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
What are the two subtypes of astrocytes?
- Protoplasmic (gray matter)
- Fibrous(white matter)
What are the functions of astrocytes?
- Maintain environment (K+, H2O, transmitter uptake), blood flow (cerebral vessels)
- Blood brain barrier
- Energy metabolites
- Synapse plasticity, activity and number
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?
- 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?
- 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
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