Thank you for joining us on this talk about neuroprotective agents. My name is Luis Efkava. I'm one of the associate professors in the Department of Neurosurgery at the University of Colorado School of Medicine. I do not have any disclosures. And we're going to talk today about knowing and identifying some of the available agents and their potential role in neuroprotection and also review what's the evidence behind these agents. When we talk about neuroprotection, basically we're trying to prevent secondary neurological injury. Obviously, there is nothing we can do as far as a primary one, being this ischemic stroke, a TBI, a supra-angular hemorrhage, which has already occurred. But there are other damages that can happen to additional brain tissue that can be very determinant in the patient's neurologic outcome. In general, neuronal damage following any kind of injury is going to trigger a cascade of events, including failure of energy formation from oxygen and glucose, membrane depolarization, intercellular calcium excess due to the influx of ions inside the damaged cells, which are going to trigger apoptotic mechanisms and mitochondrial damage and also the formation of free oxygen radicals, which are going to be really neurotoxic as well. Looking for agents or for treatments that can prevent further neurological neuronal damage by interfering with these mechanisms that I'm showing right here is something that we have been looking in neurosciences for quite a long time. Unfortunately, some of these agents have shown some benefit in particular populations of patients, but that utility cannot be generalized, you know, even to a subcategory of neurological damage. And more research and randomized clinical trials are needed in order to determine the actual benefit that these agents can provide to our patients. Neuroprotection, like I said at the beginning, is the prevention of further neuronal loss interfering with cellular pathways and then basically saving the neurons in the brain from further irreversible injury. So there is a point at which these neurons can actually be safe before they go into apoptosis. And, you know, drugs of different categories, and some of them we use them already, you know, for example, you know, anti-Alzheimer's, anti-Parkinson's agents, they do have some neuroprotective effect, you know, in these diseases and also antischemics, as we're going to review. And these agents basically, you know, decrease or aim to decrease inflammatory processes and apoptosis, attenuate the oxidative stress, and the reduction of free radicals. It could potentially be, you know, associated with improved functional outcome, but that's mostly an individual case-by-case basis. And like I said, more research is needed to make a generalization of the utility of these agents. And we need to, you know, basically have more data before we're able to standardize the use of neuroprotective agents. There are several types of injury that can actually trigger the mechanisms that lead to further neuronal death. You know, ischemic stroke is one of them, definitely the lack of oxygen supplies and glucose to the brain due to endovascular occlusion is going to cause a release of excitatory neurotransmitters, and also, you know, a free radical shock, you know, with low blood pressure is going to affect as well the brain. You guys are probably really familiar, you know, with hypoxic and oxygen injury, and that occurs basically in a status of shock when there is not enough, you know, blood supply to the brain or cerebral blood flow that can lead to neuronal death as well. Sepsis, not only for the effects of sepsis in the blood pressure, but also for the inflammatory state that, you know, generalizes to the brain as well. Traumatic brain injury, you know, due to high intracranial pressure, hematomas, cerebral edema, also can, you know, play an important role in the cellular decay. And other conditions such as supraagnohemorrhage, especially cerebral vasospasm, which is a very good example of neuroprotection with the use of nemoripine, and we'll talk a little bit more about that in a couple of slides, that, you know, prevents the development of delay, cerebral ischemia, calcium influx, and so forth. Talking about, you know, particular agents that can actually intervene in neuroprotection. One of our examples is nemoripine that I was, you know, referring to before, and it's the only agent that has been proven to improve neurological outcome in aneurysmal supraagnohemorrhage in humans. It has extensive clinical use. We have used it in a significant fashion in supraagnohemorrhage, and sometimes in also post-traumatic and post-infectious, part-infectious, excuse me, vasospasm. And basically, contrary to the common belief that nemoripine actually causes a vasodilation of the intercranial vasculature, what it actually does is inhibits the intracellular influx of calcium, therefore preventing the activation of the apoptosis cascade. So this is just a first example of a neuroprotective agent, you know, that we are already using with a lot of evidence behind it. And basically, we're going to go, you know, from here, describing other agents. The classification of them, you know, one of them was nemoripine, in the case of calcium channel blockers. We also have glutamate blockers, glutamate and NMDA channel blockers, statins, hematopoietic growth factors, free radical scavengers, actually mucamist, you know, can also be used as a neuroprotective agent, and beta blockers, especially in the case of trauma, TBI, and autonomic dysregulation, and also COX-2 inhibitors. Let's go and see what, you know, each particular class of drug that can be used as a neuroprotective agent. One of them is glutamate blockers. And they basically inhibit the glutamate binding to especially the NMDA receptors. They also reduce the oxidative stress and preserve the mitochondria and reduces the influx of calcium and a different mechanism as nemoripine, you know, so to speak, and also has a clinical effect that has been studied in animal models and humans as well of reducing the infarct volume, cerebral swelling, and improving functional outcomes. This is very important to take into consideration because glutamate and the NMDA receptor especially are really involved in an array of different neurological diseases, you know. One of them is NMDA receptor encephalitis, for example, and the blockage of that receptor actually leads to better outcomes. But in general, you know, any glutamate blocker that can potentially be used in any kind of neurologic injury. A very common, you know, electrolytes that we use, magnesium, can also have effects on blocking the glutamate receptors and NMDA channels. There was a prolonged use or a long history of use of magnesium in subarachnoid hemorrhage, but now the evidence basically supports that intravenous magnesium does not provide with additional protection against delayed cerebral ischemia in subarachnoid hemorrhage. We do believe nowadays that it's a concentration of magnesium in the CSF, the one that can have some neuroprotective effects, and there is a lot of research that is being done in this regard, you know, with intrathecal placement of magnesium in hopes to, you know, decrease the risk of developing or improving the severity of vasospasm. Free radical scavengers, of course, is a no-brainer. The main issue with this is also the metrics of outcome. What are we looking into, right? Are we looking into a good functional outcome? Modifying rack-and-scale is different. And I think that the studies need to be done in a little bit more homogeneous population model, you know, proving it not for all kinds of neurologic disease at once, but in each particular subset of them. And there is several agents, especially Oxiris-Beratrol, for example, that is very promising. But at this point, there is no proven effectivity in human trials, and we need to, again, you know, focus on more specific direction of the research in each particular subset of a neurological injury. Beta blockers, as we were, you know, talking about at the beginning, particularly in the case of traumatic brain injuries, and especially with the use of propranolol, as you guys are probably more than naturally, you know, familiar with, can lead to lower mortality rate and also reduce the infarct volume as well, with some effect of attenuating inflammation mechanisms, you know, through blocking TNF and interleukin-1 beta and also inhibiting apoptosis. Another agent that has been used for a long time as well in suprarhino hemorrhage for the prevention of secondary injury due to cerebral vasospasm and delayed cerebral ischemia. You know, the evidence is still kind of shaky. There is several centers that were still using statins, you know, in combination with nemolepine in suprarhino hemorrhage patients. And our studies have been proven to have a strong antioxidant and anti-inflammatory action. So that's something that's very important about the properties, of course. Mucamys, you know, in acetylcysteine has several mechanisms that can potentially help, amongst them increasing the levels of glutathione in the cells that prevent oxidative stress, increasing, you know, the tissue oxygenation through the mechanism of nitric oxide, also acting as an electron donor, preventing free radical damage, and also decreasing the inflammatory effect of TNF that would lead to endothelial apoptosis. Thiopental, barbiturate that is not used as extensively as it used to be in the past, but any barbiturate actually has the ability to suppress neuronal function, so to speak, putting the neurons to sleep, suppressing, you know, electrophilographic activity, and hence decreasing the amount of energy that a cell needs to survive. So basically, it's something that has to be used, you know, with care, especially, you know, nowadays, as you guys know, we use pentobarbital in cases of severe refractory, you know, status epilepticus, and also refractory increased intracranial pressure, and with good results in terms of decreasing the amount of oxygen that the cells require in order to function, somewhat providing in that fashion a neuroprotective effect. The next one is ketamine, which is a quite interesting agent, because also blocks the, or is an antagonist of the NMDA receptors, and actually, you know, has a good effect in terms of actually controlling the ICP, contrary to some belief that ketamine can increase ICP. It does not increase the ICP, but actually can have an effect of decreasing the ICP, and also preventing post ischemic, you know, damage of the neurons. If you remember during the COVID days, not too long ago, when we ran out of, you know, anesthetics, such as Propofol, for example, to keep patients on the ventilator, we used ketamine, you know, quite extensively, and actually had a very good experience in terms of ICP control, and, you know, some of them actually leading to believe that there is a neuroprotective effect as well from the blocking of the NMDA receptors. So it's a drug that is really good to keep an eye on in terms of when we want to preserve neurological function, especially in patients with increased intracranial pressure. Other agents, the calcineurin inhibitors have been known for a while to have some neuroprotective effect. As you guys know, there are also immunosuppressants that are used, for example, in trauma, I'm sorry, in transplant patients, and also in patients without immune diseases, of course. But it does have, you know, an effect on reducing inflammatory cascades that can lead to hypoptotic, you know, processes and neuronal death as well. Imidate is another drug that we sometimes use, you know, rapidly, you know, induction for intubation in patients that, you know, cannot protect their airways. But it also has effects of decreasing brain metabolism, inhibiting, you know, post ischemic epiremia, which can cause, you know, a release of free radicals in a significant fashion, and also mediating, you know, vascular inflammation. But also, it has, unfortunately, an effect in inhibiting the natrioxysynthetase, which can actually intensify the ischemic insult form due to vasoconstriction. Another agent that was talked about for quite a long time, you know, is acetylcholine. It actually has good properties in terms of, you know, increasing neurotransmitter levels in CNS and, you know, reducing inflammation at the same time. It has been used extensively in some centers, you know, for Alzheimer's, stroke, Parkinson's. It also has an effect of reducing intraocular pressure. But at this point, you know, there is more trials that are needed in order to demonstrate its efficacy as a neuroprotective agent. The next consideration would be also hypothermia. It's not a pharmacological agent, obviously, but it's a measure that can be taken sometimes in order to, you know, seek to protect the brain, decreasing the amount of oxygen that the neurons are consuming. Granted, there is no evidence that actually provides neuroprotection, but up to now, and I think there are more trials that are more homogeneous are needed with particular subsets of patients with no crossover between pathologies or severity of pathologies. I think that if a good design trial is conducted, we can potentially see some neuroprotective properties of hypothermia. But what it does for sure, and indirectly, you know, will be neuroprotective as well, is it has a significant effect in controlling intracranial pressure, which can increase definitely, you know, cerebral blood flow and, you know, prevent neuronal death in that fashion. But like I said, that's not proven. It's used currently for controlling intracranial pressure and, again, indirectly, you know, providing neuroprotection in that regard. So those are the agents and the measures that I wanted to show you, and I basically wanted to conclude this brief presentation that, you know, the reason why there is not a protocol or there is not a, you know, widespread use of these agents for neuroprotective purposes is that we need, you know, more strong evidence in clinical outcomes and the speed of patient recovery. The strongest evidence that we can find in the literature, you know, basically support the use of ketamine, etomidine, acetylcholine, in a case-by-case basis. And the level B2, you know, evidence, you know, for barbiturates and beta blockers. Basically, more research needs to be done, and I think these agents and measures have a lot of potential. And, again, you know, designing a more homogeneous clinical trials, hopefully, will lead for us to find more strategies and use of these agents to prevent secondary neurologic injury. I wanted to thank you for the attention and the time, and I hope you guys found this presentation useful in your practices. Thank you.

Neuroprotective agents

cellular pathways

oxidative stress

intracranial pressure

neurological injuries