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Biomedicine & Pharmacotherapy =... Apr 2022Neuroprotective and neurorestorative therapy represent two major drug intervention strategies for ischemic stroke. Multiple factors such as excitotoxicity, inflammation,... (Review)
Review
Neuroprotective and neurorestorative therapy represent two major drug intervention strategies for ischemic stroke. Multiple factors such as excitotoxicity, inflammation, angiogenesis, and neurogenesis are the main pathological processes that underlie acute and chronic ischemic brain injury. Furthermore, their intimate interactions mediate blood-brain barrier permeability, increase neurovascular unit structural damage as well as a hemorrhagic transformation during ischemic stroke. We aimed to review the current understandings of the underlying mechanisms of neuroprotection and neurorestoration in ischemic stroke. Notably, traditional Chinese medicine (TCM) has notable advantages in the comprehensive treatment and overall regulation of multi-site and multi-target diseases. Therefore, we reviewed the recent advances in natural compounds from medicinal herbs that possess the bioactivities of simultaneously promoting neuroprotection (e.g., excitotoxicity, oxidative stress, apoptosis, inflammation, and autophagy) and neurorestoration (e.g., angiogenesis, neurogenesis, and axonal sprouting) following brain ischemia injury. These natural compounds were divided into glycosides (astragaloside IV, gastrodin, ginsenoside Rg1 and salidroside), flavonoids (baicalin, icariin, puerarin and breviscapine), phenols (resveratrol, curcumin and salvianolic acid B), and terpenes (ginkgolide B and catalpol). We found that all compounds exhibited anti-brain ischemia activities in vivo and in vitro experiments by promoting neuroprotection and, or neurorestoration. This review tracks and summarizes the progress of the past five years to explore the active compounds and the underlying molecular mechanisms of TCMs that produce pro-neuroprotection and pro-neurorestoration. Additionally, we provide another basis of reference supporting the advantages of TCMs, which could ultimately lead to the development of precise clinical medications for ischemic stroke treatment.
Topics: Brain Ischemia; Humans; Ischemic Stroke; Medicine, Chinese Traditional; Neuroprotection; Neuroprotective Agents; Plants, Medicinal; Stroke
PubMed: 35168073
DOI: 10.1016/j.biopha.2022.112719 -
Experimental Neurology Jan 2021Stroke is the leading cause of disability and thesecond leading cause of death worldwide. With the global population aged 65 and over growing faster than all other age... (Review)
Review
Stroke is the leading cause of disability and thesecond leading cause of death worldwide. With the global population aged 65 and over growing faster than all other age groups, the incidence of stroke is also increasing. In addition, there is a shift in the overall stroke burden towards younger age groups, particularly in low and middle-income countries. Stroke in most cases is caused due to an abrupt blockage of an artery (ischemic stroke), but in some instances stroke may be caused due to bleeding into brain tissue when a blood vessel ruptures (hemorrhagic stroke). Although treatment options for stroke are still limited, with the advancement in recanalization therapy using both pharmacological and mechanical thrombolysis some progress has been made in helping patients recover from ischemic stroke. However, there is still a substantial need for the development of therapeutic agents for neuroprotection in acute ischemic stroke to protect the brain from damage prior to and during recanalization, extend the therapeutic time window for intervention and further improve functional outcome. The current review has assessed the past challenges in developing neuroprotective strategies, evaluated the recent advances in clinical trials, discussed the recent initiative by the National Institute of Neurological Disorders and Stroke in USA for the search of novel neuroprotectants (Stroke Preclinical Assessment Network, SPAN) and identified emerging neuroprotectants being currently evaluated in preclinical studies. The underlying molecular mechanism of each of the neuroprotective strategies have also been summarized, which could assist in the development of future strategies for combinational therapy in stroke treatment.
Topics: Animals; Clinical Trials as Topic; Humans; Ischemic Stroke; Neuroprotection; Neuroprotective Agents
PubMed: 33144066
DOI: 10.1016/j.expneurol.2020.113518 -
International Journal of Molecular... Feb 2023Ischemic stroke is the main cause of death and the most common cause of acquired physical disability worldwide. Recent demographic changes increase the relevance of... (Review)
Review
Ischemic stroke is the main cause of death and the most common cause of acquired physical disability worldwide. Recent demographic changes increase the relevance of stroke and its sequelae. The acute treatment for stroke is restricted to causative recanalization and restoration of cerebral blood flow, including both intravenous thrombolysis and mechanical thrombectomy. Still, only a limited number of patients are eligible for these time-sensitive treatments. Hence, new neuroprotective approaches are urgently needed. Neuroprotection is thus defined as an intervention resulting in the preservation, recovery, and/or regeneration of the nervous system by interfering with the ischemic-triggered stroke cascade. Despite numerous preclinical studies generating promising data for several neuroprotective agents, successful bench-to-bedside translations are still lacking. The present study provides an overview of current approaches in the research field of neuroprotective stroke treatment. Aside from "traditional" neuroprotective drugs focusing on inflammation, cell death, and excitotoxicity, stem-cell-based treatment methods are also considered. Furthermore, an overview of a prospective neuroprotective method using extracellular vesicles that are secreted from various stem cell sources, including neural stem cells and bone marrow stem cells, is also given. The review concludes with a short discussion on the microbiota-gut-brain axis that may serve as a potential target for future neuroprotective therapies.
Topics: Humans; Neuroprotection; Brain Ischemia; Ischemic Stroke; Prospective Studies; Stroke; Neuroprotective Agents; Neural Stem Cells
PubMed: 36901765
DOI: 10.3390/ijms24054334 -
Neurobiology of Disease Jul 2020Microglia-induced neuroinflammation plays a vital role in the etiology and progression of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease...
Microglia-induced neuroinflammation plays a vital role in the etiology and progression of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and multiple sclerosis. The neuroprotective role of androgens, including testosterone and its metabolite dihydrotestosterone (DHT), has been increasingly demonstrated in these diseases, but few studies investigated the effects of androgen on neuroinflammation. This study investigated the role of DHT in lipopolysaccharide (LPS)-induced neuroinflammation, neuronal damage and behavioral dysfunction, as well as underlying mechanisms. We showed that DHT inhibited LPS-induced release of proinflammatory factors, including TNF-α, IL-1β, IL-6; iNOS, COX-2, NO, and PGE2 in BV2 cells and primary microglia by suppressing the TLR4-mediated NF-κB and MAPK p38 signaling pathways, thus protecting SH-SY5Y neurons from inflammatory damage induced by activated microglia. In an LPS-induced neuroinflammation mouse model, endogenous DHT depletion by castration exacerbated inflammatory responses by upregulating the levels of TNF-α, IL-1β, IL-6, iNOS, and COX-2 in the serum and brain by increasing the LR4-mediated NF-κB and MAPK pathway activation, but these effects were restored by exogenous DHT supplementation. Moreover, DHT also regulated the mRNA levels of the anti-inflammatory cytokines IL-10 and IL-13 in the brain. In addition, DHT modulated the expression of Aβ, the apoptotic proteins caspase-3, Bcl-2, and Bax, and synaptophysin, as well as neuronal damage in LPS-treated mouse brains. Further behavioral tests revealed that DHT ameliorated LPS-induced spatial and learning impairment and motor incoordination, and partly improved the locomotor activity in LPS-injected mice. Therefore, this study suggests that DHT exerts anti-neuroinflammatory and neuroprotective effects; thus, androgen replacement therapy is a potential therapeutic strategy for improving cognitive and behavioral function in neuroinflammation-related diseases.
Topics: Androgens; Animals; Anti-Inflammatory Agents; Brain; Cyclooxygenase 2; Cytokines; Dihydrotestosterone; Inflammation; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Microglia; NF-kappa B; Neurons; Neuroprotection; Neuroprotective Agents; Nitric Oxide Synthase Type II; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha
PubMed: 32087283
DOI: 10.1016/j.nbd.2020.104814 -
British Journal of Pharmacology Feb 2023Astrocytic nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a potential therapeutic target of ischaemic preconditioning (IPC). Icariside II (ICS II) is a...
BACKGROUND AND PURPOSE
Astrocytic nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a potential therapeutic target of ischaemic preconditioning (IPC). Icariside II (ICS II) is a naturally occurring flavonoid derived from Herba Epimedii with Nrf2 induction potency. This study was designed to clarify if exposure to ICS II mimicks IPC neuroprotection and if Nrf2 from astrocytes contributes to ICS II preconditioning against ischaemic stroke.
EXPERIMENTAL APPROACH
Mice with transient middle cerebral artery occlusion (MCAO)-induced focal cerebral ischaemia and primary astrocytes challenged with oxygen-glucose deprivation (OGD) were used to explore the neuroprotective effect of ICS II preconditioning. Additionally, Nrf2-deficient mice were pretreated with ICS II to determine whether ICS II exerts its neuroprotection by activating Nrf2.
KEY RESULTS
ICS II pretreatment mitigated cerebral injury in the mouse model of ischaemic stroke along with improving long-term recovery. Furthermore, proteomics screening identified Nrf2 as a crucial gene evoked by ICS II treatment and required for the anti-oxidative effect and anti-inflammatory effect of ICS II. Also, ICS II directly bound to Nrf2 and reinforced the transcriptional activity of Nrf2 after MCAO. Moreover, ICS II pretreatment exerted cytoprotective effects on astrocyte cultures following lethal OGD exposure, by promoting Nrf2 nuclear translocation and activating the OXPHOS/NF-κB/ferroptosis axis, while neuroprotection was decreased in Nrf2-deficient mice and Nrf2 siRNA blocked effects of ICS II.
CONCLUSION AND IMPLICATIONS
ICS II preconditioning provides robust neuroprotection against ischaemic stroke via the astrocytic Nrf2-mediated OXPHOS/NF-κB/ferroptosis axis. Thus, ICS II could be a promising Nrf2 activator to treat ischaemic stroke.
Topics: Mice; Animals; NF-kappa B; Neuroprotection; NF-E2-Related Factor 2; Signal Transduction; Brain Ischemia; Ferroptosis; Stroke; Flavonoids; Neuroprotective Agents; Ischemic Stroke
PubMed: 36166825
DOI: 10.1111/bph.15961 -
Indian Journal of Ophthalmology Feb 2022Neuroprotective therapies in glaucoma may play a role in preventing ischemia and oxidative damage that results in apoptosis of retinal ganglion cells and optic nerve... (Review)
Review
Neuroprotective therapies in glaucoma may play a role in preventing ischemia and oxidative damage that results in apoptosis of retinal ganglion cells and optic nerve damage. Although intraocular pressure (IOP) is the only known modifiable risk factor for glaucoma, disease progression commonly occurs despite IOP control, suggesting that factors other than IOP play a role in its pathogenesis and can potentially act as targets for neuroprotection. Factors including mediators of apoptosis, ischemic changes, poor ocular blood flow and neurotoxins have been hypothesized to play a role in glaucoma progression. Neuroprotective targets include glutamate-induced neurotoxicity, nitric oxidase synthetase, neurotropins, calcium channel receptors, free radicals, vascular insufficiency, the rho-kinase pathway, and more. Drugs related to these factors are being evaluated for their role in neuroprotection, although this area of investigation faces several challenges including limited evidence for these agents' efficacy in clinical studies. Additionally, while IOP-lowering therapies are considered neuroprotective as they generally slow the progress of glaucoma progression, they are limited by the extent of their effect beyond IOP control. The aim of this article is to review the current treatment options available for neuroprotection and to explore the drugs in the pipeline.
Topics: Glaucoma; Humans; Intraocular Pressure; Neuroprotection; Neuroprotective Agents; Retinal Ganglion Cells
PubMed: 35086201
DOI: 10.4103/ijo.IJO_1158_21 -
Nutrients Aug 2021Nutrition and rehabilitation are crucial in post-stroke recovery, especially in the elderly. Since stroke is the leading cause of long-term disability, there is a need... (Review)
Review
Nutrition and rehabilitation are crucial in post-stroke recovery, especially in the elderly. Since stroke is the leading cause of long-term disability, there is a need to promote special, individually tailored nutrition strategies targeting older patients with low motor ability. Chronic stroke survivors have higher risk of developing nutrition-related chronic diseases, such as sarcopenia, anemia, type 2 diabetes mellitus and osteoporosis. Moreover, reduced motor activity, cognitive impairment and depression might be aggravated by poor malnutrition status. Accumulated data suggest that nutritional supplements and neuroprotective diets can be associated with better effectiveness of post-stroke rehabilitation as well as brain recovery. Therefore, this review focuses on preventive strategies that can improve dietary intake and change dietary patterns. We highlight the importance of neuroprotective diets, the problem of dysphagia and the role of nutrition in rehabilitation. This article focuses on potential nutritional supplements and neuroprotective diets that may have an impact on functional recovery during and after rehabilitation. Moreover, a new approach to post-stroke neuroplasticity including the use of agents from marine sources such as fucoxanthin and tramiprosate as compounds that might be used as potential neuroprotectants with antioxidative and anti-inflammatory properties is introduced.
Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents; Antioxidants; Diet; Dietary Supplements; Eating; Female; Humans; Male; Malnutrition; Neuroprotection; Neuroprotective Agents; Nutrition Therapy; Nutritional Status; Recovery of Function; Stroke; Stroke Rehabilitation
PubMed: 34444864
DOI: 10.3390/nu13082704 -
International Journal of Molecular... Nov 2019Neurodegenerative diseases are among the most serious health problems affecting millions of people worldwide, and their incidence is dramatically growing together with...
Neurodegenerative diseases are among the most serious health problems affecting millions of people worldwide, and their incidence is dramatically growing together with increased lifespan [...].
Topics: Animals; Biological Products; Humans; Neurodegenerative Diseases; Neuroprotection; Neuroprotective Agents
PubMed: 31703472
DOI: 10.3390/ijms20225570 -
Epilepsy & Behavior : E&B Apr 2023We present the rationale for testing ketamine as an add-on therapy for treating benzodiazepine refractory (established) status epilepticus. In animal studies, ketamine... (Review)
Review
We present the rationale for testing ketamine as an add-on therapy for treating benzodiazepine refractory (established) status epilepticus. In animal studies, ketamine terminates benzodiazepine refractory status epilepticus by interfering with the pathophysiological mechanisms and is a neuroprotectant. Ketamine does not suppress respiration when used for sedation and anesthesia. A Series of reports suggest that ketamine can help terminate refractory and super refractory status epilepticus. We propose to use 1 or 3 mg/Kg ketamine intravenously based on animal-to-human conversion and pharmacokinetic studies. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.
Topics: Ketamine; Anticonvulsants; Benzodiazepines; Neuroprotective Agents; Seizures; Status Epilepticus; Humans
PubMed: 36609129
DOI: 10.1016/j.yebeh.2022.109066 -
Pediatric Research Jun 2023Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in... (Review)
Review
Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in term and near-term infants has proven beneficial, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. There is therefore a critical need to find additional pharmacological and non-pharmacological interventions that improve the outcomes for these children. There are many potential candidates; however, it is unclear whether these interventions have additional benefits when used with TH. Although primary and delayed (secondary) brain injury starting in the latent phase after HI are major contributors to neurodisability, the very late evolving effects of tertiary brain injury likely require different interventions targeting neurorestoration. Clinical trials of seizure management and neuroprotection bundles are needed, in addition to current trials combining erythropoietin, stem cells, and melatonin with TH. IMPACT: The widespread use of therapeutic hypothermia (TH) in the treatment of neonatal encephalopathy (NE) has reduced the associated morbidity and mortality. However, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. This review details the pathophysiology of NE along with the evidence for the use of TH and other beneficial neuroprotective strategies used in term infants. We also discuss treatment strategies undergoing evaluation at present as potential adjuvant treatments to TH in NE.
Topics: Infant, Newborn; Child; Humans; Infant; Neuroprotection; Intensive Care Units, Neonatal; Hypothermia, Induced; Infant, Newborn, Diseases; Brain Injuries; Hypoxia-Ischemia, Brain; Neuroprotective Agents
PubMed: 36195634
DOI: 10.1038/s41390-022-02295-2