Stroke research at a crossroad: asking the brain for directions

Iadecola, Costantino; Anrather, Josef

doi:10.1038/nn.2953

Cited by 355 publications

(289 citation statements)

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“…Pleiotropic interventions such as exercise and EE to enhance motor recovery following stroke appear to hold great promise given the widespread failure of monotherapeutic approaches [88]. The same strategy may be beneficial for cognitive recovery but the research in this area is less advanced.…”

Section: Discussionmentioning

confidence: 99%

Exercise and Environmental Enrichment as Enablers of Task-Specific Neuroplasticity and Stroke Recovery

et al. 2016

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Improved stroke care has resulted in greater survival, but >50 % of patients have chronic disabilities and 33 % are institutionalized. While stroke rehabilitation is helpful, recovery is limited and the most significant gains occur in the first 2-3 months. Stroke triggers an early wave of gene and protein changes, many of which are potentially beneficial for recovery. It is likely that these molecular changes are what subserve spontaneous recovery. Two interventions, aerobic exercise and environmental enrichment, have pleiotropic actions that influence many of the same molecular changes associated with stroke injury and subsequent spontaneous recovery. Enrichment paradigms have been used for decades in adult and neonatal animal models of brain injury and are now being adapted for use in the clinic. Aerobic exercise enhances motor recovery and helps reduce depression after stroke. While exercise attenuates many of the signs associated with normal aging (e.g., hippocampal atrophy), its ability to reverse cognitive impairments subsequent to stroke is less evident. It may be that stroke, like other diseases such as cancer, needs to use multimodal treatments that augment complimentary neurorestorative processes.

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Section: Discussionmentioning

confidence: 99%

Exercise and Environmental Enrichment as Enablers of Task-Specific Neuroplasticity and Stroke Recovery

et al. 2016

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“…The mechanisms that drive CA‐, myocardial ischemia–, and stroke‐induced cell death have been extensively investigated in animals, but pharmacologic interventions that improve outcome in animals have largely failed in clinical trials 3, 4, 5. This translational roadblock has been widely discussed; however, the potential role of aging has not received much attention 2.…”

Section: Introductionmentioning

confidence: 99%

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

Shen

Yan

Zhao

et al. 2018

JAHA

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BackgroundThe mechanisms underlying worse outcome at advanced age after cardiac arrest (CA) and resuscitation are not well understood. Because protein homeostasis (proteostasis) is essential for cellular and organismal health, but is impaired after CA, we investigated the effects of age on proteostasis‐related prosurvival pathways activated after CA.Methods and ResultsYoung (2–3 months old) and aged (21–22 months old) male C57Bl/6 mice were subjected to CA and cardiopulmonary resuscitation (CPR). Functional outcome and organ damage were evaluated by assessing neurologic deficits, histological features, and creatinine level. CA/CPR‐related changes in small ubiquitin‐like modifier conjugation, ubiquitination, and the unfolded protein response were analyzed by measuring mRNA and protein levels in the brain, kidney, and spinal cord. Thiamet‐G was used to increase O‐linked β‐N‐acetylglucosamine modification. After CA/CPR, aged mice had trended lower survival rates, more severe tissue damage in the brain and kidney, and poorer recovery of neurologic function compared with young mice. Furthermore, small ubiquitin‐like modifier conjugation, ubiquitination, unfolded protein response, and O‐linked β‐N‐acetylglucosamine modification were activated after CA/CPR in young mice, but their activation was impaired in aged mice. Finally, pharmacologically increasing O‐linked β‐N‐acetylglucosamine modification after CA improved outcome.ConclusionsResults suggest that impaired activation of prosurvival pathways contributes to worse outcome after CA/CPR in aged mice because restoration of proteostasis is critical to the survival of cells stressed by ischemia. Therefore, a pharmacologic intervention that targets aging‐related impairment of proteostasis‐related pathways after CA/CPR may represent a promising therapeutic strategy.

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“…Two major types of ischemic stroke are embolic and thrombotic. r-tPA introduced in 1996 is presently the only available stroke treatment with limitations of a narrow therapeutic window (National Stroke Association; Iadecola et al, 2011). Brain injury due to stroke involves generation of free radicals, excitotoxicity, ion influx disruption, enzymatic alterations, stimulation of the inflammatory responses, endothelin release, platelets and leukocytes activation, delayed coagulation and endothelial dysfunction (Gupta et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Phospholipid complexation of NMITLI118RT+: way to a prudent therapeutic approach for beneficial outcomes in ischemic stroke in rats

et al. 2016

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(2016) Phospholipid complexation of NMITLI118RT+: way to a prudent therapeutic approach for beneficial outcomes in ischemic stroke in rats, Drug Delivery, 23:9, 3606-3618, DOI: 10.1080/10717544.2016 ), its pharmaceutical characterization and evaluation of its neuro-protective potential against experimenal stroke in rats in continuation with their previous work in this area. The phytosomal complex (NIMPLC) was prepared by following a cohesive optimization design and was characterized on the basis of solubility, dissolution profile, FT-IR, DSC-TGA analysis, zeta potential, physical stability, forced degradation and photolytic degradation. Results were suggestive of a pharmaceutically acceptable formulation. NIMPLC was taken up further for biological evaluation using the middle cerebral artery occlusion (MCAO) model in rats. It could be demonstrated that the beneficial effects of NMITLI118RT + could be augmented by NIMPLC in 1 h pre and 6 h post treatment as was evident from reduction in MDA levels, increment in GSH levels, reduction in neurological deficit (ND) scores and reduction in infarct size. The study could successfully demonstrate the beneficial effects of NIMPLC in brain function restoration following stroke.

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Stroke research at a crossroad: asking the brain for directions

Cited by 355 publications

References 50 publications

Exercise and Environmental Enrichment as Enablers of Task-Specific Neuroplasticity and Stroke Recovery

Exercise and Environmental Enrichment as Enablers of Task-Specific Neuroplasticity and Stroke Recovery

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

Phospholipid complexation of NMITLI118RT+: way to a prudent therapeutic approach for beneficial outcomes in ischemic stroke in rats

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