01 November 2022

Article by Deppo Juneja

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Stroke, also known as cerebral infarction, is a critical medical condition that compromises respiratory and cardiovascular function and causes severe neurological deficits [1]. A considerable number of people experience recurrent or new stroke incidences each year [2]. Strokes can be classified into 2 main categories: Ischemic strokes. These are strokes caused by blockage of an artery (or, in rare instances, a vein). About 87% of all strokes are ischemic. Haemorrhagic stroke. These are strokes caused by bleeding. About 13% of all strokes are haemorrhagic [1].

StrokePreventive measures and improved healthcare led to a decrease of age-standardized stroke mortality rates over the last few decades, while the absolute number of people affected per year by a new stroke, stroke-related deaths, and the number of stroke survivors living in our societies considerably increased leading to a growing burden of disease and related disability [2]. From 1990 to 2010, mortality rates decreased in high income (−37%, 95% confidence interval [CI] −31 to −41%) and in low- and middle-income countries (−20%, 95% CI −15 to −30%). In the same time stroke-related deaths (absolute number), number of new stroke survivors, number of stroke survivors living in the society, and lost disability-adjusted life-years all increased (on average by +26, +68, +84, +12%, respectively). Similarly, the Global Burden of Disease Study 2015 group reported an increase of ischemic stroke prevalence (number of stroke survivors living in societies) by 21.8% from 2005 to 2015 (i.e., from 20,467.3 to 24,929.0) and of years lived with disability by 22.0% (i.e., from 2,999.9 to 3,659.9) during that time [3]. With the demographic developments to be foreseen, (population on average growing older in many countries or less dying from communicable diseases) these trends will continue and societies around the globe are well-advised to plan their healthcare resources and societal efforts to cope with the increase in neuro-disabilities efficiently.

Today, the standard treatments for stoke include aspirin regimens, recombinant tissue plasminogen activator (rtPA), and arterial recanalization technology [1, 4]. rtPA is the only Food and Drug Administration (FDA) approved treatment for acute ischemic stroke and works through a process called thrombolysis, but only half of the patients on this medication recover fully [1]. rtPA presents multiple contraindications, a modest success rate (around 35%), and a restricted time window for its efficacy [4]. There are safety concerns of using this method to treat patients who have undergone surgical procedures and those with other possible comorbidities. Due to these inadequacies, research on the drug has adopted the approach of mixing it with other substances to improve its effectiveness.

Neuroprotection is one of the major foci of drug research. Initiatives in neuroprotective medication aim to minimize the destruction caused to the neuronal tissue during stroke. Some of these drugs have shown promising results in animal tests but cannot replicate their effect during human clinical trials [5].

Drug Research
StrokeThe current approach for treating stroke concentrates on treating the acute phase [6]. This approach slows down ischemia progress, then effects reperfusion and reescalation of brain parenchyma. Moreover, the treatment entails minimizing neuronal cell damage and death triggered by ischemia and the metabolic cascade caused by abrupt reperfusion. The process involves using neuroprotective strategies and pharmacological approaches to slow down inflammatory feedback. Moreover, the treatment emphasizes retardation and rehabilitation of vascular disease progression to prevent additional strokes. A discussion of several pharmacological agents used in treating stroke provides an in-depth understanding of the drug development strategies. Generally, all pharmacologic treatments have three main objectives: prevention, neuroprotection, and reperfusion [5].

Most studies of stroke medication are based on models of ischemic stroke that analyse various mechanisms that occur during cerebral ischemic injuries. Insufficient oxygen levels trigger energy deprivation, and the arterial thromboembolic episode at the beginning is an ischemic cascade. The purpose of current trials on acute ischemic stroke is to liberate and reinstate ischemic penumbra within a particular treatment window [7]. Otherwise, energy abrogation will deteriorate ion homeostasis and trigger an increase in the extracellular concentration of potassium ions and a reduction in chloride and sodium ions in the same region. The anoxic depolarization causes glutamate release, development of reactive oxygen species, and dysregulation of calcium ions within the intercellular area. Expeditious recanalization must occur to avoid an ischemic case that causes neuronal tissue infarction. Several drugs are undergoing tests for their capability to encourage neuroprotective pathways, alleviate ischemic injuries, degrade fibrin, and hinder platelet coagulation and aggregation. Neuroprotective agents can shield ischemic neurons during the acute phase of the stroke.

Intravenous Thrombolysis (IVT): IVT intervention using alteplase is the primary form of treatment for patients with ischemic stroke, as long as physicians begin the treatment within five minutes of symptom onset. IVT with alteplase has been shown to improve clinical results and revive inflammatory response in patients with cerebral ischemia [8]. The reason for the urgency is because the benefits of alteplase are highly time-dependent [7]. Alteplase is a recombinant tPA and it works by initiating local fibrinolysis by binding fibrin within a thrombus and converting the entrapped plasminogen into plasmin. The resultant plasmin dissolves the thrombus [4].

Mechanical Thrombectomy: Mechanical thrombectomy is suitable for patients with acute cases of ischemic stroke because it involves making a large arterial occlusion within the anterior circulation. In most cases, these patients undergo an IVT before they are treated using the mechanical thrombectomy procedure, a treatment called bridging therapy [9].

Antithrombotic DrugsStroke
Antithrombotic drugs consist of fibrinolytics, anticoagulants, and antiplatelets. Fibrinolytics dissolve clots, anticoagulants stop the formation of fibrin strands, and antiplatelets hinder platelet aggregation. These medications do not affect existing clots, unlike thrombolytics which dissolve existing ones, but instead aim to limit their growth [10]. An example of a recently developed antithrombotic drug is Eptifibatide, an antiplatelet medication under the glycoprotein inhibitor class. This drug works by binding onto glycoprotein IIb or IIIa between an activated platelet’s arms, effectively stopping the binding agent from fibrinogen and constraining thrombi formation [11]. Researchers have combined the drug with heparin, aspirin, and intravenous rtPA treatments in varying doses to improve the shortfalls of rtPA medicine [4, 11]. 

Neuroprotective Therapy
Researchers have been studying neuroprotective medications for their potential to prevent partially damaged neurons from further injuries. These drugs seek to enhance functional recovery of damaged nerve cells in ischemic stroke patients. Essentially, they reduce stroke’s impact on brain tissues. Research on neuroprotective drugs is mostly focused on how these drugs can enhance neuronal healing and protect penumbral nerve ending from irreversible damage. Several neuroprotective agents exist, and these include glutamate receptors and related glutamate targets, magnesium sulfate, statins, melatonin, erythropoietin, and immunosuppressant drugs. Out of all the possible treatment modalities for stroke, neuroproteins have wide potential to provide an effective method for improving brain function [5].

Glutamate Receptors: Glutamine occurs throughout the human brain. Given its potential impact on neural function, the body must closely regulate glutamatergic neurotransmission levels to avert over-activating the system. Glutamate receptors are highly probable candidates for the development of neuroprotective medication, due to the role of glutamate during the excitotoxic cascade. However, studies on glutamate receptors have produced ambiguous results. Some studies have shown that activated GluN2A with receptors has a beneficial effect. Specifically, the application of GluN2A with NVP-AAM077 and NMDA receptors could improve neuronal apoptosis induced by oxygen-glucose deprivation, exacerbate excitotoxicity induced by DL-threo-betahydroxyaspartate or NMDA and encourage ischemic damage flowing ischemia [12].

NXY-059L: Diener et al. (2008) confirmed the potential of the agent NXY-059 in trapping free radicals and serving as a neuroprotectant. In these randomized, double blind, and placebo-controlled trials, ischemic stroke patients were administered intravenous infusion of NXY-059 within six hours before the onset of stroke symptoms [13].

Deferoxamine: Deferoxamine is an iron chelator and an FDA-approved drug for treating acute iron overload and chronic iron intoxication resulting from transfusion-dependent anaemia. Deferoxamine can penetrate the Blood Brain Barrier rapidly and accumulate within the brain tissue following systemic administration. Deferoxamine chelates iron by establishing a stable complex that bars iron from participating in more chemical reactions. In vivo, deferoxamine can minimize hematoma and haemoglobin–induced oedema. Some studies have demonstrated that deferoxamine reduces intracerebral haemorrhage-induced neural death, neurological deficits, and brain atrophy [14]. Deferoxamine works by binding ferric iron and preventing hydroxyl radical formation via the Fenton/Haber–Weiss reaction. Deferoxamine reduces haemoglobin-induced brain K+/Na+ ATPase inhibition and neural toxicity. Favourable effects of iron chelator therapy have been reported in multiple ischemia models [15]. Deferoxamine also acts as a free radical scavenger which can induce ischemic tolerance in the brain. However, the compound may cause hypersensitivity reactions, hypertension, and weight loss.

In conclusion, further research is needed to develop a drug that can effectively treat stroke. Although studies have explored a wide range of drugs, the main categories of potential treatment modalities include antithrombotic, thrombolytic, and neuroprotective drugs. While the FDA has approved a therapy to treat systems associated with acute ischemic stroke, especially thrombolytics, its side effects prevent widespread use. Current studies work to determine the impact of stroke and the drugs that could effectively treat these symptoms. Although studies have explored a wide range of drugs, the main categories to emerge from this research include antithrombotic drugs, thrombolytic drugs, and neuroproteins. Neuroproteins have demonstrated significant potential to relieve stroke symptoms through considerable research and more research on neuroprotection will elucidate these options.

1.    Tomkins, A.J., et al., Tissue Plasminogen Activator for preclinical stroke research: Neither "rat" nor "human" dose mimics clinical recanalization in a carotid occlusion model. Sci Rep, 2015. 5: p. 16026.
2.    Feigin, V.L., et al., Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet, 2014. 383(9913): p. 245-54.
3.    Disease, G.B.D., I. Injury, and C. Prevalence, Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet, 2016. 388(10053): p. 1545-1602.
4.    Gonzalez, R.G., et al., Good outcome rate of 35% in IV-tPA-treated patients with computed tomography angiography confirmed severe anterior circulation occlusive stroke. Stroke, 2013. 44(11): p. 3109-13.
5.    Chamorro, A., et al., The future of neuroprotection in stroke. J Neurol Neurosurg Psychiatry, 2021. 92(2): p. 129-135.
6.    Herpich, F. and F. Rincon, Management of Acute Ischemic Stroke. Crit Care Med, 2020. 48(11): p. 1654-1663.
7.    Ho, J.P., Acute ischemic stroke: emergency department management after the 3-hour window. Emerg Med Pract, 2021. 23(Suppl 6): p. 1-33.
8.    Seiffge, D.J., Intravenous Thrombolytic Therapy for Treatment of Acute Ischemic Stroke in Patients Taking Non-Vitamin K Antagonist Oral Anticoagulants. JAMA, 2022. 327(8): p. 725-726.
9.    Jadhav, A.P., S.M. Desai, and T.G. Jovin, Indications for Mechanical Thrombectomy for Acute Ischemic Stroke: Current Guidelines and Beyond. Neurology, 2021. 97(20 Suppl 2): p. S126-S136.
10.    Best, J.G., et al., Antithrombotic dilemmas in stroke medicine: new data, unsolved challenges. J Neurol Neurosurg Psychiatry, 2022.
11.    Jost, A., et al., Low-Dose Eptifibatide for Tandem Occlusion in Stroke: Safety and Carotid Artery Patency. AJNR Am J Neuroradiol, 2021. 42(4): p. 738-742.
12.    Wu, Q.J. and M. Tymianski, Targeting NMDA receptors in stroke: new hope in neuroprotection. Mol Brain, 2018. 11(1): p. 15.
13.    Diener, H.C., et al., NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II Trials. Stroke, 2008. 39(6): p. 1751-8.
14.    Zeng, L., et al., Deferoxamine therapy for intracerebral hemorrhage: A systematic review. PLoS One, 2018. 13(3): p. e0193615.
15.    Imai, T., et al., Deferasirox, a trivalent iron chelator, ameliorates neuronal damage in hemorrhagic stroke models. Naunyn Schmiedebergs Arch Pharmacol, 2021. 394(1): p. 73-84.