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2024 AANS Neurosurgical Topics for APPs - On-Deman ...
Neuroprotective Agent – Luis Cava
Neuroprotective Agent – Luis Cava
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Video Transcription
Hello, everyone. I want to welcome you to this quick talk about neuroprotective agents, and I also want to thank the American Academy of Neurological Surgeons for giving me this opportunity to reach to you for the records I have not disclosed to report. And the objectives of this talk are basically to know the available agents and their potential use in neuroprotection, as well as the evidence that's behind the use of these agents. When we talk about neuronal damage, we can talk of several biochemistry pathways in which they are going to occur, mostly because of the failure of the formation of energy in the form of ATP because of the replenishment of oxygen and glucose due to systemic and cerebral perfusion. Also, acidosis, membrane depolarization and cerebral edema, the influx of calcium ions inside the neurons, which are going to trigger apoptosis, mitochondrial damage, and also the formation of free oxygen radicals. Neuroprotection basically means that we're going to try to prevent the neuronal loss that is caused by several pathways that are quite complicated, hence making neuroprotection more difficult to attain. And the main objective is to preserve the function and the structure of the neurons. They should be able to use to save ischemic neurons from irreversible injury basically. And examples of other neurological agents that can be considered also as neuroprotective ones are the Alzheimer's, anti-Parkinson's, and anti-ischemic medicines that we use in our practices. The mechanism of action of these agents basically goes through the decrease or inhibition of inflammatory processes and apoptosis, the attenuation of oxidative stress, and also the decrease in the formation of free radicals. Their use could potentially be associated with better functional outcomes. However, there is a lot of data that is lacking and more work that needs to be done. And the efficacy of these agents is still controversial, as I mentioned, due to the data that we have up to date. General concepts and general conditions that can cause further neuronal damage is ischemic stroke, basically formation of free radicals, influx of calcium ions inside the neurons that trigger apoptosis, shock due to the decrease of ATP formation, the decrease in the pH, you know, that is going to cause metabolic neuronal arrest, sepsis due to the oxidative effect of free radical formation from pro-inflammatory processes as well. TBI, because, as we know, increases intercanial pressure for contusion, and then that can lead to cerebral damage as well, cerebral death. And other conditions such as under-recent rupture, subarachnoid hemorrhage, that can lead to cerebral vasospasm, delayed cerebral ischemia, apoptosis due to the calcium influx. So all of those examples basically lead to what we call secondary neurologic injury. And we cannot change the fact that primary neurological injury has occurred already from an IPH, TBI, subarachnoid hemorrhage, brain tumor, so to speak, and cerebral edema. But the potential usefulness of these agents to prevent secondary neurological injury that can potentially make the morbidity and mortality, you know, be higher in our patient populations. Amongst the drugs that we count in this category of neuroprotective agents, we can call, you know, the calcium channel blockers, glutamate blockers, the ones that act on the NMDA channels, HGF, free radical scavengers, N-acetylcysteine, beta-adenergic receptors, and as well as COX-2 inhibitors. Calcium channel blockers, I think the main example of this category is nemolipine, which is the only agent that is proven to improve the outcome in under-recent subarachnoid hemorrhage in humans and has extensive clinical use. What it does is basically inhibits the intracellular influx of calcium, therefore prevents the patient's neurons from going into apoptosis. So it's not necessarily just a basal dilatory effect, but it's actually the decrease of the influx of calcium inside the neurons. Glutamate blockers, basically because they block the excitatory effects of the NMDA and AM receptors, decreases the risk of oxidative stress, reduces the influx of calcium as well, and reduces, potentially induces, the infarct volume, cerebral swelling, and improves some functional outcomes due to the fact that it's going to prevent further neurological damage. Other glutamate blockers, NMDA channel blockers, and magnesium have been shown to activate the enzymatic process to increase the formation of ATP, regulating the intracellular calcium availability as well, optimizing mitochondrial function. Magnesium also, to some extent, blocks NMDA receptors and hence can lead to analgesia and neuroprotection, and it has been used, you know, sometimes to neuroprotective effects in hemorrhagic and ischemic strokes. What we know for sure, because the data is very lacking as far as the use of magnesium, is that low serum levels is associated to high mortality rate, and high CSF levels is associated with worsening, you know, cerebral ischemia due to cerebral vasospasm. Free radical scavengers, effectiveness is due to the entrapment of free radicals, decreasing the oxidative damage to proteins that they can cause. Several agents, you know, oxy-resveratrol, when it's been talked about a lot over the last few years, or other agents like PEG-SALT or NXY-059, but there is no proven effectivity in human trials thus far, but the concept is definitely very appealing, you know, for use at some point to find a molecule that will provide with effective neuroprotection. Beta blockers such as Esmolol, Labetarol, Metoprolol, or others, especially used in traumatic brain injuries, has been shown to decrease mortality rate, also to treat autonomous reflixia, which can cause increase in cerebral oxygen consumption, which can lead to increased ICP and worse outcome as well, and also inhibition of apoptosis. Stylings are another example, you know, thermostatin, rosuvastatin, basically ischemic stroke and supra-angiohemorrhage, mostly for their antioxidant, anti-inflammatory action. There is a lot of studies that have been done over the last few years in terms of stylings as improving outcome of their anticancer hemorrhage as well, due to their anti-oxidative effect. Inositylcysteine increases the level of glutathione, basically blocking the effect of free radicals and preventing oxidative stress, inhibits, you know, the nitric oxide synthetase, and hence is going to increase the tissue oxygenation, and also inhibits further vascular damage, you know, and the TNF-alpha activation as well. Thiopental and other vibratory rates, you know, suppress basically the brain, suppresses it effectively in the electrocephalogram, decreases the amount of cerebral consumption of oxygen, then reducing the amount of required ATP to keep the neurons alive, basically that reduces the metabolic activities of the brain, hence providing for neuroprotection. Ketamine is a drug that we have been using more and more lately for both intracranial hypertension and also refractory status epilepticus. It does not increase ICP, it actually decreases it, and it can decrease the postischemic nerve cell death due to the activation of NMDA receptors. Cyclosporine and tracrolimus, most commonly used, you know, in transplant medicine, they have some qualities that decrease the ischemia-related, you know, to brain injury through inhibiting the calcineurin and also decreasing the interleukin-2, basically, you know, blocks inflammatory response that will lead to further neurological injury. It terminates that we use quite commonly in the ICU for rapid sequence intubation, and sometimes in some procedures it has the ability to decrease the brain metabolism and also inhibits the nitric oxide synthetase, which could potentially, you know, intensify the ischemic insult. So we've got to be careful with this dual effect. CD calling is something that, especially in Europe, is used extensively as a neuroprotective agent because it can increase the neurotransmitters levels in the CNS, and it has been used, you know, in the potential neuroprotection in Alzheimer's, stroke, Parkinson's, glaucoma, and others as well. But more data, more clinical trials are needed. Other measures that can be used besides, you know, pharmacological agents for neuroprotection and something that has been talked about a way for a long time now, there are some clinical trials that are ongoing for it, is hypothermia. We know hypothermia works for control of intercanic hypertension. We know that hypothermia decreases the cellular consumption of oxygen, but so far it has not been proven to improve neurological outcome, but more trials are needed. There are trials ongoing as far as, you know, the effect of hypothermia in the outcome of TBI, for example. So in general, you know, the use of neuroprotective agents should be supported by strong evidence improvements in clinical outcomes and the patient's speed of recovery. For level A evidence, you know, ketamine, atomy, and CT calling for neuroprotective agents can be used in a case basis. Ketamine, like I said, intercanic hypertension, refractory status epilepticus, CT calling, acute ischemic stroke. Level 2 evidence for thiopentel due to the effect of decreasing, and other barbiturates, of course, for the effect of decreasing the cellular consumption of oxygen, beta blockers, and basically the bottom line is that we need more research, we need more randomized clinical trials in order to start using these drugs more effectively and widely. That was the end of my short talk. I want to thank everybody for your attention, and I hope to see you next year as well. Thank you.
Video Summary
The talk discusses neuroprotective agents, focusing on their potential to prevent neuronal damage through mechanisms like reducing oxidative stress and inhibiting apoptosis. While some agents like calcium channel blockers and glutamate blockers show promise, there is still insufficient evidence for widespread use. Various conditions causing secondary neurological injury, such as ischemic strokes and traumatic brain injuries, are explored. Drugs like ketamine, beta blockers, and cyclosporine are considered for their neuroprotective effects. Adjunctive measures like hypothermia are also mentioned. The speaker emphasizes the need for more research and clinical trials to validate these treatments' effectiveness.
Keywords
neuroprotective agents
oxidative stress
ischemic strokes
traumatic brain injuries
clinical trials
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