The future of neuroprotection in stroke

Abstract

Investigators acknowledge the limitations of rodent or non-human primate stroke models, hundreds of putative neuroprotectants have been evaluated in preclinical models, but not one has entered the clinical realm. Initial studies focused on the neuron, but in recent years the focus has widened to also include other neural cells including astrocytes, pericytes and endothelial cells, which together form the neurovascular unit. Some new developments raise renewed hope for neuroprotection: the appearance of new compounds with multiple mechanisms of action, or the promulgation of new standards for a rigorous preclinical testing. At the bedside in the last 5 years, uric acid and nerinetide are the only compounds tested for clinical efficacy in randomised controlled trials (RCTs), where all patients had to receive reperfusion therapies, either intravenous thrombolysis and/or mechanical thrombectomy. In addition, otaplimastat, 3K3A-activated protein C (APC), intra-arterial verapamil and intra-arterial hypothermia were also assessed in combination with reperfusion therapy, but in RCTs that only included feasibility or safety outcomes. Some of these compounds yielded promising results which are discussed in this review. Altogether, a deeper knowledge of the mechanisms involved in the ischaemic death process at the neurovascular unit, an improved preselection and evaluation of drugs at the preclinical stage and the testing of putative neuroprotectants in enriched clinical studies of patients receiving reperfusion therapies, might prove more effective than in the past to reverse a dismal situation that has lasted already too long.

Cerebral Ischemia-Reperfusion Is Associated With Upregulation of Cofilin-1 in the Motor Cortex

“…Unfortunately, therapeutic options for ischemic stroke are limited (Wang et al, 2019). In the last 5 years, reperfusion therapies, either intravenous thrombolysis or mechanical thrombectomy, have been the first line of care in a growing number of eligible acute ischemic stroke patients (Powers et al, 2018;Chamorro et al, 2020). There are potential risks in the application of reperfusion (Huang et al, 2019;Thorén et al, 2020).…”

“…While irretrievable neuronal loss occurs after a series of spatiotemporal pathological changes, especially in the infarct core area where blood flow drops quickly, the surrounding hypoperfused penumbra region (peri-infarct area) is at risk of delayed cell death. Neuroprotection aims to preserve the penumbra (Chamorro et al, 2020), especially the penumbra region in the motor cortex. Neuroprotection includes not only reducing injury (such as anti-inflammation and anti-apoptotic), but also promoting restoration (such as neurogenesis and regeneration).…”

Improved post-stroke spontaneous recovery by astrocytic extracellular vesicles

“…Studies in animal models attempted to elucidate a time-limited period of heightened plasticity after focal brain injury and the mechanisms behind spontaneous recovery 6,10 . Cumulative data indicate that axonal repair, neurogenesis, and inflammation resolution mechanistically intervene in this recovery 11,12 .…”

Microglial Plasticity Contributes to Recovery of Bone Marrow Mononuclear Cells during Experimental Stroke

“…The central nervous system (CNS) is affected by acute and chronic neural disorders. In acute neural disorders, like stroke, spinal cord injury (SCI) and brain trauma, neuronal and glial loss happens quickly with inexorable cell loss and functional impairment [1][2][3][4][5]. In chronic neurodegenerative diseases, including Parkinson's, Huntington's, Alzheimer's diseases and Amyotrophic Lateral Sclerosis (ALS) progressive cell loss occurs over decades with inexorable functional loss and sensory-motor and/or cognitive declines [1,5].…”

“…Stroke is a vascular disorder characterized by obstruction (ischemic) or rupture of blood vessels (hemorrhagic). Following this primary pathological event, further outcomes are diverse and characterized by a multitude of factors, excitotoxicity, oxidative stress, metabolic acidosis, periinfarct depolarization, apoptosis and uncontrolled neuroinflammation, which contributes to cell death and functional impairment in both experimental animals and humans [1][2][3][4][5][8][9][10].…”