Flashcards in Module 2: Neurological and Psychiatric Disorders of the Central Nervous System Deck (391)
What are the different categories of acute stroke?
- Cerebral ischaemic stroke (CI) roughly 80%
- Primary intracranial cerebral haemorrhage (ICH)
- Sub-arachnoid haemorrhage (SAH)
Wha are current treatments for CI to improve blood flow?
- mechanical thrombectomy
- anti-platelet drugs
What are some examples of prophylaxis for acute stroke?
- ACE Inhibitors
What is the penumbra?
- An area where tissue viability may be sustained
- A realistic target for treatment
- Penumbra represents tissue at risk of infarction where perfusion is adequate to maintain cell viability but not adequate for normal neuronal function
What is the blood flow in Cerebral Ischaemia?
- Normal: >50ml/100g/min
- Olighaemia: 22 - 50ml/100g/min
(Hypoperfusion but likely to survive due to factors such as collateral blood vessels)
- Ischaemic penumbra: < 22ml/100g/min
(Misery perfusion likely to progress to infarction)
- Rapid cell death: <10ml/100g/min
What is the therapeutic window for stroke?
Describe energy failure in stroke
- Reduced blood flow
- ATP reduced (20% of total O2 consumption used by the brain which is ~ 2% body weight)
- Ion gradients, Na+ pump fails and hence membrane potential NOT maintained
- Extracellular glutamate (GLU) elevated
- Energy dependent GLU transporters inactivated
- Na+ and Cli- entry accompanied by H20 (passive) leads to oedema
Describe the mechanisms of calcium overload in stroke
- Caused by NMDA receptor activated calcium entry and depolarisation
- Leads to activation of:
- Proteolytic enzymes (actin degradation)
- Phospholipase A2 and Cyclo-oxygenase (free radical generation)
- Nitric oxide synthase (NO generation)
- Calcium causes mitochondrial swelling, reduced oxidative phosphorylation (loss of mitochondrial trans-membrane potential-proton motive force), cytochrome c loss (mitochondrial transition pore) ---> APOPTOSIS
What are the different types of nitric oxide synthase?
- nNOS: retrograde messenger
- eNOS: vasodilator
- iNOS: immune mediator
What does each NOS do?
- nNOS: Causes toxic levels of NO free radicals- neuronal lesion
- eNOS: improves cerebral blood flow
- iNOS: Enhances toxic effects in ischaemia
What are some examples of exogenous antioxidants and free radical scavengers?
- Superoxide dismutase
- Glutathione peroxidase
- Ascorbic acid
Describe severe insult due to NMDA receptor mediated neurotoxicity
- Ca2+ entry
- Ca2+ uptake into the mitochondria
- Free radical generation
- Severe ATP depletion
- Mitochondrial swelling
Describe mild insult due to NMDA receptor mediated neurotoxicity
- Transient depolarisation
- ATP levels reduced
- Ca2+ loaded mitochondria
- Cytochrome c release from mitochondria
What is the experimental evidence that NMDA receptors mediate tissue damage?
- NR2A KO decreases infarct size (focal ischaemia)
- Interruption of signalling using a 2B subunit antibody affecting PSD95 interaction reduces ischaemic damage
- NR1 antibody given at 4h after MCAO reduces infarct size from 25% to 15% (+/- tPA) (Macrez et al)
What is the experimental evidence that AMPA receptors mediate tissue damage?
- GluR2 antisense knockdown increases injury (global)- AMPA receptor more Ca2+ permeable.
What are limitations of NMDA and AMPA antagonists?
- HIGHLY effective up to ~2h after insult BUT have psychotomimetic (NMDA) and respiratory depressive properties
What is the ischaemic cascade?
- A cascade of reactions which are self-perpetuating and no longer subject to physiological regulation ('vicious cycle') leading to cell death initially necrotic and later apoptotic
- In parellel, neuroprotective mechanisms are activated and balance between the two mechanisms determines the fate of the new cell
What example of early response genes does glutamate activate?
- Inducible transcription factors (IEGs) which activate/repress other genes
- Enzymes such as COX-2 which underlie developmental and behavioural responses
- Neuroprotective mechanisms e.g. HSPs which counter damaging effects
How does glutamate activate transcription?
- NMDA Receptor Ca2+ entry ---> Ca2+-calmodulin kinase IV pathway (CAMKIV) ---> Phosphorylation of cAMP-response element binding protein ---> CREB/CREB binding protein complex activates transcription (transcription factors and neurotrophic factors)
- This pathway mediates an injury response that can contribute to cell survival or cell death
What are the penumbra/peri-infarct effects of glutamate?
- Elevated extracellular K+ and glutamate depolarisation in penumbra
- Upregulation in injury response genes (e.g. c-jun, ATF3 and HSPs)
- Extends area of infarct
- Sensitive to glutamate antagonists
Is chronic treatment with COX2 selective inhibitors a viable treatment for Stroke?
- COX2 selective inhibitors, whilst lacking gastric toxicity, decrease prostacyclin (vasdilator) and lack COX1 anti-thrombotic properties which potentiates cardiovascular events
What are heat shock proteins?
- Act as protein chaperones facilitating the transfer of proteins between subcellular compartments
- Following a noxious stimulus (heat, ischaemia) HSPs are induced which target abnormal proteins for degradation
- HSPs are also anti-apoptotic and antioxidant (HSP27)
What does Sulindac do? (Stroke)
It's an NSAID which increase HSP27 and decreases infarct size
What is ischaemic pre-conditioning (IPC)?
- IPC is a process in which brief exposure to ischaemia provides robust protection/tolerance to subsequent prolonged ischaemia (~TIA)
- HSP involvement in IPC has been demonstrated in cardiac and cerebral ischaemia (Sun et al 2010) mediated through the NF-kB pathway(Tranter et al 2010).
- Ischaemic preconditioning reduces infarct size in mouse
How does inflammation play a part in stroke?
- Neutrophils enter the brain parenchyma (30 min) and later, lymphocytes and macrophages (5-7 days) (iNOS elevated).
- Enabled by the disruption in the Blood brain barrier
- Production of mediators of inflammation:
- TNF alpha
- Platelet activating factor
- Interleukin 1 beta
- Adhesion molecules on endothelial cell surface (ICAM-1, p and E-selectins)
Describe the cellular inflammatory response of stroke in more detail
- Neutrophils accumulate within 30 minutes on vascular endothelial cells
- Cell adhesion molecules (Selectins, Integrins, Immunoglobulins) promote adherence leading to infiltration of cells into the brain parenchyma.
- Neutrophils cause tissue damage by releasing O2 free radicals & proteolytic enzymes
- Other cells entering the tissue e.g. lymphocytes promote tissue damage (24h)
Describe the role of cytokines and chemokines in stroke
- Produced by a range of activated cell types (endothelial cells, microglia, neurones, astrocytes, platelets, leukocytes, fibroblast) within the first few
hours after ischaemia
- IL-1 and TNF upregulate adhesion molecules promoting neutrophil migration
- CSF levels of IL-1, IL-6 and TNF at 24h correlate
with infarct size
- Chemokines (e.g. CINC and MCP-1) detected in
the brain between 6 and 24h attract neutrophils &
What are some neuroprotective examples against cytokines?
- IL-1b receptor antagonists
- TNF-alpha neutralising antibodies and antisense nucleotides
- TGF b and IL-10 produced by lymphocytes limit
leukocyte invasion and reduce immune responses
- Complex protective/harmful effects are seen due
to multiple sites of action.
Is neutrophil infiltration correlated with infarct size?
- Preliminary studies supported this concept
- However, Phase III anti-neutrophil drugs
failed to improve stroke outcome and antiICAM
(n=625) increased mortality(Becker et
al 2002). [Thought to be due to neutrophil activation by
the mouse antibody (complement)].
- Neutrophils may have both proinflammatory or anti-inflammatory phenotypes (Easton 2013)