Lecture 28; Ischemia Brain Injury 5

Question 1

What treatments are successfully neuroprotective?

Answer 1

Many things have been tried and many things have been found to be neuroprotective.

Esp. EEA blockers

Question 2

How many Current successful clinical trials of drug induced neuroprotection in adult stroke or perinatal brain injury exist?

Answer 2

~1 Thrombolytic agent

BUT

Must be given within 3hrs and is only useful for 1% of stroke patients.

Question 3

Does excitotoxicity play a role in brain damage?

Answer 3

Accumulation of excitatory NT and brain damage has very little correlation

Question 4

What did they find when they antagonised NMDA receptors?

Answer 4

Glutamate antagonists reduce neuron loss

But also extend hypothermia…

Then in normothermia trails the protection was lost opening up a line of inquiry for hypothermia protection

Question 5

Why was NMDA not being neuroprotective predictable?

Answer 5

Predictable b/c NMDA receptor is not the major source of Ca into the cell during ischemia.

Also Ca is only ONE trigger of intracellular death pathways

Question 6

Whats the major source of Ca into the cell during ischemia?

Answer 6

NCX is reverses when the gradient is lost.

Also non specific Ca leakage and other channels.

Question 7

Whats the relationship between hypothermia and the onset of ischemia depolarisation?

Answer 7

Temperature linearly delays the onset of ischemic depolarisation

Question 8

What does hypothermia do to the cells?

Answer 8

Decreases metabolism during global ischemia, delays onset of ischemia depolarisation (minutes)

Question 9

How does hypothermia change the time to 50% cell death?

Answer 9

Hypothermia drastically extends the time it takes for 50% cell death to occur and extends the duration of ischemic depolarisation. (Time it takes for ATPase to gain back function)

As well as the onset time.

As measured by DC

Therefore Hypothermia is more than just delayed energy depletion..

Question 10

How does temperature and metabolism correlate?

Answer 10

Every degree drop in temperature reduces metabolism by 5%

Question 11

Describe the relationship between hypothermia and metabolism?

Answer 11

Protection of hypothermia is disproportionate to the reduction in metabolism.

Disproportionate increase in the resistance to hypothermia.

Note* very few actually reached the estimated 50% cell death in these investigations

Question 12

Does hypothermia affect glutamate accumulation?

Answer 12

Hypothermia suppresses glutamate accumulation

Question 13

Does hypothermia affect Ca?

Answer 13

Hypothermia does not affect the rate of fall of Ca2+or the nadir of fall during Ischemia

Effect parallels onset of anoxic Depolarisation

Suggests that hypothermia is protective through other mechanisms

Question 14

What disproves glutmate causes damage?

Answer 14

Same duration and level of hypercalcemia regardless of temp.

Therefore Glutamate has no effect

Question 15

When cells were cooled and exposed to toxic levels of Ca did it have an effect?

Answer 15

Cooling during glutamate exposure = no effect

Question 16

What is the summery of the glutamate hypothermia studies?

Answer 16

Intra-ischemic hypothermic protection does notdepend on reducing toxins

In fact even in vitro, hypothermia seems acting by alleviating some of the downstream effects of ischemia

Question 17

What did cooling after HI do?

Answer 17

cooling after HI preserved oxidative metabolism

Cooling 0-12 h after hypoxia-ischaemia prevents failure of oxidative metabolism

NTP measure used to indicate energy metabolism

Question 18

What did immediate cooling in rats after HI show?

Answer 18

Cooling reduced infarct size

Question 19

What questions were developed after discovering that cooling during the latent phase reduced damage?

Answer 19

How latecan we wait?
How long is long enough?
How much should we cool?

Question 20

What happens in the latent phase?

Answer 20

Mitochondrial failure starts as measured by cyotchome oxidase

Prev. lectures

Question 21

What did EEG show for cooling group?

Answer 21

They had preserved background activity

Also cooling suppressed secondary swelling

Question 22

When does cooling need to occur?

Answer 22

Within the first 6 hrs, ASAP for best results

Question 23

How cool can you go?

Answer 23

32-34 for sheep is optimal

Deeper cooling results in neuronal damage and loss of protection

Question 24

How long do we cool for?

Answer 24

Needs to last through secondary events, short brief cooling is ineffective

Question 25

Summerise the timing of cooling;

Answer 25

Delay in cooling until the secondary phase dramatically reduces neuroprotection.

Cooling at 33-34°C is most optimal when started within the first few hours after the insult

Tx in the latent phase (first ~~ 6 hours after injury) appears to be critical but not sufficient

Question 26

What does hypothermia do?

Answer 26

Decreases inflammation and caspase 3 activation