Week 9 Flashcards
How can inflammation injure the brain?
Infection
↓
PAMPS
- Bacterial cell wall components e.g. LPS
- Bacterial nucleic acids
- Viral nucleic acids
- And others
↓
Immune cell activation
↓
Inflammatory mediators
↓
Effects on nervous system:
- Leaky blood brain barrier
- Neuronal damage/degeneration
- Glial activation
- Mitochondrial dysfunction
- Demyelination
- Endothelial damage
OR
Sterile injury:
- Autoimmunity
- Trauma, burns
- Pancreatitis
- Hypoxia
↓
DAMPS:
- ATP
- NO
- Fatty Acids
- And others
↓
Immune cell activation
↓
Inflammatory mediators
↓
Effects on nervous system:
- Leaky blood brain barrier
- Neuronal damage/degeneration
- Glial activation
- Mitochondrial dysfunction
- Demyelination
- Endothelial damage
How is the developing brain different when it comes to injury?
Innate and adaptive immune responses are immature
Microglial responses can be exaggerated
Cytokines, chemokines and complement used as signalling moleclules in the developing brain
Developmental processes sensitive to change in the inflammatory environment
What does Zika virus do?
Causes mircocephaly
What does inflammation affect in the developing brain?
Proliferation and differentiation
- Reduces proliferation in the cortical ventricular zon and also alters the neuronal differentiation
Also regulates neuronal arborisation
- a multi-step biological process by which neurons form new dendritic trees and branches to create new synapses.
What do inflammatory mediators do to the glia?
Regulates the glial cells
So regulates:
In the prenatal brain
NPC phagocytosis
NPC-migroglia signalling
- Cxcl12
- Cxcr4
- Reactive oxygen species
Axon phagocytosis
In the early postnatal brain
Myelinogenesis
Synaptic plasticity
Synapse pruning
- Complement
Microglial mediated synaptic pruning associated with local connectivity, plasticity and behavioural development
What are the microglial-neuronal interactions?
Evidence of phagocytosis of synapses; knockout results in a transient increase in dendritic spines more
Altered CX3CR1 results in transiently reduce microglia with altered morphology
Altered CX3CR1 results in age specific sensitivity to seizures
What do microglia and astrocyte have to do to regulate brain development?
Cross-talk
What do we know about inflammation and white matter injury?
Inflammation prevents the cross-talk between microglia and proliferation
Altered astrocyte signalling affects microglia production of TGF-ß
Decrease in myelination
In the healthy brain, how does astrocyte signalling affect the microglia?
Reduces their production of TGF-ß, facilitating oligodendrocyte proliferation
What happens to the blood brain barrier in response to inflammation?
Breakdown of the BBB
Inflammation causes age-dependent break down of blood brain barrier
Summarise the effect of inflammation on brain development:
Inflammation normally a response to injury or infection, but molecules used to signal to immune cells (e.g. cytokines and chemokines) are used to regulate aspects of brain development (proliferation etc.)
Microglia and astrocytes also regulate developmental events (e.g. synapse formation)
There is a cross talk between immune mediators, glial cells and the vasculature that regulate inflammatory signalling in the brain
There is also cross talk between the brain and periphery, that can both cause and regulate brain development and/or injury
How could intrauterine environment cause preterm brain injury?
Placental dysfunction
Intrauterine infection
Gestational diabetes
Chronic hypoxia
LEADS TO INFLAMMATION
How could ex-utero environment affect an existing preterm brain injury?
Absence of maternal hormones
Inflammation caused by comorbidities
Hyperoxygenemia
Continuation of injury from intrauterine environment
What are some neurodevelopmental disorders following preterm brain injury that could develop?
ADHD
ASD
Conduct disorders
Emotional disorders
What was seen in inflammation in utero? What did it cause
EARLY INFLAMMATION (week 1-2):
C-reactive protein
TNF-alpha
IL-8
ICAM-1
Erythropoietin
LATE INFLAMMATION (week 3-4):
C-reactive protein
VEGF-R2
Thyroid-stimulating hormone
IL-8
ICAM-1
Causes:
Low IQ
Moderate to severe cognitive development
When is myelination vulnerable to inflammation?
Week 23-32
Premyelinating stage
What happens in inflammation to affect myelination?
Oligodendrocyte differentiation is altered, reducing myelination
What is the genetic influence on white matter development in preterm?
Functional gene relationships based on protein-protein, protein-DNA, and genetic interactions, pathways, reactions, gene and protein expression data, and protein domains
Genetic differences in lipid metabolism might regulate susceptibility to white matter damage
What are some important lipid metabolism pathways?
Glycine Serine and Threonine metabolism
- PPAR signalling pathway
- Alpha-linolenic acid metabolism
- Ether lipid metabolism
Glycerolipid metabolism
Phosphatidylinositol signalling system
Adipocytokine signalling pathway
- glycosylphosphatidylinositol GPI anchor biosynthesis
Fatty acid metabolism
What are some non-specific anti-inflammatory therapies for neuroprotection?
Allopurinol
Deferoxamine
N-acetylcysteine
Melatonin
Minocycline
IL-1ra
Other:
Trophic support, e.g. BDNF, IGF-1, EPO - enhanced neurogenesis
Anti-cell death therapies (e.g. caspase, p53 inhibition)
Symptomatic control - anti-psychotics, Glut/GABA agonists/antagonists (depending on timing)
Currently in clinical trial:
Melatonin
EPO
Allourinol
Are there currently any approved therapies for preterm brain injury?
NO!
Preclinical success does not necessarily translate to clinical success
Is there epidemiological evidence of inflammation in the disease process?
Yes
There is evidence of systemic inflammation in disease aetiology
- Yes, systemic and central inflammation correlate with injury
Is there evidence of inflammation in the neuropathology?
- Yes, astrocyte and microgliosis clearly present in injury - animal studies suggest production of inflammatory mediators as a result of there cross talk contribute to injury
Do anti-inflammatory agents ameliorate neuropathology or cognitive/behavioural deficit?
- Maybe… yes, in animals; still to be determined in clinical trials
What are some neurodevelopmental disorders?
Cerebral palsy
Autism spectrum disorder
Epilepsy
Schizophrenia
ADHD
Intellectual impairment
When does systemic inflammation cause memory and myelin deficits postnatally?
When induced from P1-P5
