Cellular mechanism of neuronal death Flashcards
What are some diseases can causes neuronal loss during development (At birth or during childhood)?
- Leukodystrophy; Loss of specific white matter in the brain
- Cerebral palsy.
What are some diseases can causes neuronal loss during Early adulthood? (Reproductive age)
- Multiple sclerosis
- Stroke
- Head trauma
- Motor neurone diseases (MND, ALS)
- Spinal cord injury
What are some diseases can causes neuronal loss during Aging? (Neurodegeneration)
- Huntington’s diseases
- Alzheimer’s
- Dementia
- Parkinson’s disease
What are the symptoms of neuronal death?
There’s a lot name any 5
- Impaired vision – in one eye or two • Impaired hearing • Odd sensations e.g. tingling or numbness • Weakness in limbs, paralysis • Cognitive disruption, including speech impairment • Behavioural changes • Memory loss • Loss of dexterity • Loss of coordination/balance • Difficulty controlling bowel movements or urination • Fatigue • Pain (anywhere) • Sleep problems • Depression • Spasms
In a flowchart like manor describe the mechanisms leading to cell death.
Starts with: Normal cell (Homeostasis) —> +Stress = some will adapt which is good. Others won’t adapt and become injured.
Injured–> might be reversible so back to homeostasis but if not then —> Apoptosis or Necrosis both are different types of cell death.
What are some of the causes of neuronal loss?
- Traumatic injury
• Environmental toxins
• Ischaemia
• Infectious agents – viruses and bacteria
• Immunologic reactions
• Nutritional imbalances
• Genetic diseases – e.g. defects in proteins and their aggregation
How can cell death occur?
- Excitotoxicity
- Apoptosis; Controlled planned.
- Necrosis; Random, irreversible, uncontrollable
Describe the process of necrosis.
- Toxicity/ stress induced cell death
- Requires little energy
- Cell swells and may burst
- Usually elicits an acute inflammatory response, neutrophils would be present to mop up.
Results in loss of functional tissue and impaired brain function.
Describe the process of Apoptosis?
- Stimulated induced cell death, regulated by a strict programme.
- Controlled by specific genes.
- Requires energy
- Cells shrink, chromatin condenses (pyknosis), and then
the nucleus fragments in a regular pattern (karyorrhexis). - The contents of the cell are kept within the membrane or
blebs and apoptotic bodies form. - All the debris is phagocytosed by local macrophages and
microglia. - No neutrophils present (e.g. no inflammation).
The results are removal of damaged or unneeded cells.
What is the main excitatory neurotransmitter in the brain?
Glutamate.
What occurs in Excitotoxicity?
- NMDA, AMPA and Kainate receptors are permeable to Ca++ and/or Na+
- Na+ influx will depolarise cells and open voltage gated calcium channels
- (Calcium has normal functions e.g. regulating receptor activity by
phosphorylation to control synaptic plasticity) - (Too much calcium is very toxic!)
- (Excitotoxicity arises when glutamate accumulates at synapses).
- Excessive release;
(can occur in epilepsy), loss of Ca++ homeostasis due to ATP rundown (e.g. after stroke). - Defective Uptake;
loss of EAAT(e.g. in MND/ALS) can lead to increased synaptic levels - Reversal of glutamate transporters due to energy depletion after stroke.
- This results in Ca2+ accumulation at the synapse
- Ca2+ can damage mitochondria and in addition can activate proteases, endonucleases, stress activated kinases, phospholipases and Nitric Oxide Synthase
What can cause Excitotoxicity?
- Head Trauma ▪ Cerebral ischemia (Stroke) ▪ Alzheimer’s, Parkinson’s and Huntington’s diseases ▪ Motor Neurone Disease (ALS) ▪ Damage following intense seizure activity (epilepsy) and alcohol withdrawal ▪ Age related cognitive decline
What are the 2 types of Stroke, and what is the most common in %?
- Ischaemic stroke (85%)
- Haemorrhagic stroke (15%)
What occurs in Ischaemic stroke?
And what can one/ is a risk factor?
- Caused by; a blood
clot blocking the
flow of blood in.
Causes/risk factors:
High blood pressure,
smoking, excessive alcohol consumption, diabetes, high
cholesterol.
What occurs in Haemorrhagic stroke?
And what can one/ is a risk factor?
- Burst blood vessel and
bleeding into the brain - Causes:
Smoking, excessive alcohol consumption, obesity, lack of
exercise.
(4x Higher initial morbidity, same
after 3 months)
How can ischaemia/ ischaemic stoke lead to cell/ neuronal death?
- Vascular occlusion/ embolism.
- Leads to reduced cerebral blood flow
- Cause apoptosis in some cells.
- Leads to a failure in high energy metabolism (due to lack of blood flow/ O₂).
- Leads to Ion homeostasis = Pump no longer works
- so increase in extracellular Ca, Na and Cl- concentration, so cells depolarise and vesicles are released.
- Leads to glutamate release.
- Glutamate no longer taken up.
- = Glutamate ecotoxicity so results in a rise of intracellular Ca++ concentration.
- Ca++ activates enzymes, which lead to free radical formation, organelle injury and ultimately cell death, then an inflammatory response which spreads the cell death to a greater area.
What occurs in Ischaemic stroke in days 1-3 (early)
- Increase in pressure • Drop in blood flow • Blood brain barrier disruption • Activation of inflammatory processes • Excitotoxicity • Oxidative stress evoked activation of apoptosis • Activation of apoptosis • Headache, neck stiffness. • Paralysis
What occurs in Ischaemic stroke in Delayed cerebral damage
days 4-10
• Activation of proapoptotic pathways • Disruption of the blood brain barrier • Arteriolar constriction • Thrombosis and dysfunction of the microcirculation • Cortical spreading ischaemia
What occurs in Ischaemic stroke in the greatest recovery (days
7-14)
- Swelling subsides • Impairments resolve • Residual impairments may lead to permanent disability
What is the survival rate in Ischaemic stroke if they get another stroke within a year?
And what % of people do get another stroke within a year and why?
14% of stroke patients
have another within 1
year.
1 year survival
~60%
5 year survival
~31%
- usually the cause of the stroke isn’t treated.
What is the treatment of Ischaemic stroke?
- Prognosis is influenced by the time of treatment after the stroke.
- Early rehabilitation is important.
- Thrombolysis (clot-busting) with tPA;
• Tissue plasminogen activator (tPA) is effective in reducing morbidity rate in strokes by 30%. - The efficacy of tPA decreases with time (no effect after 3 hours).
- It is used to treat moderate severe strokes that are not improving in the ER.
Also physiotherapy;
Rehab through exercise.
What are some preventatives for stroke?
- Stop smoking
• Eat healthier, lower cholesterol intake
• Become active
• Aspirin – antiplatelet – to reduce platelet aggregation
• Anticoagulants – Warfarin, apixaban etc prevent clotting
• Antihypertensives – to reduce blood pressure
• Statins – to reduce cholesterol
How would we prevent, block or reverse the effects of cerebral ischaemia (stroke) ?
glutamate receptor blockers, thrombolytic agents.
Summarise the main pathophysiological events underlying cell death after cerebral ischaemia
(stroke)
- Energy depletion
- glutamate transporter reversal
- generation of reactive oxygen species
- cell death.
