Module 2: Neurological and Psychiatric Disorders of the Central Nervous System Flashcards Preview

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Flashcards in Module 2: Neurological and Psychiatric Disorders of the Central Nervous System Deck (391)
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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?

- tPA

- mechanical thrombectomy

- aspirin

- anti-platelet drugs


What are some examples of prophylaxis for acute stroke?

- Statins

- ACE Inhibitors

- Anti-platelets

- Anti-hypertensives


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?

3 hours


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

- Acidosis

- 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

- Catalase

- Alpha-tocopherol

- 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?

NMDA Receptors:

- 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?

- No

- 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)


How does apoptosis occur in stroke?

- Delayed cell death occurring in the penumbra

- Triggered by free radicals, death receptor, DNA
damage, protease action, ion imbalance

- Release of cytochrome c from mitochondria
activates the formation of an apoptosome complex
(APAF1 + procaspase 9) and caspase 3 activation
(detected at ~8h) leading to DNA fragmentation

- Caspase 3 selective inhibitors (zDEVD.FMK) are
effective up to 9h after reversible ischaemia.

- Broad specificity caspase inhibitors (zVAD)/
caspase 1 deletion protects against ischaemia.