Stroke: Evolution of newer treatment modalities for acute ischemic stroke

Table 1 Summary of modalities for treatment of stroke

Ref.	Basis	Advantage	Disadvantage
Established treatment modalities[66]
Alteplase, reteplasea, and tenecteplase	Thrombolytic (fibrin)-convert plasminogen to plasmin directly and within 4.5 hours	FDA approved treatment modality. Good outcome when treated within specified time window. Incomplete recanalization	Disrupts blood brain barrier. Chances of hemorrhagic transformation. Reperfusion injury and brain swelling
Streptokinase and staphylokinase	Thrombolytic (non-fibrin activators)	Same as above	Same as above
Ancrod	Defibrinogenating agent derived from snake venom	Favourable functional recovery. Lower prevalence of intracerebral hemorrhage	Potential risk of bleeding
Endovascular therapy	Overall outcome of acute ischemic stroke patients with proximal middle cerebral artery or internal carotid artery occlusion was improved when endovascular thrombectomy was performed within either 6 hours, 8 hours, or 12 hours of symptom onset	FDA approved invasive treatment modality. Promising result. Less chances of disrupting blood brain barrier. Less chances of haemorrhagic transformation	Applicable in anatomically more proximal large vessel occlusion only not for small vessels. Needs expertise. Done in selective centres only. Reperfusion injury. Downstream embolization
Nimodipine[67]	Second-generation 1,4-dihydropyridine calcium channel blocker. Neuroprotective effect by preventing calcium overload in ischemic neurons	Useful in aneurysmal SAH. Can also be administered through nasogastric tube	Risk of hypotension. Drug interactions need consideration
Early drain (outcome after early lumbar cerebrospinal fluid-drainage in aneurysmal SAH)[68]	Lumber drainage vs external ventricular drain. Erythrocyte sedimentation by weight and potentially easier removal by lipid droplets	Associated with benefits in relation to rates of vasospasm, secondary cerebral infarctions, and mortality, without an increased risk of adverse events	Needs further trials. Limited to aneurysmal SAH cases only
Antiseizure medications	For 7 days in patients with seizures but without prior epilepsy	Prevents post stroke epilepsy	Needs further research
Newer modalities
Hydrogen gas therapy[69]	Mop up the reactive oxygen species into free water. Buffer the effects of oxidative stress	Basic study on neutralizing free oxygen radical and reducing oxidative stress	Researched in animal model but yet to be exploded in human
Nicotinamide adenine dinucleotide phosphate oxidase inhibitor[70]	Rho-kinase inhibitor inhibits the nicotinamide adenine dinucleotide oxidase and limits reactive oxygen species production	Reduces oxidative stress thus delayed neuronal death	Researched in rat models of ischemia/reperfusion injury. Studied in asthmatic pt not in stroke pt
Edaravone (matrix metalloproteinase inhibitor)	Scavenges free radical by preventing matrix metalloproteinase in neuronal cell membrane	Prevent blood brain barrier leakage. Reduces brain edema. Attenuate microglia induced neuronal death	Further research is needed. Side effects are lymphoma, deranged lung function test, renal toxicity, thrombocytopenia, pneumonia
Fingolipod[34,35,71]	S1P1 receptor modulator. It downregulates the S1P1 receptor in T lymphocyte which prevents egress of lymphocyte to inflamed tissue. Acts synergistically on glycoprotein receptor on platelet and prevent platelet aggregation and further thrombus formation	More effective after receiving tPA treatment by reducing haemorrhagic transformation (fingolimod plus alteplase < 6 hours from last known well) in human study. Also attenuates blood brain barrier leakage and reduces infarct volume, reduced blood lymphocyte counts, and improved mRS at day 90	Ineffective in thrombocytopenic pt and patients on antiplatelet therapy. More human study needed. Small trials
Caspase Inhibitors[37,38]	Cytochrome c mediated caspase activation which leads to apoptotic cell death after hypoperfusion and reperfusion period VX-740 (pralnacasan) and VX-765 (belnacasan) are two analogue peptidomimetic inhibitors of caspase 1	Protect blood brain barrier integrity. Post-experimental mice are healthy and fertile	Targeted drug delivery is a major hindrance for blood brain barrier. Liver toxicity in long term use. Very few clinical trials in animal
Uric Acid[40]	Uric acid in combination with tPA has good stroke outcome by its free radical scavenging property	Uric acid in combination to intravenous thrombolysis and mechanical thrombectomy reduced mortality (8%–4%), good result in human study	More trials are needed
Metformin therapy[39]	Metformin acts by adenosine monophosphate activated protein kinase activation in brain tissue and also by reducing oxidative stress	Post-stroke chronic treatment enhances long-term functional recovery and brain repair within clinically relevant therapeutic windows	Very narrow therapeutic window in stroke pt. Time of administration is also an issue. Needs more studies
3K3A[41]	APC, a protease with anticoagulant and cytoprotective activities. Protects neurons and cerebrovascular endothelium from ischemic injury. Newer recombinant 3K3A-APC has been studied with less anticoagulant effect and more neuroprotective activity	Though rAPC bleeding is an expected pharmacological side effect, there was no other systemic side effect noted in experimental animals and that is a strong support for proposal for human study	Recombinant APC, drotrecogin alfa (activated) was approved by the FDA for the treatment of sepsis but has dose limited chance of bleeding. Still in preclinical trial for stroke (used in severe sepsis which is FDA approved)
Iv glyburide[42]	Acts by blocking sulfonylurea receptor 1-transient receptor potential melastatin 4 chnnel	Prevent midline shift by reducing penumbral edema	Results of human studies are promising
AI[43]	AI has changed prehospital assessment by imaging in ambulance, diagnosing, selecting patient for further treatment	Massive impact in golden hours in form of prompt imaging, diagnosis and treatment. Cost effective. Time saving. Can be started treatment during prehospital transit	Necessity for high quality data, “black box problem” i.e. machine needs continuous upgradation with newer data for reasoning and accuracy
Stem cell therapy[48,49]	Neurorestorative benefits. Three types are in study BMSC, NSC and umbilical cord blood stem cell	NSC has robust safety margin but pending further trial. MSC and BMSC has also immunomodulatory property to attenuate poststroke inflammation along with neuro regenerative property	BMSC treatment of stroke has proven safe, but otherwise ineffective in clinical trials. All are in preclinical trial stage
Nano technology for targeted drug deliver[50]	Nano particle containing magnetic particle with thrombolytic agent has been studied for loosening of clot by sono stimulation and magnetic stimulation	More powerful effect. Longer half life. Increased clot penetration. Making the thrombolytic agent safe. Precise delivery confirms more detail delineation of image	Studies have been conducted in otherwise healthy animal but patients suffering from stroke may have reduced cerebral reserve

APC: Activated protein C; AI: Artificial intelligence; BMSC: Bone marrow stem cell; FDA: Food and Drug Administration; NSC: Neural stem cell; SAH: S-adenosyl homocysteine; S1P1: Sphingosine 1-phosphate; tPA: Tissue plasminogen activator; mRS: Modified Rankin Scale.