor that blocks the ability of the cell to express molecules needed for axon growth ⇒ if KLF4 gene is knocked out, adult retinal ganglion cells are able to regenerate in the optic nerve
- This limits their ability to regenerate axons
axotomy near the soma is likely to result in what?
cell death
- Young neurons are more likely to undergo cell death in response to axotomy regardless of the position of the axotomy
- In adult neurons, they may die but are more likely to atrophy if regeneration fails
why do neurons die? (5)
- normal development
- disease => neurodegenerative, metabolic, infectious
- toxins
- trauma
- hypoxia => heart attack, stroke, drowning, carbon monoxide
functional plasticity
the nervous system learns to perform missing functions with remaining neurons
- Generation of new neurons by CNS is minimal
clinical approaches to replacing neurons? (3)
- Transplantation of embryonic neurons
- Transplantation of stem cell derived neurons
- Reprogramming glia to become neurons
what disease is helped with transplanting neurons from human embryos?
Parkinsons disease
- ignoring ethical issues it is impractical because it requires large amounts tissue and excessive embryo amounts
stem cells
capable of self renewal indefinitely and generating multiply types of differentiated cells
types of stem cells (5)
- Embryonic stem cells (ESC)
- Umbilical cord stem cells
- Induced pluripotent stem cells (iPSC)
- Neuronal stem cells (NSC)
- Other stem cells from adult tissues
Embryonic stem cells (ESC)
embryo produced in vitro fertilization and ESC are generated from inner cell mass of blastula
- Can be used as a source of neural tissue
- When this is done the resulting tissue is heterogenous and may form teratomas in vivo ⇒ multiple tissue types
Induced pluripotent stem cells (iPSC)
can be generated from many different types of differentiated cells ⇒ usually made from skin cells
- Can be generated from the person requiring treatment which has a reduced risk of rejection
Neuronal stem cells (NSC)
divide in culture and lead to neurospheres
- neurospheres
- have been isolated from many parts of the adult nervous system
neurospheres (do 3 things)
give rise to neurons, astrocytes, and oligodendrocytes
where can neuronal stem cells be found in the brain? (6)
- Subventricular zone ⇒ base of lateral ventricles
- Subgranular zone (hippocampus)
- Cerebellum
- Midbrain
- Retina
- Spinal cord
what is glial cell reprogramming
glia becomes reactive following injury and are susceptible to reprogramming
- Treat with proneural transcription factors
- Glial cells develop into neurons
- Develop appropriate morphology
- Make and receive functional synapses
what does successful therapeutic neuron replacement require? (7)
- Appropriate donor cell type
- Purified donor cell populations at proper stage of development
- Delivery of new cells to proper location
- Survival of afferent and target cell populations
- Growth of axons from new cells to appropriate targets
- Connection of original afferent to new cells
- Myelination of new axons
what kills neurons? (4)
- Normal development => more neurons are born than needed
- Trauma
- Toxins
- Disease
apoptosis
programmed cell death due to events within the cell ⇒ tightly regulated in mature neurons since they are built to last a lifetime
- Various cell signals can initiate it
results of apoptosis? (4)
- Mitochondrial malfunction
- Cell shrinkage and or blebbing
- Breakup of nucleus
- Cutting off DNA into characteristic 185 bp pieces
Traumatic brain injury (TBI)
a brain insult causing temporary or permanent impairment (physical, cognitive, or psychosocial) and resulting from an external force
closed vs open trauma
- Closed trauma: Skull is not penetrated
- Includes wartime blast trauma, which can be severe - Open trauma: Something penetrated the skull and stayed there ⇒ bullet/skull fragment
- Perforating injury
sources of TBI (4)
- sports injuries
- Car accidents
- Gunshots
- Explosions, etc.
results of TBI (3)
- Necrotic cell death
- Less severe TBI may result in apoptosis
- Specific neuronal populations may be more susceptible
- GABA neurons in hippocampal dentate gyrus
edema
swelling from a collection of fluid
why does necrotic cell death occur?
- Loss of blood supply due to laceration of vessels
- Contusion (bruising) ⇒ edema ⇒ compression of vessels and loss of blood supply
what areas of neurons in the dentate gyrus are highly affected after injury?
Hilus
- dentate makes C shape at bottom interlocking with the hippocampus ⇒ where they interlock the damage tends to be worse
hypoxia
the body is receiving less oxygen than needed
- The normal oxygenation is hemoglobin > 90% saturated with oxygen
- Often measured with a pulse oximeter
- Low oxygen can lead to cyanosis
cyanosis
skin turns blue
pathological consequences of hypoxic cell death? (7)
(blocked aerobic metabolism in the brain)
1. Decreased ATP
2. Failure of Na+/K+ ATPase
3. Depolarization ⇒ excitotoxicity
4. Loss of Mg++ block of NMDA receptors ⇒ excitotoxicity
5. Opening of NMDA receptors ⇒ excitotoxicity
6. Ca++ inflow ⇒ excitotoxicity
7. Mitochondrial damage, release of toxins, apoptosis or necrosis ⇒ excitotoxicit
excitotoxicity
the depolarization of nerve cells including loss of magnesium and calcium inflow (excess calcium)
- NMDA receptors open and mitochondrial damage
causes of hypoxia (2 areas)
- Local
- Global
Local hypoxia
comes from ischemic stroke
Global hypoxia (6)
- Cardio respiratory dysfunction ⇒ covid, pneumonia, severe lung disease, heart attack
- Cerebral edema ⇒ trauma or altitude
- Cerebral compression ⇒ hydrocephalus making clogged CSF/blood in SSS (could be local)
- Altitude ⇒ >26,000 ft/8,000 meters leads to death
- Carbon monoxide poisoning
- Drowning
Neurotoxins
toxins that kill you by interfering with the nervous system or kill nerve cells themselves
toxins that kill by interference? (5)
- Nerve gas
- botulinum toxin
- curare
- tetanus toxin
- tetrodotoxin
nerve gas
blocks breakdown of acetylcholine
Botulinum toxin
blocks neurotransmitter release
Curare
blocks nicotinic acetylcholine receptor
Tetanus toxin
blocks release of inhibitory neurotransmitters
Tetrodotoxin
from puffer fish and blocks voltage gated sodium channels
toxins that kill neurons (6)
- ethanol
- fetal alcohol syndrome
- Excitotoxins (glutamate agonists)
- lead
- mercury
- arsenic
ethanol (def + 5)
brain tends to shrink and have neural loss
- Apoptosis of cerebral cortical neurons
- Mitochondrial dysfunction
- Vitamin deficiencies ⇒ particularly thiamine?
- Acetaldehyde: reactive ethanol metabolite
- Ethanol encourages inflammation
fetal alcohol syndrome
interferes with myelination so Glia may die
- Unclear if neurons die
Excitotoxins (glutamate agonists)
if you take in an agent that acts like glutamate it causes cells to fire more ⇒ not necessarily a good thing => shellfish poisoning
- Domoic acid
Domoic acid
produced by algae and accumulated by shellfish, sardines, etc. ⇒ red tide is produced by the algae that produce domoic acid
- Glutamate (AMPA and NMDA) agonist ⇒ excites neuron and depolarizes it which removes the magnesium block from the NMDA receptor and the agonist allows calcium in which kills the cell
what happens when you ingest Domoic acid? (3)
- Damage to hippocampus and amygdala
- Loss of short term memory
- Kidney damage at lower doses than cause brain damage
lead
directly inhibits NMDA receptors and substitutes for Ca++ (controls many enzymes) ⇒ can decrease normal cell functions without calcium
- Lead water pipes and lead paint (leaded gasoline)
Induces apoptosis
- Unclear to what extent it kills neurons rather than disabling them
- Significantly fewer hippocampal microglia after low level lead exposure in mice
mercury
different forms of toxicity depend on the chemical form
- Hg+ and Hg++ ⇒ Either ionic form can damage the kidney
- Elemental metallic Hg and organic Hg go to the brain
organic Hg
(still a hazard) methyl mercury; dimethyl mercury and is an important environmental hazard
- Coal burning ⇒ atmosphere ⇒ rain ⇒ lakes
- Concentrated up the food chain such as in fish ⇒ found in MN fish
- 50 year half life in the body
methyl mercury
for industrial use and inhibits Na+/K+/ATPase as well as ATP production by mitochondria
- Minamata Disease in japan
- Lab accidents ⇒ Karen Wetterhahn and now its regulated different by US FDA
Arsenic
poisons mitochondria and induces release of inflammatory agents (cytokines) and results in widespread apoptosis in the cerebral cortex, cerebellum, etc.
- Sourced from groundwater
- Serious problem in Bangladesh and problem in parts of the US including parts of MN
disease types that kill neurons or glia (5)
- Metabolic
- Psychiatric diseases
- Infectious diseases
- Immunological diseases
- Neurodegenerative diseases
Diabetes mellitus
diabetic neuropathy which kills axons in peripheral nerves ⇒ lose vasculature that supplies blood to nerves in the periphery
- Distal regions (hands, feet) are affected more than proximal regions (upper arms, thighs, chest)
- Affects sensory and motor axons
Very common in half of people with type 2 diabetes
how does pathology of diabetes work?
Vascular damage ⇒ ischemia ⇒ axon death
- Long axons are harder to regenerate
functional losses of diabetes (motor [2] and sensation [2])
- Motor function:
- decreased conduction velocities
- decreased Na+/K+/ATPase - Sensation:
- loss of touch, vibration, pain
- Loss of sensation ⇒ vulnerable to injury due to loss of blood supply
Note: Untreated injuries ⇒ amputation
Psychosocial stress
depression in rat models
- Increased inflammatory markers in brian
- Reduced neurogenesis in hippocampus
- Apoptosis in hippocampus
infectious diseases that kill neurons (3)
- Polio
- rabies
- herpes simplex
Poliomyelitis (polio)
caused by poliovirus
- Epidemics through the 1950’s in the US
- Nearly eliminated by vaccination
- Still exists in some countries
- Transmitted through fecal contamination of water
- Most infections lead to minimal effects but 1% lead to CNS involvement
how does polio kill neurons?
infected neurons die from the virus
- Spinal motoneurons
- Brain stem neurons
- Can be fatal if respiratory control is lost
- Iron lung is used to help people breath during acute viral phase
- Cases in older individuals likely to be more severe
Rabies
caused by the rabies virus and transmitted through bites/scratches by infected animals
- Relatively long incubation ⇒ 1 week-6 years after exposure but typically 1-2 months
- Virtually always fatal
2 forms of rabies
- Encephalitic (furious) form: hyperactivity, agitation, aggression with a terrifying presentation in ⅔ of cases
- Paralytic form: hypoactive in ⅓ of cases
how does rabies kill neurons?
The virus is retrogradely transported from periphery to CNS and replicated in the CNS killing neurons ⇒ likely overwhelms cellular metabolism
- Apoptosis can occur but may be a protective reaction
- Death of cell ⇒ loss of axonal transport ⇒ decreased infection in neurons innervated by cell (we don’t know for sure)
herpes simplex
cause varying degrees of encephalitis in
- Type 1 is cold sores and Type 2 is genital sores
encephalitis
inflammation in the brain
- This is rare and mostly in immunocompromised people
when does each type of herpes cause encephalitis
- HS1 And HS2 can cause encephalitis in neonates
- HS1 can cause severe encephalitis in adults
how does herpes kill neurons?
- Reported to induce apoptosis in neurons and microglia
- Higher fever from infection can also kill neurons
Guillain-Barre syndrome (kills glia)
in the PNS as an autoimmune attack on peripheral myelin
- PNS myelin are composed of Schwann cells
- Macrophages phagocytose and eat myelin
- Demyelination ⇒ poor axonal function ⇒ death by respiratory arrest in severe cases
neurodegenerative diseases (4)
- Amyotrophic lateral sclerosis ⇒ Lou Gherigs disease
- Huntington disease
- Parkinson disease
- Alzheimer disease
