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The ischemic cascade in stroke
- [Voiceover] So we know that when you have stroke a blood vessel has been obstructed somehow and brain tissue subsequently dies. So I wanna show you some of the more important things that happen to neurons on a sort of zoomed in cellular level during a stroke. So here we've zoomed in quite a bit and you can see it's really, really complicated, but actually this is still a pretty simplified view of the set up of cells in our brain. I've shown just a handful here, but there are actually about a 100 billion neurons in your brain. So these here in blue, these are the neurons here, and they're connected to each other so they can pass messages between themselves and that allows the brain to control our bodies. So these connections are called synapse. Now just quickly, these here in green, these are astrocytes. These are really important cells in the central nervous system. For example, they reinforce the blood-brain barrier, they nourish our neurons, and they have many, many other roles. These here in this sort of dark bluey, purple here, these are oligodendrocytes. And what they do is they give structural support to our neurons. And they also allow our neurons to transmit their signals a bit faster. Of course these are blood vessels here, little bits of capillaries. So during a stroke when a blood vessel has been obstructed, and I'll just show a bit of an obstruction here, a clot of some kind, let's just look at some of the key events that happen on a neuron level. A series of events called the ischemic cascade, which is actually a slight misnomer, because many of these events happen at the same time, and they don't necessarily depend on each other to happen, but you'll see what I mean as we get into it a bit. So the ischemic cascade. So without blood supply, and therefore a lack of oxygen, neurons will lose their ability to create energy in the form of ATP through aerobic metabolism. So the neuron then goes onto plan B for energy production, it switches over to anaerobic metabolism, which is what happens in the absence of oxygen. But there's two problems with anaerobic metabolism in humans. First, it doesn't produce even close to the amount of energy that we need, it produces about 15 times less energy than aerobic metabolism. And second, it produces a byproduct called lactic acid, which if in high enough quanities it disrupts the normal acid-base balance within the brain. And it can actually damage your neurons. So we don't want too much lactic acid hanging around. So I mentioned that the cell has less energy production happening, how exactly does this change the cell's function? Well, in a few different ways. So let's start with the cell's membrane transport system. So you got this sodium potassium pump embedded in the cell membrane, and what it does is it pumps sodium out of the cell and it brings potassium back into the cell, and without ATP this pump stops working because it relies on ATP energy, it relies on that ATP energy to do its job. So sodium starts to build up inside the neuron, because it's not being pumped out, right? And when water, in this extra cellular fluid, this ECF here, notices this high concentration of sodium in the intracellular fluid, in the ICF, the water rushes inside the neuron to try to dilute out that high concentration of sodium in the neuron. So what ends up happening from there is that the neuron now starts to swell because it's being filled with so much water that's trying to dilute that high sodium concentration. And this situation is called cytotoxic edema. Cyto referring to our cell here, toxic because it can kill the cell, and edema meaning swelling. And this happens early, this is one of the earliest things that happens when there's not enough energy around. What else happens? Well this sodium calcium pump stops working as well, and you'll see how important this is. It normally brings sodium into the cell and sends calcium out of the cell, but if it stops working you end up with this ever increasing amount of calcium building up inside of the cell and that's not really what we want for three major reasons. So for one, and up here we'll just call this excitotoxicity, and you'll see what I mean in a second. So high calcium in the cell causes messengers, like glutamate, to be released from the end of the neuron. So these messengers are collectively called neurotransmitters. So you get this neurotransmitter release because of the high calcium, and this neurotransmitter then diffuses off and excites other neurons, because it's an excitatory neurotransmitter. And so in their excitement these other neurons bring in calcium themselves, which in turn causes them to release more glutamate, and then this glutamate goes on to excite other neurons, and so on. So it's a bit of a vicious cycle of neuron excitement and neurotransmitter release that goes on. Which ultimately is a bad thing, because over-exciting neurons is potentially toxic to them. The second reason we don't want too much calcium in our neurons is because too much calcium will activate degradative enzymes. So the calcium will activate proteases, which break down proteins inside your neuron. And the calcium will activate lipases, which break down the neuron cell membrane. Obviously that sounds pretty bad. So you can imagine that if your cell membrane starts to break down all sorts of other ions and harmful chemicals will enter the neuron and start to cause damage, so that's no good. And the third reason we don't want too much calcium is that too much calcium causes free radicals and reactive oxygen species to be generated. So these are little harmful chemicals that lead to further neuron damage, particularly of the cell membrane. So I described cells dying by cytotoxic edema, and by calcium dependent mechanisms, but there's also another important way that neurons can die after a stroke. You might be familiar with mitochondria, the organelle responsible for energy production in the cell. Well with all these toxic chemicals swirling around in the cell and the lack of their normal environment happening in the cell the mitochondria themselves start to break down. And when they break down they release proteins called apoptotic factors into the cytoplasm. So they have a funny name, apoptotic factors, but what they do isn't quite as funny, because they cause the apoptosis cascade to happen. And that causes cells to essentially commit suicide. So there's a look at some of the major events that happen as part of the ischemic cascade and three ways that cells might die as a part of the ischemic cascade.