ReviewFoundationCurrent therapies in ischemic stroke. Part B. Future candidates in stroke therapy and experimental studies
Section snippets
Desmoteplase
Desmoteplase from the saliva of vampire bats might be more fibrin-specific, in comparison to recombinant tissue plasminogen activator (rtPA), and therefore might be a safe thrombolytic agent because it has the effect of catalyzing the conversion of plasminogen to plasmin. In comparison to rtPA, desmoteplase has a high fibrin selectivity (100 000- versus 550-fold increase in catalytic activity), shows no neurotoxicity, and no apparent negative effect on the blood–brain barrier (BBB) [4]. In the
Augmentation of thrombolysis with combination therapies
Glycoprotein IIb/IIIa inhibitors prevent platelet aggregation and thrombus formation. They could provide a complementary mode of clot disruption. The combination of glycoprotein IIb/IIIa inhibitors with rtPA has been used in studies for acute coronary syndrome with improvement in reperfusion but also with increased rates of bleeding. This might be an eligible approach in stroke therapy [4].
Case series of patients with stroke comparing intra-arterial urokinase alone with a combination of
Hericenone B
Hericenone B has a strong anti-platelet activity and owing to its novel mechanism it might be a novel compound for antithrombotic therapy. Hericium erinaceus, an extract of several species of mushrooms potently inhibits platelet aggregation induced by collagen. Hericenone B selectively inhibits collagen-induced platelet aggregation, but it does not suppress the aggregation induced by U46619 (stable synthetic analog of the prostaglandin PGH2), adenosine diphosphate, thrombin, or adrenaline.
Metal chelation
Iron chelators were shown to induce neuroprotection against brain injury [16]. Iron chelators prevent hydroxyl radical formation by sequestering redox-active iron. An additional neuroprotective mechanism of iron chelators is their ability to upregulate, or to stabilize the transcriptional activator, hypoxia-inducible factor-1α (HIF-1α). HIF-1α stability within the cells is under the control of a class of iron-dependent and oxygen-sensor enzymes that target HIF-1α for degradation. An emerging
Free-radical scavengers and trapping agents
Free radicals are produced in the brain during ischemia, during reperfusion and during intracranial hemorrhage. Removal of pathologically produced free radicals is therefore a viable approach to neuroprotection. It is known that free radicals have a significant pathogenetic role of cerebral tissue damage following both ischemia and reperfusion [16]. Four compounds with free radical scavenging activity (tirilazad, ebselen, edaravone) or free radical trapping properties (NXY-059) have been
Glutamate oxaloacetate transaminase
Ischemic stroke is associated with an excessive release of glutamate into the neuronal extracellular space [43]. A decrease in blood glutamate levels could provide a mechanism to remove it from the brain tissue, by increasing the brain–blood gradient. In this regard, the ability of alanine aminotransferase (ALT) also known as glutamate oxaloacetate transaminase (GOT) to metabolize glutamate in blood could represent a potential neuroprotective tool for ischemic stroke. Campos et al. revealed
Combination strategies of acute and neuroprotective stroke agents
The complementary approach aiming at promoting cerebrovascular integrity and blocking adverse cerebral vascular events might increase the thrombolytic efficacy of rtPA and reduce rtPA-induced hemorrhagic transformation, and, thereby, might make thrombolytic therapy more accessible to the aged population. The combination of neuroprotective agents and rtPA might become a promising approach for the treatment of stroke. A recent animal study evaluated that the treatment with a selective proteasome
Concluding remarks
Cerebral ischemia is a multifactorial disorder which includes several pathways for progression of injury to brain cells. Over the years investigations focus more and more on neuroprotection with many new promising agents under investigation.
These novel approaches including extending penumbral survival for the later use of reperfusion therapy, reducing reperfusion injury after successful reperfusion, and using drugs with both neuroprotective and recovery enhancing effects will open new
Erasmia Broussalis, MD received her doctorate in human medicine from the University of Graz in 2001. She is a clinical Neurologist working at the Department of Neurology at the Paracelsus Medical University (PMU). Her research interests include cerebrovascular diseases, predominantly stroke and neurointervention.
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Neuropeptide Y Y2 and Y5 receptors as promising targets for neuroprotection in primary neurons exposed to oxygen-glucose deprivation and in transient focal cerebral ischemia in rats
2017, NeuroscienceCitation Excerpt :Ischemic stroke accounts for ∼85% of all stroke cases and it is caused by occlusion of a major cerebral artery by a thrombus or an embolism, which leads to cessation or critical reduction of cerebral blood flow (CBF) that results in oxygen and energy deprivation and then tissue damage in the affected area (Gibson, 2013; Pedata et al., 2016). The sequence of biochemical events, termed the ischemic cascade that occurs during ischemia, includes: glutamate-mediated excitotoxicity and calcium overload, free radical formation, nitric oxide (NO) production, membrane degradation, mitochondrial damage, inflammation, activation of various enzymes: caspases, calpains, liposomal proteases, and endonucleases, oxidative stress, DNA deamination and consequently cell death by necrosis and/or apoptosis (Lipton, 1999; Broussalis et al., 2012; Sutherland et al., 2012; Wang et al., 2015b). Neuroprotection, which is the principal therapeutic strategy to treat ischemic stroke that antagonizes, interrupts or slows down the sequence of events within the ischemic cascade has been extensively explored for many years (Liu et al., 2012; Fluri et al., 2015).
Nanomedicines and stroke: Toward translational research
2015, Journal of Drug Delivery Science and TechnologyCitation Excerpt :Neuroprotective therapies aim at structurally preserve the intact tissue until adequate blood supply can be reestablished, either through spontaneous or therapeutic recanalization, or via collateral blood flow. The elucidation of biochemical and molecular events and the identification of intracellular mediators of the ischemic injury allowed the development of pathophysiological rational for extended classes of neuroprotectants [111,112]. Most of these strategies tend to: (i) decrease neuroexcitotoxicity using calcium channels blockers, glutamate antagonists or GABA agonists, (ii) to decrease oxidative stress with anti-oxidants and NO down-regulatory molecules, (iii) to decrease the inflammatory response, (iv) to avoid the no-reflow phenomenon by inhibiting leukocytes and neutrophiles adhesion and activation, and (v) to inhibit apoptosis pathways with caspase-3 inhibitors and modulation of the Bcl-2 family.
C-Phycocyanin protects SH-SY5Y cells from oxidative injury, rat retina from transient ischemia and rat brain mitochondria from Ca<sup>2+</sup>/phosphate-induced impairment
2012, Brain Research BulletinCitation Excerpt :Oxidative stress is a crucial factor in the pathophysiology of ischemic stroke and acts by either damaging cellular structures or participating in signaling pathways (Saito et al., 2005). Compounds inhibiting this neurotoxic process have been considered as promising therapeutic candidates against ischemic stroke (Broussalis et al., 2012). C-PC was shown to have a strong antioxidant activity in several in vivo experiments, including global ischemia–reperfusion damage in the brain (Pentón-Rol et al., 2011a) and the heart (Khan et al., 2006a), doxorubicin-induced injury in cardiomyocytes (Khan et al., 2006b), experimental autoimmune encephalomyelitis (Pentón-Rol et al., 2011b), atherosclerosis (Riss et al., 2007), paraquat-induced lung damage (Sun et al., 2011), activated platelets (Hsiao et al., 2005) and thymic atrophy (Gupta et al., 2011).
Noscapine alleviates cerebral damage in ischemia-reperfusion injury in rats
2021, Naunyn-Schmiedeberg's Archives of Pharmacology
Erasmia Broussalis, MD received her doctorate in human medicine from the University of Graz in 2001. She is a clinical Neurologist working at the Department of Neurology at the Paracelsus Medical University (PMU). Her research interests include cerebrovascular diseases, predominantly stroke and neurointervention.
Monika Killer, MD is a fully trained neurosurgeon who is specialized in neurointerventional therapy. Her clinical skills and scientific interests are focused on diagnosis and treatment of cerebrovascular diseases and spinal vascular malformations. Dr. Killer graduated in 1993 as M.D. from the University of Vienna, Medical School. She received her license as Specialist in Neurosurgery from the Austrian Medical Chamber in 1999 and her International Master (MSc) for Neurovascular Diseases in 2002 from Université Paris Sud-Faculté de Médecine de Bicêtre. Since 2004, Dr. Killer has been the attending Neurointerventionalist at Christian Doppler Clinic Salzburg. Since 2005 she is the Head of the Division Experimental Neurointervention of the Neuroscience Institute Salzburg and since 2009 Associate Professor of Neurointervention at Paracelsus Medical University. She is a peer reviewer for multiple international journals as Stroke, AJNR, Neuroradiology and Acta Neurochirurgica and author of more than 50 scientific articles.
Jörg Kraus, MD is a clinical Neurologist working at the Department of Neurology at the Paracelsus Medical University (PMU). He received ‘Venia Legendi’ at the PMU in 2007. He is currently the leading physician (“Leitender Oberarzt”) of the Multiple Sclerosis outpatients’ clinic and of the ward for Neuroimmunology and Neurooncology. Moreover, he is the head of the research group for Neuroimmunology and Multiple Sclerosis. His research work primarily focuses on biomarkers in multiple sclerosis and other neurologic diseases based upon neuroimmunologic changes at the blood-brain barrier. He is author of about 60 scientific publications in the field of multiple sclerosis and cerebrovascular diseases.