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Cell Death Pathways in Ischemic Stroke and Targeted Pharmacotherapy Aishika Datta 1 & Deepaneeta Sarmah 1 & Leela Mounica 1 & Harpreet Kaur 1 & Radhika Kesharwani 1 & Geetesh Verma 1 & Pabbala Veeresh 1 & Vignesh Kotian 1 & Kiran Kalia 1 & Anupom Borah 2 & Xin Wang 3 & Kunjan R. Dave 4 & Dileep R. Yavagal 5 & Pallab Bhattacharya 1 Received: 21 December 2019 / Revised: 4 March 2020 / Accepted: 10 March 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract Ischemic stroke is one of the significant causes of morbidity and mortality, affecting millions of people across the globe. Cell injury in the infarct region is an inevitable consequence of focal cerebral ischemia. Subsequent reperfusion exacerbates the harmful effect and increases the infarct volume. These cellular injuries follow either a regulated pathway involving tightly structured signaling cascades and molecularly defined effector mechanisms or a non-regulated pathway, also known as accidental cell death, where the process is biologically uncontrolled. Classical cell death pathways are long established and well reported in several articles that majorly define apoptotic cell death. A recent focus on cell death study also considers investigation on nonclassical pathways that are tightly regulated, may or may not involve caspases, but non-apoptotic. Pathological cell death is a cardinal feature of different neurodegenerative diseases. Although ischemia cannot be classified as a neurodegenerative disease, it is a cerebrovascular event where the infarct region exhibits aberrant cell death. Over the past few decades, several therapeutic options have been implicated for ischemic stroke. However, their use has been hampered owing to the number of limitations that they possess. Ischemic penumbral neurons undergo apoptosis and become dysfunctional; however, they are salvageable. Thus, understanding the role of different cell death pathways is crucial to aid in the modern treatment of protecting apoptotic neurons. Keywords Ischemic stroke . Cell death pathway . Apoptosis . Necroptosis . Ferroptosis . Pyroptosis

Introduction

Aishika Datta and Deepaneeta Sarmah contributed equally to this work. * Pallab Bhattacharya [email protected]; [email protected] 1

Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat 382355, India

2

Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India

3

Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

4

Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA

5

Department of Neurology and Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, USA

Cell death is an essential aspect for living beings as it plays a pivotal role in development, metamorphosis, and the maintenance of homeostasis [1, 2]. The imbalan