Present Status and Future Challenges of New Therapeutic Targets in Preclinical Models of Stroke in Aged Animals with/without Comorbidities

Popa‐Wagner, Aurel; Glavan, Daniela-Gabriela; Олару, Андрей; Olaru, Denissa-Greta; Mărgăritescu, Otilia Clara; Tica, Oana Sorina; Surugiu, Roxana; Sandu, Raluca Elena

doi:10.3390/ijms19020356

Cited by 19 publications

(9 citation statements)

References 108 publications

(116 reference statements)

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“…For example, tumor-secreted exosomes may act as mediators in cancer metastasis by maintenance and enhancement of tumor microenvironment ( Salido-Guadarrama et al, 2014 ; Cheng et al, 2017 ; Li et al, 2018 ). Likewise, several studies have reported high levels of cholesteryl ester (CE), triacylglycerol (TAG) and cardiolipin in exosomal preparations fueling concerns about increasing the risk of stroke instead of having a beneficial effect ( Llorente et al, 2007 ; Van Meer et al, 2008 ; Strauss et al, 2010 ; Record et al, 2014 ; Skotland et al, 2017 ; Popa-Wagner et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Multicellular Crosstalk Between Exosomes and the Neurovascular Unit After Cerebral Ischemia. Therapeutic Implications

et al. 2018

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Restorative strategies after stroke are focused on the remodeling of cerebral endothelial cells and brain parenchymal cells. The latter, i.e., neurons, neural precursor cells and glial cells, synergistically interact with endothelial cells in the ischemic brain, providing a neurovascular unit (NVU) remodeling that can be used as target for stroke therapies. Intercellular communication and signaling within the NVU, the multicellular brain-vessel-blood interface, including its highly selective blood-brain barrier, are fundamental to the central nervous system homeostasis and function. Emerging research designates cell-derived extracellular vesicles and especially the nano-sized exosomes, as a complex mean of cell-to-cell communication, with potential use for clinical applications. Through their richness in active molecules and biological information (e.g., proteins, lipids, genetic material), exosomes contribute to intercellular signaling, a condition particularly required in the central nervous system. Cerebral endothelial cells, perivascular astrocytes, pericytes, microglia and neurons, all part of the NVU, have been shown to release and uptake exosomes. Also, exosomes cross the blood-brain and blood-cerebrospinal fluid barriers, allowing communication between periphery and brain, in normal and disease conditions. As such exosomes might be a powerful diagnostic tool and a promising therapeutic shuttle of natural nanoparticles, but also a means of disease spreading (e.g., immune system modulation, pro-inflammatory action, propagation of neurodegenerative factors). This review highlights the importance of exosomes in mediating the intercellular crosstalk within the NVU and reveals the restorative therapeutic potential of exosomes harvested from multipotent mesenchymal stem cells in ischemic stroke, a frequent neurologic condition lacking an efficient therapy.

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Section: Discussionmentioning

confidence: 99%

Multicellular Crosstalk Between Exosomes and the Neurovascular Unit After Cerebral Ischemia. Therapeutic Implications

et al. 2018

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“…This consecutive, multistage and evolutionary conserved defensive reaction is termed as reactive astrogliosis, exhibiting altered expression of many genes, distinct morphological and functional features in CNS disease pathogenesis and the recovery process. The astrocytes also play a significant role in the glial scar formation following a focal tissue insult, and upregulation of various cellular markers, and other proliferating cell markers, have been described to be compromised in aged Sprague-Dawley rats as compared to younger ones (Popa-Wagner et al, 2007 , 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Korean Red Ginseng Pretreatment Protects Against Long-Term Sensorimotor Deficits After Ischemic Stroke Likely Through Nrf2

Liu

Vollmer

Fernández

et al. 2018

Front. Cell. Neurosci.

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Endogenous neuroprotective mechanisms by which the brain protects itself against noxious stimuli and recovers from ischemic damage are key targets of stroke research, ultimately facilitating functional recovery. Transcriptional factor Nrf2, enriched in astrocytes, is a master regulator of endogenous defense systems against oxidative stress and inflammation. Korean Red Ginseng (Ginseng), one most widely used herbal medicine, has exhibited promising potentials in neuroprotection. Our study aimed to determine whether the standardized Ginseng extract pretreatment could attenuate acute sensorimotor deficits and improve long-term functional recovery after ischemic stroke though Nrf2 pathway and whether reactive astrogliosis is associated with such effect. Adult Nrf2−/− and matched wildtype control (WT) mice were pretreated with Ginseng orally for 7 days prior to permanent distal middle cerebral artery occlusion (pdMCAO). Using an optimized method that can accurately assess either severe or mild pdMCAO-induced sensorimotor deficits, neurobehavioral tests were performed over 28 days. The progression of lesion volume and the evolution of astrocytic and microglial activation were determined in the acute stage of ischemic stroke after pdMCAO (0–3 days). Nrf2-downstream target antioxidant genes expression levels was assessed by Western blot. We found that Ginseng pretreatment ameliorated acute sensorimotor deficits and promoted long-term functional recovery, prevented the acute enlargement of lesion volume (36.37 ± 7.45% on day 3), attenuated reactive astroglial progression but not microglia activation, and enhanced the induction of Nrf2-downstream target proteins after ischemic insult in WT mice, an effect which was lost in Nrf2 knockouts. The spatiotemporal pattern of reactive astrogliosis evaluation correlated well with acute ischemic damage progression in an Nrf2-dependent fashion during the acute phase of ischemia. In contrast, Nrf2 deficiency mice exhibited exacerbated ischemic condition compared to WT controls. Together, Ginseng pretreatment protects against acute sensorimotor deficits and promotes its long-term recovery after pdMCAO, at least partly, through Nrf2 activation, highlighting the potential efficacy of oral consumption of Ginseng for stroke preventative intervention in patients who are at great risk of recurrent stroke or transient ischemic attack. The attenuated reactive astrogliosis contributes to the Nrf2 pathway related neuroprotection against acute ischemic outcome and substantially long-term sensorimotor deficits in the context of ischemic stroke under pdMCAO.

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“…The pathophysiology of neurodegenerative disorders, whether acute as epitomized by stroke, or chronic as in AD, is complex and involves different vulnerable cell types across different brain regions responding to a diverse array of extrinsic and intrinsic challenges. Despite this, many of the main pathogenic mechanisms present in ischemia and AD as well as other acute and long-term neurodegenerations are common and include excitotoxic neurotransmitters, inflammatory pathways, oxidative damage, ionic imbalance and apoptosis [ 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. The terminal results of acute ischemic cascades are neuronal death along with an irreversible loss of neuronal function.…”

Section: Discussionmentioning

confidence: 99%

“…The terminal results of acute ischemic cascades are neuronal death along with an irreversible loss of neuronal function. Thus, understanding the underlying mechanisms of neuronal death is important in developing new therapies for neurological disorders such as stroke or, indeed, any neurodegenerative disease [ 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. Neuroprotective pharmacological therapies are extremely important approaches to preserve damaged brain regions.…”

Section: Discussionmentioning

confidence: 99%

Pomalidomide Ameliorates H2O2-Induced Oxidative Stress Injury and Cell Death in Rat Primary Cortical Neuronal Cultures by Inducing Anti-Oxidative and Anti-Apoptosis Effects

Tsai

Chang

Lai

et al. 2018

IJMS

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Due to its high oxygen demand and abundance of peroxidation-susceptible lipid cells, the brain is particularly vulnerable to oxidative stress. Induced by a redox state imbalance involving either excessive generation of reactive oxygen species (ROS) or dysfunction of the antioxidant system, oxidative stress plays a central role in a common pathophysiology that underpins neuronal cell death in acute neurological disorders epitomized by stroke and chronic ones such as Alzheimer’s disease. After cerebral ischemia, for example, inflammation bears a key responsibility in the development of permanent neurological damage. ROS are involved in the mechanism of post-ischemic inflammation. The activation of several inflammatory enzymes produces ROS, which subsequently suppress mitochondrial activity, leading to further tissue damage. Pomalidomide (POM) is a clinically available immunomodulatory and anti-inflammatory agent. Using H2O2-treated rat primary cortical neuronal cultures, we found POM displayed neuroprotective effects against oxidative stress and cell death that associated with changes in the nuclear factor erythroid derived 2/superoxide dismutase 2/catalase signaling pathway. POM also suppressed nuclear factor kappa-light-chain-enhancer (NF-κB) levels and significantly mitigated cortical neuronal apoptosis by regulating Bax, Cytochrome c and Poly (ADP-ribose) polymerase. In summary, POM exerted neuroprotective effects via its anti-oxidative and anti-inflammatory actions against H2O2-induced injury. POM consequently represents a potential therapeutic agent against brain damage and related disorders and warrants further evaluation.

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Present Status and Future Challenges of New Therapeutic Targets in Preclinical Models of Stroke in Aged Animals with/without Comorbidities

Cited by 19 publications

References 108 publications

Multicellular Crosstalk Between Exosomes and the Neurovascular Unit After Cerebral Ischemia. Therapeutic Implications

Multicellular Crosstalk Between Exosomes and the Neurovascular Unit After Cerebral Ischemia. Therapeutic Implications

Korean Red Ginseng Pretreatment Protects Against Long-Term Sensorimotor Deficits After Ischemic Stroke Likely Through Nrf2

Pomalidomide Ameliorates H2O2-Induced Oxidative Stress Injury and Cell Death in Rat Primary Cortical Neuronal Cultures by Inducing Anti-Oxidative and Anti-Apoptosis Effects

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