When things go wrong part 2 Flashcards
What is pain?
Unpleasant sensory & emotional experience associates with actual or potential tissue damage, described in terms of such damage
Dimensions of pain
1 - Sensory/discriminative: sensation of stimulus
2 - cognitive: degradation & evaluation of pain
3 - Motivational aspects of pain: reward or punishment
Physiological pain
(fast) Good/acute pain - sudden onset & receded during healing process
Pathological pain
(slow) Chronic/bad pain - such as that caused by nerve injury which may be due to toxins, ischemia or diabetes
Classification of nociceptors by modality:
1 - mechanical
2 - chemical
3 - thermal
4 - polymodal: responds to combinations of stimuli
Pain stimuli received through usually multimodal receptor such as:
Vallinoid receptor (TVRP-1)
Layers of grey matter found in:
- layers 1-6
- layers 7-9
- Layer 10
- Laminae 1-6 = in the dorsal horn
- Laminae 7-9 = in the ventral horn
- Lamina 10 = surrounds central canal
Which pathway carries pain?
Spinothalamic/anterolateral pathway
The two fibres that bring signals of pain innervate 2nd order neurons in different layers:
A. A-delta fibres: laminae 1-5
B. C fibres : laminae 1 &2
What is a stroke
a focal neurological deficit due to disruption of regional blood supply. it is a short-term phenomenon & happens suddenly, but typically over hours
Three implications with regards to cerebral blood flow
- suboptimal cerebral blood flow - neurological dysfunction
- cessation of cerebral blood flow for 5-10s - loss of conciousness
- cessation of cerebral blood flow for ~5min - irreversible neurological damage
Factors that regulate cerebral blood flow
- cerebral autoregulation
- CO2 (PaCO2)
- Oxygen (PO2)
- Body temperature
- Autonomic system
- Local factors
Hypercarbia & Hypocarbia
Hypercarbia = induced cerebral vasodilation when there is too much CO2 Hypocarbia = induced cerebral vasoconstriction when there is too little CO2 dissolved in the interstitial fluid
Stroke risk factors
- Atherosclerosis - plaque build-up in arteries
- Hypertension
- Diabetes Mellitus
- Smoking
- Family history
- Cardiac disorders
- Obesity
- Drugs - alcohol/cocaine/amphetamines
- vascular malformations (aneurysms)
- Clotting disorders/anticoagulants
Microglia cells functions:
- resident innate immune cells
- 1st line immune defense in the CNS
- protect against foreign elements
- scavenges the brain for damaged neurons, abnormal proteins & infectious agents
- Phagocytes
- important role in brain development ==> synaptic pruning
- involved in promoting synaptic plasticity
Astrocytes functions
- structural support (scaffold) of NS
- Metabolic support to neurons (lactate)
- Neurotrophic factors; NGF, BDNF
- Maintain synapses –> regulate ion concentrations in extracellular space
- NT uptake & release
- Glial scar - brain injury
- Support myelin coverage
- BBB support
- Regulation of blood flow
Both astrocytes & microglial cells have regional heterogeneity - meaning:
They have different functions in different brain regions
Cytokines are involved in “house-keeping” functions:
- Memory
- Behaviour
- Regulation of sleep
- Synaptic plasticity
- Neuronal transmission
- Intracellular signalling mechanisms
- Perception of pain
M1 Polarization:
- Neuro-damaging by increased cytokines & oxidative stress
- reduced scavenging function
- sustained pro-inflammatory response
M2 polarization:
- Anti-inflammatory response
- repair & remodeling of injury
A1 Astrocytes;
- Neuro-damaging
- produce neurotoxic substances
- decrease new synapses
- decrease synaptic support
- decrease glutamate uptake & lead to excitotoxicity
- decrease glymphatic clearance
- increase pro-inflammatory cytokines
A2 astrocytes:
- increase neurotrophic factors (growth)
- neuronal protection
- neuronal repair
- increase anti-inflammatory cytokines
Mechanism of entry of Sars-Cov-2 into CNS:
1 - Olfactory system 2- Paracellular transport 3- Transcellular transport 4 - Adsorptive transcytosis 5 - Receptor-mediated endocytosis 6- Trojan Horse trafficking
Astrocyte activation name & charcateristics
Astrogliosis - characterized by increase in the number & size of astrocytes during inflammation
Astrocyte activation results in:
- regulate BBB integrity
- Recruit infiltering immune cells
- activate inflammatory signalling pathways
Mechanism of Neuroinflammation
1 - pathogens - activate astroycte & microglia
2 - activation - release of cytokines, 2nd messengers, chemokines, ROS
3 - these cause:
- cell responses: proliferation, migration
- gene induction/ upregulation
- impaired BBB functions
- sometimes neurodegeneration
Molecular Mechanisms of Neuroinflammation
- peripheral immune cells activate to release pro-inflammatory cytokines
- cytokines travel through blood –> brain
- Cross BBB or bind to receptors on endothelium causing glial cells to release cytokines in parenchyma
- Cytokines in the parenchyma bind to target cells (other glial cells)
- Triggers signalling pathways (multiple steps of molecule activation including activation of TFs)
- Inflammatory actions translocate TFs into nucleus of microglial cells
- TFs bind to DNA & encode for inflammatory molecules - cytokines, chemokines etc to be released
When does cell death occur in the NS:
- during development of NS
- neurodegenerative diseases
- after ns injury
How is Amyloid Beta protein formed?
forms from proteolytic cleavage of APP (amyloid precursor protein)
Excitotoxicity - how does it occur?
Excitotoxicity = over-excitation of neurons
- glutamate stimulation
- neurons could be over excited
- resulting in excessive Ca2+ influx into the cell
- triggers cell death (apoptosis)
Neuronal Death after injury/stroke
1- Necrotic cell death:
- first wave; immediate destruction of cells
2- Apoptotic cell death:
- delayed effects of injury - reperfusion stress
- linked to inflammatory process
- second wave
- prolonged consequences
Requirements for functional axon regeneration
1) injured nerve cells must be able to survive after lesion & re-express genes required for axon outgrowth (growth cones)
2) The surrounding tissue (mircroenvironment) must be conducive to axon re-growth
3) re-growing axons must be able to find their proper target areas & establish synaptic contact
Axon regrowth after injury
- motoneuron innervating muscle fibre
- after cut - wallerian degeneration sets in neuron swelling, chromatolysis, myelin degenerates, schwann cells de-differentiate
- Schwann cells form a substrate for axon growth
- functional connection is restored
How do Schwann cells support axon regeneration?
- Phagocytose & recycle cellular debris
- Provid growth-promoting substrate (cell adhesion molecules - provided by de-differentiated schwann cells)
- support neuron survival & axon re-growth - production of neurotrophic factors
The 2 hallmarks of AD
1 - amyloid beta deposits
2 - neurofibrillary tangles - hyperphosphorylated Tau proteins
Neuroinflammation in depression
- activated microglia cells express translocator protein (TSPO) on their mitochondira
- radio ligand PK11195 binds to TSPO
(w PET scan)
Resident immune cells of the CNS, phagocytic & assume an amoeboid shape when activated
Microglia
The most numerous glial cells, have star-shaped morphology & immunocompetent
Astrocytes
Made up of part of BBB & have TJs to control movement of substances
Endothelial cells
Windows of the brain that have an incomplete or absent BBB
Circumventricular organs
An inflammatory response within the CNS mediated by cytokines & chemokines
Neuroinflammation
An irreversible damage to neurons that underlies development of neurological diseases following infection:
Neurodegeneration
Chemical mediator of immune response released by glial cells for communication during infection
Cytokines
Mechanism used by toxoplasma parasite, HIV & possible SARS-cov2 virus to enter brain. Characterized by WBCs crossing BBB to parenchyma
Trojan Horse Trafficking
Mechanism used by Rabies & Polo virus. Characterised by invasion of motoneuron before transport to CNS
transneural retrograde transport
Misfolded protein molecules which cause Mad cow disease & transported to CNS via the enteric NS which innervates the gut:
Prions
