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Oxidative stress and mitochondrial dysfunctions and signaling pathways involved in ischemic stroke. MPTP mitochondrial permeability transition pore, ROS Reactive oxygen species, ATP Adenosine triphosphate, HIF-1 Hypoxia-induced factor, Nrf2 Nuclear factor E2-related factor 2, ARE Antioxidant response element, CK2 Casein kinase 2, PARP-1 Poly ADP-ribose polymerase 1, AIF Apoptosis-inducing factor, PINK1: PTEN induced putative kinase 1, NF-kB Necrosis factor-kB
Source publication
Ischemic stroke is caused primarily by an interruption in cerebral blood flow, which induces severe neural injuries, and is one of the leading causes of death and disability worldwide. Thus, it is of great necessity to further detailly elucidate the mechanisms of ischemic stroke and find out new therapies against the disease. In recent years, effor...
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CTP is an important diagnostic tool in managing patients with acute ischemic stroke, but challenges persist in the agreement of stroke lesion volumes and ischemic core-penumbra mismatch profiles determined with different CTP post-processing software. We investigated a systematic method of calibrating CTP stroke lesion thresholds between deconvoluti...
Citations
... Molecular mechanisms by which damage occurs in a CVA are diverse, including decreased oxygen and nutrient supply to the affected and surrounding neuronal tissue [3], increased reactive oxygen species (ROS) [4], and augmented inflammation [5]. Consequently, there is an increase in apoptosis and neuronal death [6]. ...
Stroke is one of the leading causes of death. It not only affects adult people but also many children. It is estimated that, every year, 15 million people suffer a stroke worldwide. Among them, 5 million people die, while 5 million people are left permanently disabled. In this sense, the research to find new treatments should be accompanied with new therapies to combat neuronal death and to avoid developing cognitive impairment and dementia. Phytocannabinoids are among the compounds that have been used by mankind for the longest period of history. Their beneficial effects such as pain regulation or neuroprotection are widely known and make them possible therapeutic agents with high potential. These compounds bind cannabinoid receptors CB1 and CB2. Unfortunately, the psychoactive side effect has displaced them in the vast majority of areas. Thus, progress in the research and development of new compounds that show efficiency as neuroprotectors without this psychoactive effect is essential. On the one hand, these compounds could selectively bind the CB2 receptor that does not show psychoactive effects and, in glia, has opened new avenues in this field of research, shedding new light on the use of cannabinoid receptors as therapeutic targets to combat neurodegenerative diseases such as Alzheimer’s, Parkinson’s disease, or stroke. On the other hand, a new possibility lies in the formation of heteromers containing cannabinoid receptors. Heteromers are new functional units that show new properties compared to the individual protomers. Thus, they represent a new possibility that may offer the beneficial effects of cannabinoids devoid of the unwanted psychoactive effect. Nowadays, the approval of a mixture of CBD (cannabidiol) and Δ9-THC (tetrahydrocannabinol) to treat the neuropathic pain and spasticity in multiple sclerosis or purified cannabidiol to combat pediatric epilepsy have opened new therapeutic possibilities in the field of cannabinoids and returned these compounds to the front line of research to treat pathologies as relevant as stroke.
... After stroke, cytokines, which are signaling molecules that play a crucial role in immune responses and inflammation, are dysregulated. 58 This dysregulation contributes to immunosuppression by promoting a proinflammatory environment and impairing the balance between proinflammatory and anti-inflammatory signaling. 59 One key observation is the increase in proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IFN-γ, after stroke in the ischemic brain. ...
... In addition to CNS injuries, sympathetic pathways are activated in response to stroke. 58,72,73 Increased sympathetic outflow leads to the release of stress hormones, such as adrenaline and noradrenaline, which can modulate immune responses, including T-cell function. Sympathetic activation induces T-cell apoptosis, 74 suppresses T-cell activation and proliferation, and alters the balance of T-cell subsets, contributing to immunodepression. ...
This review article discusses the potential of nanomaterials in targeted therapy and immunomodulation for stroke-induced immunosuppression. Although nanomaterials have been extensively studied in various biomedical applications, their specific use in studying and addressing immunosuppression after stroke remains limited. Stroke-induced neuroinflammation is characterized by T-cell-mediated immunodepression, which leads to increased morbidity and mortality. Key observations related to immunodepression after stroke, including lymphopenia, T-cell dysfunction, regulatory T-cell imbalance, and cytokine dysregulation, are discussed. Nanomaterials, such as liposomes, micelles, polymeric nanoparticles, and dendrimers, offer advantages in the precise delivery of drugs to T cells, enabling enhanced targeting and controlled release of immunomodulatory agents. These nanomaterials have the potential to modulate T-cell function, promote neuroregeneration, and restore immune responses, providing new avenues for stroke treatment. However, challenges related to biocompatibility, stability, scalability, and clinical translation need to be addressed. Future research efforts should focus on comprehensive studies to validate the efficacy and safety of nanomaterial-based interventions targeting T cells in stroke-induced immunosuppression. Collaborative interdisciplinary approaches are necessary to advance the field and translate these innovative strategies into clinical practice, ultimately improving stroke outcomes and patient care.
... Kekurangan energi dapat menyebabkan terjadinya stress dan kematian sel yang memicu pelepasan berbagai mediator pro-inflamasi dan anti-inflamasi (Qin et al., 2022). Mediator proinflamasi berperan dalam meningkatkan respon inflamasi yang dapat memperparah luaran neurologis pasien. ...
Acute ischemic stroke is an acute episode of neurological dysfunction caused by focal infarction or damage that persists for ≥24 hours in the brain, spine, and retinal. Stroke is the second highest cause of death worldwide. The total prevalence of stroke continues to increase in the world and in Indonesia. However, stroke treatment is still less effective, so adjuvant therapy needs to be developed; one of them is MLC901. However, this therapy still needs to be studied further regarding its effect on acute ischemic stroke and the biomarkers used as the prognostic factors, such as red cell distribution width (RDW). This paper aims to determine the effect of MLC901 therapy on RDW values in acute ischemic stroke by analyzing various previous studies from different databases as a reference. Increased RDW values are associated with poor outcomes of acute ischemic stroke. MLC901 was shown to have neuroprotective and neurorestorative abilities in neurons that are under stress due to ischemia. MLC901 also can reduce inflammatory responses, reduce oxidative stress, and increase erythropoietin (EPO) production. So, administration of adjuvant MLC901 therapy can reduce RDW values and improve neurological outcomes in acute ischemic stroke.
... Ischemic stroke accounts for 87% of all stroke cases [2]. The main cause of ischemic stroke is thrombosis in the cerebral blood vessels, which interrupts cerebral blood flow, thus inducing brain cell death, brain tissue necrosis, and neuronal damage [3]. Brain tissue damage can effectively be reduced if thrombolytic treatment is provided within the temporal window; however, reperfusion of blood flow beyond the temporal window may exacerbate the damage by causing cerebral ischemia-reperfusion injury (CIRI) [4]. ...
Cerebral ischemia–reperfusion injury (CIRI) is the second leading cause of death worldwide, posing a huge risk to human life and health. Therefore, investigating the pathogenesis underlying CIRI and developing effective treatments are essential. Ferroptosis is an iron-dependent mode of cell death, which is caused by disorders in iron metabolism and lipid peroxidation. Previous studies demonstrated that ferroptosis is also a form of autophagic cell death, and nuclear receptor coactivator 4(NCOA4) mediated ferritinophagy was found to regulate ferroptosis by interfering with iron metabolism. Ferritinophagy and ferroptosis are important pathogenic mechanisms in CIRI. This review mainly summarizes the link and regulation between ferritinophagy and ferroptosis and further discusses their mechanisms in CIRI. In addition, the potential treatment methods targeting ferritinophagy and ferroptosis for CIRI are presented, providing new ideas for the prevention and treatment of clinical CIRI in the future.
... However, to our knowledge, such trials for ischaemic stroke have not been conducted yet. Other therapeutic approaches involving cytokines and chemokines have also yielded promising results, especially in animal models [76][77][78][79] . ...
The systemic inflammatory response following acute ischaemic stroke remains incompletely understood. We characterised the circulating inflammatory profile in 173 acute ischaemic stroke patients by measuring 65 cytokines and chemokines in plasma. Participants were grouped based on their inflammatory response, determined by high-sensitivity C-reactive protein levels in the acute phase. We compared stroke patients’ profiles with 42 people experiencing spontaneous cervical artery dissection without stroke. Furthermore, variations in cytokine levels among stroke aetiologies were analysed. Follow-up samples were collected in a subgroup of ischaemic stroke patients at three and twelve months. Ischaemic stroke patients had elevated plasma levels of HGF and SDF-1α, and lower IL-4 levels, compared to spontaneous cervical artery dissection patients without stroke. Aetiology-subgroup analysis revealed reduced levels of nine cytokines/chemokines (HGF, SDF-1α, IL-2R, CD30, TNF-RII, IL-16, MIF, APRIL, SCF), and elevated levels of IL-4 and MIP-1β, in spontaneous cervical artery dissection (with or without ischaemic stroke as levels were comparable between both groups) compared to other aetiologies. The majority of cytokine/chemokine levels remained stable across the study period. Our research indicates that stroke due to large artery atherosclerosis, cardioembolism, and small vessel occlusion triggers a stronger inflammatory response than spontaneous cervical artery dissection.
... Systematic review registration This systematic review has been recorded in the International Prospective Register of Systematic Reviews (PROSPERO), with the assigned reference number: CRD42023381420 BACKGROUND Stroke represents the second leading cause of global mortality and the predominant cause of long-term disability. 1 The ischaemic stroke is the major subtype of stroke 2 caused by an abrupt decrease in brain tissue perfusion due to cerebral artery occlusion which causes multiple pathological events leading to tissue damage and death. 3 Current therapeutic strategies for ischaemic stroke include thrombolytic therapy administrated within the critical 4.5 hours time window following the onset of ischaemia. ...
... Ischaemic stroke stands as a leading cause of global mortality and disability. 1 Currently, thrombolytic therapy constitutes the primary approved treatment for ischaemic stroke patients. Nevertheless, this strategy is encumbered by several limitations, including a limited time window of only 4.5 hours after the ischaemic onset for its application, perceived inefficacy in certain high-risk patients and some major complications such as intracranial bleeding leading to haemorrhagic stroke. ...
Background
Stroke is a major cause of global mortality and disability. Currently, the treatment of acute ischaemic stroke through reperfusion has posed several challenges, raising the need for complementary options to protect the ischaemic penumbra. Recent investigations have indicated that certain epigenetic factors, specifically, histone deacetylases (HDACs) and sirtuins, can be promising for ischaemic stroke therapy, with recent studies suggesting that inhibitors of HDACs or sirtuins may provide neuronal protection after ischaemic stroke. However, the impact of specific HDAC/sirtuin isoforms on the survival of neuronal cells following stroke is still uncertain. This study aims to provide a comprehensive overview of the function of HDACs and their modulators in the treatment of acute ischaemic stroke.
Methods
This systematic review and meta-analysis will encompass animal intervention studies that explore the efficacy of modulation of HDACs and sirtuins in the acute phase of ischaemic stroke. The review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Electronic searches will be conducted in PubMed, Web of Science and Scopus, with subsequent screening by independent reviewers based on the established eligibility criteria. Methodological quality will be evaluated using the SYRCLE risk of bias tool. The primary outcomes will be infarct volume and functional response, with the secondary outcomes established a priori. Data pertaining to infarct volume will be used for random-effects meta-analysis. Additionally, a descriptive summary will be conducted for the functional response and secondary outcomes.
Discussion
No systematic review and meta-analysis on the treatment of ischaemic stroke through HDAC modulation has been conducted to date. A comprehensive analysis of the available literature on the relevant preclinical investigations can yield invaluable insights in discerning the most effective trials and in further standardisation of preclinical studies.
Systematic review registration
This systematic review has been recorded in the International Prospective Register of Systematic Reviews (PROSPERO), with the assigned reference number: CRD42023381420
... Severe cerebral ischemia, mostly in the elderly, can cause irreversible damage to brain function and even death (Kaviarasi et al. 2019). Recently, many efforts have been made in the treatment of cerebral ischemia, mainly in the direction of natural medicines and pathophysiological signaling pathways, but the prospect is not satisfactory (Qin et al. 2022;Tao et al. 2020). Intrinsically, the survival of neurons greatly affects the integrity and stability of brain function, and their loss can directly lead to cerebral functional deficits, indicating the indispensable role of neurons in the treatment of cerebral ischemia . ...
Objective
Catalpol (CAT) has various pharmacological activities and plays a protective role in cerebral ischemia. It has been reported that CAT played a protective role in cerebral ischemia by upregulaing NRF1 expression. Bioinformatics analysis reveals that NRF1 can be used as a transcription factor to bind to the histone acetyltransferase KAT2A. However, the role of KAT2A in cerebral ischemia remains to be studied. Therefore, we aimed to investigate the role of CAT in cerebral ischemia and its related mechanism.
Methods
In vitro, a cell model of oxygen and glucose deprivation/reperfusion (OGD/R) was constructed, followed by evaluation of neuronal injury and the expression of METTL3, Beclin-1, NRF1, and KAT2A. In vivo, a MCAO rat model was prepared by means of focal cerebral ischemia, followed by assessment of neurological deficit and brain injury in MCAO rats. Neuronal autophagy was evaluated by observation of autophagosomes in neurons or brain tissues by TEM and detection of the expression of LC3 and p62.
Results
In vivo, CAT reduced the neurological function deficit and infarct volume, inhibited neuronal apoptosis in the cerebral cortex, and significantly improved neuronal injury and excessive autophagy in MCAO rats. In vitro, CAT restored OGD/R-inhibited cell viability, inhibited cell apoptosis, LDH release, and neuronal autophagy. Mechanistically, CAT upregulated NRF1, NRF1 activated METTL3 via KAT2A transcription, and METTL3 inhibited Beclin-1 via m ⁶ A modification.
Conclusion
CAT activated the NRF1/KAT2A/METTL3 axis and downregulated Beclin-1 expression, thus relieving neuronal injury and excessive autophagy after cerebral ischemia.
... Second, there is an overexpression of mitogen-activated protein kinase (MAPK) and nuclear factor NF-κB [21]. Furthermore, apoptosis also occurs via downregulation of PI3K/Akt signalling [22]. Finally, release of H 2 O 2 species deranges mitochondrial membrane permeability, promotes chromatin condensation, and stimulates endoplasmic reticulum stress. ...
... Apart from phagocytosis, AIS is related to mechanisms other non-caspase-mediated cell death mechanisms, such as ferroptosis, parthanatos, and pyroptosis [22]. Ferroptosis consists in abnormal metabolism of iron and causing lipid peroxidation, resulting in membrane rupture. ...
Acute ischemic stroke (AIS) is a challenging disease, which needs urgent comprehensive management. Endovascular thrombectomy (EVT), alone or combined with iv thrombolysis, is currently the most effective therapy for patients with acute ischemic stroke (AIS). However, only a limited number of patients are eligible for this time-sensitive treatment. Even though there is still significant room for improvement in the management of this group of patients, up until now there have been no alternative therapies approved for use in clinical practice. However, there is still hope, as clinical research with novel emerging therapies is now generating promising results. These drugs happen to stop or palliate some of the underlying molecular mechanisms involved in cerebral ischemia and secondary brain damage. The aim of this review is to provide a deep understanding of these mechanisms and the pathogenesis of AIS. Later, we will discuss the potential therapies that have already demonstrated, in preclinical or clinical studies, to improve the outcomes of patients with AIS.
... Neurological diseases or events such as stroke and Spinal Cord Injury (SCI) are conditions that can generate limitations in mobility and motor functions [6,7]. This is because the communication pathways between the brain and the peripheral nervous system are usually affected, interrupting the synaptic connections that allow the generation of movement or sensory response [8]. Robotic devices emerge as an alternative for the rehabilitation or assistance of these people because mechatronic structures, such as exoskeletons, can support the subject during the performance of tasks, improving independence and quality of life [1,6]. ...
Common Spatial Pattern (CSP) has been recognized as a standard and powerful method for the identification of Electroencephalography (EEG)-based Motor Imagery (MI) tasks when implementing brain-computer interface (BCI) systems towards the motor rehabilitation of lost movements. The combination of BCI systems with robotic systems, such as upper limb exoskeletons, has proven to be a reliable tool for neuromotor rehabilitation. Therefore, in this study, the effects of temporal and frequency segmentation combined with layer increase for spatial filtering were evaluated, using three variations of the CSP method for the identification of passive movement vs. MI+passive movement. The passive movements were generated using a left upper-limb exoskeleton to assist flexion/extension tasks at two speeds (high-85 rpm and low-30 rpm). Ten healthy subjects were evaluated in two recording sessions using Linear Discriminant Analysis (LDA) as a classifier, and accuracy (ACC) and False Positive Rate (FPR) as metrics. The results allow concluding that the use of temporal, frequency or spatial selective information does not significantly (p < 0.05) improve task identification performance. Furthermore, dynamic temporal segmentation strategies may perform better than static segmentation tasks. The findings of this study are a starting point for the exploration of complex MI tasks and their application to neurorehabilitation, as well as the study of brain effects during exoskeleton-assisted MI tasks.
... Other major observation after stroke attack is disrupted connections between different regions of the brain. This is mainly caused due to neuronal network mutilations [12] (Fig. 1). ...
... Whereas activation of extra-synaptic NMDARs induces neuronal damage and death by dephosphorylation of CREB thereby diminishing CREB activity. Furthermore, it also suppresses the extracellular signal-regulated protein kinase (ERK), which supports the activation of CREB [12]. ...
Molecular pathways involved in cerebral stroke are diverse. The major pathophysiological events that are observed in stroke comprises of excitotoxicity, oxidative stress, mitochondrial damage, endoplasmic reticulum stress, cellular acidosis, blood–brain barrier disruption, neuronal swelling and neuronal network mutilation. Various biomolecules are involved in these pathways and several major proteins are upregulated and/or suppressed following stroke. Different types of receptors, ion channels and transporters are activated. Fluctuations in levels of various ions and neurotransmitters have been observed. Cells involved in immune responses and various mediators involved in neuro-inflammation get upregulated progressing the pathogenesis of the disease. Despite of enormity of the problem, there is not a single therapy that can limit infarction and neurological disability due to stroke. This is because of poor understanding of the complex interplay between these pathophysiological processes. This review focuses upon the past to present research on pathophysiological events that are involved in stroke and various factors that are leading to neuronal death following cerebral stroke. This will pave a way to researchers for developing new potent therapeutics that can aid in the treatment of cerebral stroke.
Graphical abstract
