Neuroprotective agents in Acute Ischemic Stroke—A Reality Check

Goenka, Luxitaa; Uppugunduri, Chakradhara Rao S.; Suresh, S.; George, Melvin

doi:10.1016/j.biopha.2018.11.041

Cited by 27 publications

(12 citation statements)

References 56 publications

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“…For pharmacologic neuroprotection, our understanding of the mechanisms of tissue damage following ischemic stroke has advanced, providing scientists with viable targets for neuroprotective therapeutics. Many developed and tested therapeutics have targeted the modulation of inflammation, oxidative stress, excitotoxicity, or apoptosis, all of which have been implicated in post-stroke tissue damage (Goenka et al, 2019;Wang et al, 2019). However, despite the relatively high levels of therapeutic benefits identified by these treatments in animal models, limited success has been observed in the clinic despite the hundreds of clinical trials run.…”

Section: Neuroprotectionmentioning

confidence: 99%

“…Still, the therapeutic efficacy of these treatments is controversial. For example, cerebrolysin (Table 3) is a mixture of brain-derived neuropeptide that exhibits antiexcitotoxicity, antioxidant, and anti-apoptotic activity that is approved for the treatment of stroke in more than 40 countries (Goenka et al, 2019). Several animal studies have demonstrated that cerebrolysin can improve outcome from stroke, for example, by reducing infarct size (Ren et al, 2007;Zhang et al, 2010).…”

Section: Neuroprotectionmentioning

confidence: 99%

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Blood-Brain Barrier Damage in Ischemic Stroke and Its Regulation by Endothelial Mechanotransduction

et al. 2020

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Ischemic stroke, a major cause of mortality in the United States, often contributes to disruption of the blood-brain barrier (BBB). The BBB along with its supportive cells, collectively referred to as the “neurovascular unit,” is the brain’s multicellular microvasculature that bi-directionally regulates the transport of blood, ions, oxygen, and cells from the circulation into the brain. It is thus vital for the maintenance of central nervous system homeostasis. BBB disruption, which is associated with the altered expression of tight junction proteins and BBB transporters, is believed to exacerbate brain injury caused by ischemic stroke and limits the therapeutic potential of current clinical therapies, such as recombinant tissue plasminogen activator. Accumulating evidence suggests that endothelial mechanobiology, the conversion of mechanical forces into biochemical signals, helps regulate function of the peripheral vasculature and may similarly maintain BBB integrity. For example, the endothelial glycocalyx (GCX), a glycoprotein-proteoglycan layer extending into the lumen of bloods vessel, is abundantly expressed on endothelial cells of the BBB and has been shown to regulate BBB permeability. In this review, we will focus on our understanding of the mechanisms underlying BBB damage after ischemic stroke, highlighting current and potential future novel pharmacological strategies for BBB protection and recovery. Finally, we will address the current knowledge of endothelial mechanotransduction in BBB maintenance, specifically focusing on a potential role of the endothelial GCX.

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Section: Neuroprotectionmentioning

confidence: 99%

Section: Neuroprotectionmentioning

confidence: 99%

Blood-Brain Barrier Damage in Ischemic Stroke and Its Regulation by Endothelial Mechanotransduction

et al. 2020

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“…At present, some glutamate receptor antagonists have shown certain neuroprotective effects in various animal experiments. However, human studies are proved to be disappointing due to narrow treatment windows and serious adverse reactions [ 124 ]. In this case, it is reasonable to speculate that the misunderstanding of the role of glutamate receptors in physiological and pathological processes may be the cause of problems in previous interventions.…”

Section: Postsynaptic Effect Of Glutamate As the Main Mechanism Of Ne...mentioning

confidence: 99%

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

Fan

Xie

Xing

et al. 2022

IJMS

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Stroke is one of the leading causes of death and disability in the world, of which ischemia accounts for the majority. There is growing evidence of changes in synaptic connections and neural network functions in the brain of stroke patients. Currently, the studies on these neurobiological alterations mainly focus on the principle of glutamate excitotoxicity, and the corresponding neuroprotective strategies are limited to blocking the overactivation of ionic glutamate receptors. Nevertheless, it is disappointing that these treatments often fail because of the unspecificity and serious side effects of the tested drugs in clinical trials. Thus, in the prevention and treatment of stroke, finding and developing new targets of neuroprotective intervention is still the focus and goal of research in this field. In this review, we focus on the whole processes of glutamatergic synaptic transmission and highlight the pathological changes underlying each link to help develop potential therapeutic strategies for ischemic brain damage. These strategies include: (1) controlling the synaptic or extra-synaptic release of glutamate, (2) selectively blocking the action of the glutamate receptor NMDAR subunit, (3) increasing glutamate metabolism, and reuptake in the brain and blood, and (4) regulating the glutamate system by GABA receptors and the microbiota–gut–brain axis. Based on these latest findings, it is expected to promote a substantial understanding of the complex glutamate signal transduction mechanism, thereby providing excellent neuroprotection research direction for human ischemic stroke (IS).

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“…Administration of synthetic adropin was reported to show neuroprotective effects and reduction of infarction by activating the eNOS [ 176 ]. Similarly, another active peptide cerebrolysin may reverse post- stroke deleterious consequences by increasing neuronal survival and reversing glutamate-induced necrotic and apoptotic cell death [ 177 , 178 ].…”

Section: Novel Exploratory Targets In Ischemic Strokementioning

confidence: 99%

A Review on Preclinical Models of Ischemic Stroke: Insights Into the Pathomechanisms and New Treatment Strategies

Singh

Kharwar

Dandekar

2022

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Background: Stroke is a serious neurovascular problem and the leading cause of disability and death worldwide. The disrupted demand to supply ratio of blood and glucose during cerebral ischemia develops hypoxic shock, and subsequently necrotic neuronal death in the affected regions. Multiple causal factors like age, sex, race, genetics, diet, and lifestyle play an important role in the occurrence as well as progression of post-stroke deleterious events. These biological and environmental factors may be contributed to vasculature variable architecture and abnormal neuronal activity. Since recombinant tissue plasminogen activator is the only clinically effective clot bursting drug, there is a huge unmet medical need for newer therapies for the treatment of stroke. Innumerous therapeutic interventions have shown promise in the experimental models of stroke but failed to translate it into clinical counterparts. Methods: Original publications regarding pathophysiology, preclinical experimental models, new targets and therapies targeting ischemic stroke have been reviewed since the 1970s. Results: We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Results : We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Conclusion: There are still many inter-linked pathophysiological alterations with regards to stroke, animal models need not necessarily mimic the same conditions of stroke pathology and newer targets and therapies are the need of the hour in stroke research.

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Neuroprotective agents in Acute Ischemic Stroke—A Reality Check

Cited by 27 publications

References 56 publications

Blood-Brain Barrier Damage in Ischemic Stroke and Its Regulation by Endothelial Mechanotransduction

Blood-Brain Barrier Damage in Ischemic Stroke and Its Regulation by Endothelial Mechanotransduction

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

A Review on Preclinical Models of Ischemic Stroke: Insights Into the Pathomechanisms and New Treatment Strategies

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