-
What are CNS glial roles?
Maintain environment, blood flow (nutrition), signal interaction and respond to injury or disease.
-
What is the basic pathophysio cause of multiple sclerosis?
Oligodendrocytes die, lose myelin, axons and function
-
What are the features of microglia?
- Resident CNS macrophages(marrow origin)
- Express CD45=leukocyte common antigen
- Tile CNS contiguously
- Motlile
-
What are the two subtypes of astrocytes?
- Protoplasmic (gray matter)
- Fibrous(white matter)
-
What are the functions of astrocytes?
- Support
- Maintain environment (K+, H2O, transmitter uptake), blood flow (cerebral vessels)
- Blood brain barrier
- Energy metabolites
- Synapse plasticity, activity and number
- Injury
-
What does the astcyte processes do?
- Near synapse
- Uptake: H2O, K+, glutamate, GABA, glycine
- Release: gliotransmitters (ATP, glutameate)
- Influence synapse formation & plasticity (thrombspondin)
-
What is “neuropil”
Fills space between neurons with dendritic branches & synapses& support glia
-
How are astrocytes excitable?
- No action potentials
- Increase cytoplasmic calcium in response to synaptically release glutamate or GABA
- Release gliotransmitters like D-serine: affect synaptic function
- Adenosine is implicated as a mediator of certain deep brain stimulus (Parkinson’s)
- Can be blocked by TTX (synapse activity)
-
How do astrocytes interact with vasculature?
- Uptake glucose from BV and process into substrates for axons(lactate)
- Release factors that vasoconstrict or dialate
- Vascoconstrict: Arachidonic acid
- Vasodialate: Prostaglandin E2 (PGE2) & NO
- Responsible for measureable fMRI scan changes of CNS function
-
How do astrocytes interact with the BBB?
End feet envelope CNS vessels at tight junction (NOT fenestrations) of capillary endothelial
-
What does the BBB do?
- Prevents charged molecules crossing (NH4+
- Allow: lipid soluble
-
What happens when the dicer from astroglia is deleted?
- Non-cell autonomous neuronal degeneration of cerebellar Purkinje neurons and granule neurons.
- Dicer: endonuclease indispensible for biogenesis of small regulatory RNAs (miRNAs)
-
What is reactive gliosis?
- Glial response to CNS insults/injury (get bigger first then proliferate if necessary)
- Glia(microglia & astrocytes) are main responders to disease and play major roles in determining clinical outcome
-
How do microglia respond to injury/disease?4
- Mediate inflammation of all forms of insult (infection, ischemia, injury, degeneration)
- Hypertrophy-> transform to macrophage-> proliferate
- Phagocytose debris & produce chemokines, cytokines and growth factors
- Attract leukocytes & activate astrocytes
- Directly effect neuronal function
- Target of HIV in NeuroAIDS & cause symptoms
-
What is reactive astrogiosis?
- Astrocyte response to all forms of injury
- Change in gene expression(molecular changes)->function
- Hypertrophy yet non-overlapping domains preserved in mild & moderate
- Sometimes scarring (severe cases): overlapping astrocytes loss of ind domains along borders to damage
- Intensity varies with severity
- Specific molecular signaling mechanisms
-
What is a key marker of reactive astrogliosis?
GFAP: glial fibrillary acidic protein
-
What are the key features of mild/moderate astrogliosis?
- GFAP+
- Preserved domains
- Little/no proliferation
- Effects on synaptic function (unptake K+, H2O, glutamate, regulate blood, energy, gliotransmitters)
- Cytokines: modulate glutamate signaling increase AMPA & NMDA receptors in dentritic spine post synaptic cells
-
What does chronic release of cytokines from glial cells lead to?
Neuronal vulnerability to excitotoxicity
-
What has evidence shown that reactive glia regulates?
- Chronic pain: from chronic stimulation changes gene expression and functional changes that influence local neurons and alter sensitivity.
- Some new meds may influence glia rather than neurons to manage pain
-
What is the astrocyte role during ischemia(stoke)?
- Ischemia->lack of ATP -> no glutamate uptake in astrocyte->ATPase pumps fail and even more glutamate may be released from astrocyte
- Extracellular glutamate-> excitotoxic cell death of neurons via NMDA receptor over activation (especially in hippocampus (memory))
- NMDA glutamate receptor overactivation: leads to excess Ca2+ signaling and excitotoxic cell death
-
What does glial scar tissue do?
- Prevents spread of inflammatory cells/signals (gFAP and CD45)into healthy tissue
- Contributes to failure of axon regeneration due to shared migration cues
-
What do reactive astrocytes do to the BBB?
Form barriers around vessels to restrict entry of inflammatory cells and microbes during CNS infections and autoimmune inflammation.
-
What is neuromyelitis optica?
- CNS autoimmune disease where autoAb selectively attack & damage astrocytes
- NMO-IgG binds to AQP4 exclusive to astrocytes
- Causes inflammatory cell lesions in the CNS and severe regions of demyelination in optic nerves& spinal cord & recurrent attacks of blindness and paralysis.
-
What are the main changes of astrogliosis?
- Change in gene expression, hypertrophy, function, scars.
- Why? Regulate inflammation, protect neurons & modulate pain.
-
How does reactive astrogliosis contribute to disease mechanisms?
- Loss of normal function: glutamate uptake, inflammation reg, energy provision, vascular reg, homeostatis, synaps
- Gain of detrimental effects: cytokines and growth factors that alter neuronal, neurotoxicity (NO, ROS, glutamate)
- Loss or changes can precipitate non-cell autonomous neuronal degeneration (astrocytopahties)
-
How do Schwann cells react to insult?
- Astrocyte like: reactive
- BUT they promote the regeneration of damaged axons (growth cones)not like astrocytes
-
What are the steps of healing a peripheral nerve transection?
- Wallerian degeneration before axon regeneration
- (1-4) myelin degenerates & macrophages phagocytose debris
- (5-7) Schwann cells become reactive & multiply to fill endoneurial space, secrete ECM and GFs
-
What is the formal definition of pain?
An unpleasant sensory and emotional experience arising from actual or potential tissue damage or described in terms of such damage.
-
Who discovered anesthesia?
- Dr. Horrace Wells from Professor Colton who demonstrated N2O, in 1845 demonstrated N2O extraction
- Dr. Morton was first anesthesia specialist
-
What are the tools required to minimize pain?
- Accurate assessment, methodical prevention & aggressive treatment
- Assessment: medical Hx, listen, self-report quantitative, scales.
-
What are 3 types of pain?
- Acute: Obvious value to organism: impending or actual tissue injury
- Post-operative: (inflammatory component) Cox-2 and opiods
- Chronic: variable etiology (arthritis, migrane) persists after initial injury, no obvious survival value
-
What are dental implications of rheumatoid arthritis?
- May involve TMJ (55% affected, 70% radiographic TMJ involvement)
- Juvenile form may lead to retrognathia
-
What is the mechanism of congenital insensitivity to pain?
- A and C fibers lose Na+ channels so that acute nociceptive pain sensation is lost.
- (could be reversed -> hypersensitivity)
-
What kind of fibers convey pain?
- Nociceptors: thin diameter primary afferent fibers
- Primarily A-delta and C fibers
-
What are the sensitivities of different parts of the teeth?
- Enamel: none
- DEJ: pain
- Dentin: pain
- Pulp: pain
- PDL: touch, warm, cold, pain
-
What is the hydrodynamic theory of dentinal pain perception?
- Puff->pain
- Drying-> less puff pain
- Dry filter paper-> pain
- Filter paper w/isotonic KCl-> NO PAIN
- Conclusion: pain due to displacement of nerves in predentin & pulp by movement of tubular fluid
- Nerve fibers reach only about 100 um into tubules therefore are only activated by fluid displacement
-
What is the chemical theory of dental pain?
- NH4+, AA, lactic acid or sucrose in dentinal cavity produced nerve impulses
- Prostaglanding E2 and F2 alpha had about 20x regular levels in painful teeth.
- Inflammatory pain: damaged tissue, immunocompetent and tumor cells release chemicals that activate and/or sensitize nociceptors, which in turn results in sensitization of CNS neurons.
- Histamine, serotonin, bradykinin, prostaglandins, ATP, H+, NGF, TNF-a, enothelins, interluekins
- Treatment options: COX2 inhibitors, opiods
-
What is peripheral sensitization?
- Charateristic of nociceptors that increases number of impulses elicited by successive stimuli at a reduced threshold.
- Initiates or increases ongoing activity.
- Involves arachidonic acid metabolites (PGs, leukotrienes)
- Other innocuous primary afferents don’t sensitize, they adapt.
-
What are the specializations of nociceptors?
- Mechanisms through which sensitization of primary afferents
- Polymodality:
- Modifiability:
- Sensitization:
-
What is the axon reflex?
- C and A-delta fibers do not just convey pain to CNS
- Generates and action potential in the collateral fibers to release neurotransmitters (neuropeptides) that activate immune competent cells, increase collagen synthesis, regulate gene expression
- Substace P-> vaso and immune effects
-
What do peptides mediate in thin-fiber sensory neurons?
Vasodilation, plasma extravasion, smooth muscle contraction, mitogenesis, collagen formation, modulates leukocytes, arachidonic acid metabolism (PGs release) and maintains mineralized tissue.
-
What happens to denerved tooth and skin?
They become friable or brittle because nerves provide nutrients and help maintain mineralized tissue.
-
What are the early and delayed central sensitation changes?
- Early: involes neuropeptides, glutamatergic receptors and substance P receptors
- Delayed (minutes, hours, days until repair) Prostaglandins
- Prostaglandins involved with both peripheral and central sensitization, that is why aspirin and ibuprofen are effective analgesics.
-
What are the features of neuropathic pain?
- Characterized by nerologic defecits and chronic pain
- Treatment options: tricyclic antidepressants, anticonvulsants, Na+ channel blockers, NMDA receptor antagonists, opiods
|
|