Effective Neuroprotective Agent Research Articles

Avicularin inhibits ferroptosis and improves cognitive impairments in Alzheimer's disease by modulating the NOX4/Nrf2 axis

BackgroundAlzheimer's disease (AD) is a widespread neurodegenerative disorder for which effective therapies remain elusive, primarily due to the complexity of its underlying pathophysiology. In recent years, natural products have gained attention for their therapeutic potential in AD, owing to their multi-targeted actions and low toxicity profiles. Avicularin (Avi), a flavonoid derived from the peels of Zanthoxylum bungeanum Maxim., has shown promise as an anti-AD agent. However, the specific mechanisms by which Avi mitigates oxidative stress and inhibits ferroptosis in AD models remain insufficiently understood. Further investigation is required to elucidate its therapeutic potential in these pathways. PurposeTherefore, this study aims to elucidate the neuroprotective effects of Avi in AD by investigating its impact on the NOX4/Nrf2 signaling pathway, as well as its role in modulating oxidative stress and ferroptosis. MethodsIn this study, an in vitro H2O2-induced oxidative stress model in SH-SY5Y cells was utilized to evaluate the pharmacological efficacy and underlying mechanisms of Avi. Molecular docking, cellular thermal shift assay and bio-layer interferometry assays were conducted to identify potential molecular targets of Avi. Additionally, in vivo models, including scopolamine (SCOP)-induced and APP/PS1 transgenic mice, were employed to assess the cognitive effects of Avi and further explore its associated molecular mechanisms. ResultsOur study demonstrates that Avi effectively attenuates H2O2-induced toxicity in SH-SY5Y cells by reducing apoptosis and enhancing cellular antioxidant defenses. This neuroprotective effect is mediated through the inhibition of NOX4 and the promotion of Nrf2 nuclear translocation. Furthermore, Avi improves cognitive function and mitigates ferroptosis in both SCOP-induced and APP/PS1 transgenic mouse models of AD. ConclusionAvi emerges as an effective neuroprotective agent against AD, offering a promising therapeutic approach by targeting the NOX4/Nrf2 signaling axis to alleviate oxidative stress and ferroptosis.

Recent Developments in Coumarin Derivatives as Neuroprotective Agents.

Neurodegenerative diseases are among the diseases that cause the foremost burden on the health system of the world. The diseases are multifaceted and difficult to treat because of their complex pathophysiology, which includes protein aggregation, neurotransmitter breakdown, metal dysregulation, oxidative stress, neuroinflammation, excitotoxicity, etc. None of the currently available therapies has been found to be significant in producing desired responses without any major side effects; besides, they only give symptomatic relief otherwise indicated off-episode relief. Targeting various pathways, namely choline esterase, monoamine oxidase B, cannabinoid system, metal chelation, β-secretase, oxidative stress, etc., may lead to neurodegeneration. By substituting various functional moieties over the coumarin nucleus, researchers are trying to produce safer and more effective neuroprotective agents. This study aimed to review the current literature to produce compounds with lower side effects using coumarin as a pharmacophore. In this review, we have attempted to compile various synthetic strategies that have been used to produce coumarin and various substitutional strategies used to produce neuroprotective agents from the coumarin pharmacophore. Moreover, structure-activity relationships of substituting coumarin scaffold at various positions, which could be instrumental in designing new compounds, were also discussed. The literature review suggested that coumarins and their derivatives can act as neuroprotective agents following various mechanisms. Various studies have demonstrated the neuroprotective activity of coumarin due to an oxaheterocyclic loop, which allows binding with a broad array of proteins, thus motivating researchers to explore its potential as a lead against various neurodegenerative diseases.

Effects of edaravone dexborneol on functional outcome and inflammatory response in patients with acute ischemic stroke

BackgroundEdaravone dexborneol has been reported as an effective neuroprotective agent in the treatment of acute ischemic stroke (AIS). This study aimed at investigating the impact of edaravone dexborneol on functional outcomes and systematic inflammatory response in AIS patient.MethodsAll participants were recruited from the AISRNA study (registered 21/11/2019, NCT04175691 [ClinicalTrials.gov]) between January 2022 and December 2022. The AIS patients were divided into two groups based on whether they received the treatment of edaravone dexborneol (37.5 mg/12 hours, IV) within 48 h after stroke onset. Inflammatory response was determined by detecting levels of cytokines (interleukin-2 [IL-2], IL-4, IL-5, IL-8, IL-6, IL-10, IL-12p70, IL-17, tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], IFN-α, and IL-1β) within 14 days after stroke onset.ResultsEighty-five AIS patients were included from the AISRNA study. Patients treated with edaravone dexborneol showed a significantly higher proportion of modified Rankin Scale score < 2 compared to those who did not receive this treatment (70.7% versus 47.8%; P = 0.031). Furthermore, individuals receiving edaravone dexborneol injection exhibited lower expression levels of interleukin (IL)-1β, IL-6, and IL-17, along with higher levels of IL-4 and IL-10 expression during the acute phase of ischemic stroke (P < 0.05). These trends were not observed for IL-2, IL-5, IL-8, IL-12p70, tumor necrosis factor-α, interferon-γ [IFN-γ], and IFN-α (P > 0.05).ConclusionsTreatment with edaravone dexborneol resulted in a favorable functional outcome at 90 days post-stroke onset when compared to patients without this intervention; it also suppressed proinflammatory factors expression while increasing anti-inflammatory factors levels.Trial registrationClinicalTrials.gov NCT04175691. Registered November 21, 2019, https://www.clinicaltrials.gov/ct2/show/NCT04175691.

Neuroprotective effects of anti-TRAIL-ICG nanoagent and its multimodal imaging evaluation in cerebral ischemia-reperfusion injury

Cerebral ischemia-reperfusion injury (CIRI) is a major challenge to neuronal survival in acute ischemic stroke (AIS). However, effective neuroprotective agents remain to be developed for the treatment of CIRI. In this work, we have developed an Anti-TRAIL protein-modified and indocyanine green (ICG)-responsive nanoagent (Anti-TRAIL-ICG) to target ischemic areas and then reduce CIRI and rescue the ischemic penumbra. In vitro and in vivo experiments have demonstrated that the carrier-free nanoagent can enhance drug transport across the blood-brain barrier (BBB) in stroke mice, exhibiting high targeting ability and good biocompatibility. Anti-TRAIL-ICG nanoagent played a better neuroprotective role by reducing apoptosis and ferroptosis, and significantly improved ischemia-reperfusion injury. Moreover, the multimodal imaging platform enables the dynamic in vivo examination of multiple morphofunctional information, so that the dynamic molecular events of nanoagent can be detected continuously and in real time for early treatment in transient middle cerebral artery occlusion (tMCAO) models. Furthermore, it has been found that Anti-TRAIL-ICG has great potential in the functional reconstruction of neurovascular networks through optical coherence tomography angiography (OCTA). Taken together, our work effectively alleviates CIRI after stoke by blocking multiple cell death pathways, which offers an innovative strategy for harnessing the apoptosis and ferroptosis against CIRI.

Remote Ischemic Postconditioning-Mediated Neuroprotection against Stroke by Promoting Ketone Body-Induced Ferroptosis Inhibition.

Neuronal death resulting from ischemic stroke is the primary cause of adult mortality and disability, and effective neuroprotective agents for poststroke intervention are still lacking. Remote ischemic postconditioning (RIPostC) has demonstrated significant protective effects against ischemia in various organs; however, the specific mechanisms are not fully understood. This study investigated the potential neuroprotective mechanisms of RIPostC in the context of ischemic stroke. Using a rat model of middle cerebral artery occlusion, we found that RIPostC mitigated neurological damage, improved movement in the open-field test, and protected against neuronal apoptosis. In terms of energy metabolism, RIPostC enhanced ATP levels, suppressed lactate content, and increased the production of ketone bodies (KBs). In the ferroptosis assay, RIPostC protected against lipoperoxidation, reversed the reduction of glutathione peroxidase 4 (GPX4), and mitigated the excessive expression of long-chain acyl-CoA synthetase family member 4 (ACSL4). In oxygen-glucose deprivation/reoxygenation-treated HT22 cells, KBs maintained GPX4 levels, suppressed ACSL4 expression, and preserved the mitochondrial cristae number. However, the effect of KBs on the expression of GPX4, ACSL4, and the number of mitochondrial cristae was blocked by erastin. Moreover, both RIPostC and KBs reduced total iron and ferrous ion content by repressing iron transporters both in vitro and in vivo. In conclusion, KBs-induced mitigation of ferroptosis could represent a new therapeutic mechanism for RIPostC in treating stroke.

Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones.

The majority of approved therapies for many diseases are developed to target their underlying pathophysiology. Understanding disease pathophysiology has thus proven vital to the successful development of clinically useful medications. Stroke is generally accepted as the leading cause of adult disability globally and ischemic stroke accounts for the most common form of the two main stroke types. Despite its health and socioeconomic burden, there is still minimal availability of effective pharmacological therapies for its treatment. In this review, we take an in-depth look at the etiology and pathophysiology of ischemic stroke, including molecular and cellular changes. This is followed by a highlight of drugs, cellular therapies, and complementary medicines that are approved or undergoing clinical trials for the treatment and management of ischemic stroke. We also identify unexplored potential targets in stroke pathogenesis that can be exploited to increase the pool of effective anti-stroke and neuroprotective agents through de novo drug development and drug repurposing.

Platinum-Loaded Cerium Oxide Capable of Repairing Neuronal Homeostasis for Cerebral Ischemia-Reperfusion Injury Therapy.

Effective neuroprotective agents are required to prevent neurological damage caused by reactive oxygen species (ROS) generated by cerebral ischemia-reperfusion injury (CIRI) following an acute ischemic stroke. Herein, it is aimed to develop the neuroprotective agents of cerium oxide loaded with platinum clusters engineered modifications (Ptn-CeO2). The density functional theory calculations show that Ptn-CeO2 could effectively scavenge ROS, including hydroxyl radicals (·OH) and superoxide anions (·O2 -). In addition, Ptn-CeO2 exhibits the superoxide dismutase- and catalase-like enzyme activities, which is capable of scavenging hydrogen peroxide (H2O2). The in vitro studies show that Ptn-CeO2 could adjust the restoration of the mitochondrial metabolism to ROS homeostasis, rebalance cytokines, and feature high biocompatibility. The studies in mice CIRI demonstrate that Ptn-CeO2 could also restore cytokine levels, reduce cysteine aspartate-specific protease (cleaved Caspase 3) levels, and induce the polarization of microglia to M2-type macrophages, thus inhibiting the inflammatory responses. As a result, Ptn-CeO2 inhibits the reperfusion-induced neuronal apoptosis, relieves the infarct volume, reduces the neurological severity score, and improves cognitive function. Overall, these findings suggest that the prominent neuroprotective effect of the engineered Ptn-CeO2 has a significant neuroprotective effect and provides a potential therapeutic alternative for CIRI.

Linarin ameliorates ischemia-reperfusion injury by the inhibition of endoplasmic reticulum stress targeting AKR1B1

Due to various factors, there is still a lack of effective neuroprotective agents for ischemic stroke in clinical practice. Neuroinflammation and neuronal apoptosis mediated by endoplasmic reticulum stress are some of the important pathological mechanisms in ischemic stroke. Linarin has been reported to have anti-inflammation, antioxidant, and anti-apoptotic effects in myocardial ischemia, osteoarthritis, and kidney disease. Whether it exerts neuroprotective functions in ischemic stroke has not been investigated. The results showed that linarin could reduce the infarct volume in cerebral ischemia animal models, improve the neurological function scores and suppress the expression of inflammatory factors mediating the NF-κB. Meanwhile, it could protect the neurons from OGD/R-induced-apoptosis, which was related to the PERK-eIF2α pathway. Our results suggested linarin could inhibit neuronal inflammation and apoptosis induced by endoplasmic reticulum stress. Furthermore, the neuroprotective effect of linarin may be related to the inhibition of AKR1B1. Our study offers new insight into protecting against ischemia-reperfusion injury by linarin treatment in stroke.

Caveolae with serotonin and NMDA receptors as promising targets for the treatment of Alzheimer's disease.

Alzheimer's disease is the most general type of cognitive impairments. Until recently, strategies that prevent its clinical progression have remained more elusive. Consequently, research direction should be for finding effective neuroprotective agents. It has been suggested oxidative stress, mitochondrial injury, and inflammation level might lead to brain cell death in many neurological disorders. Therefore, several autophagy-targeted bioactive compounds may be promising candidate therapeutics for the prevention of brain cell damage. Interestingly, some risk genes to Alzheimer's disease are expressed within brain cells, which may be linked to cholesterol metabolism, lipid transport, endocytosis, exocytosis and/or caveolae formation, suggesting that caveolae may be a fruitful therapeutic target to improve cognitive impairments. This review would highlight the latest advances in therapeutic technologies to improve the treatment of Alzheimer's disease. In particular, a paradigm that serotonin and N-methyl-d-aspartate (NMDA) receptors agonist/antagonist within caveolae structure might possibly improve the cognitive impairment. Consequently, cellular membrane biophysics should improve our understanding of the pathology of the cognitive dysfunction associated with Alzheimer's disease. Here, this research direction for the purpose of therapy may open the potential to move a clinical care toward disease-modifying treatment strategies with certain benefits for patients.

DRhQ: a novel therapeutic that improves cognition and mitochondrial function and reduces neuroinflammation in beta‐amyloid overexpressing Mice

AbstractBackgroundNeuroinflammation and mitochondrial dysfunction are central to the progression of Alzheimer’s disease (AD), provoking neuronal loss and cognitive decline. Identifying strategies for mitigating these responses could therefore be of significant therapeutic relevance. Evidence suggests that the inflammatory axis mediated by macrophage migration inhibitory factory (MIF) binding to its receptor, CD74, plays an important role in many central nervous system (CNS) disorders like AD. Our group has developed DRhQ, a novel CD74 binding construct that competitively inhibits MIF binding, blocks T‐cell and macrophage activation and migration into the CNS, enhances anti‐inflammatory microglia cell numbers and reduces pro‐inflammatory gene expression. DRhQ treatment resulted in reduced neuroinflammation and disease severity in a mouse model of multiple sclerosis. Because neuroinflammation is a prominent in the AD brain as well we hypothesized that DRhQ could be a similarly effective neuroprotective agent in the context of AD. We evaluated this hypothesis using the 5xFAD mouse model of β‐amyloid (Aβ) accumulation.MethodSix month old male and female 5xFAD mice and their wild‐type littermates will be treated with 0 or 100 ug of DRhQ subcutaneously for five days followed by a 3 day booster series weekly for the next 3 weeks. During the 4th week of treatment mice were evaluated cognitively using the novel object recognition test and brain tissue was harvested to evaluate mitochondrial function, Aβ pathology as well as markers of microglial activation and neuroinflammation.ResultDRhQ improved cognition and reduced neuroinflammatory markers in both male and female 5xFAD mice. DRhQ also significantly attenuated deficits in cortical mitochondrial function in female 5xFAD mice and elicited a similar, though non‐significant, effect in male 5xFAD mice. Aβ plaque burden was likewise reduced in the hippocampus and cortex of female 5xFAD mice but not significantly reduced in male 5xFAD animals.ConclusionThese results suggest that DRhQ attenuates Aβ pathology, mitochondrial dysfunction and neuroinflammation and improves cognitive function in 5xFAD mice. Future experiments will explore dose response effects and investigate the apparent sex differences in the magnitude of effect of DRhQ on specific endpoints in these mice as well as evaluate the effects of DRhQ in models of tauopathy.

Caffeic acid alleviates cerebral ischemic injury in rats by resisting ferroptosis via Nrf2 signaling pathway.

There are few effective and safe neuroprotective agents for the treatment of ischemic stroke currently. Caffeic acid is a phenolic acid that widely exists in a number of plant species. Previous studies show that caffeic acid ameliorates brain injury in rats after cerebral ischemia/reperfusion. In this study we explored the protective mechanisms of caffeic acid against oxidative stress and ferroptosis in permanent cerebral ischemia. Ischemia stroke was induced on rats by permanent middle cerebral artery occlusion (pMCAO). Caffeic acid (0.4, 2, 10 mg·kg-1·d-1, i.g.) was administered to the rats for 3 consecutive days before or after the surgery. We showed that either pre-pMCAO or post-pMCAO administration of caffeic acid (2 mg·kg-1·d-1) effectively reduced the infarct volume and improved neurological outcome. The therapeutic time window could last to 2 h after pMCAO. We found that caffeic acid administration significantly reduced oxidative damage as well as neuroinflammation, and enhanced antioxidant capacity in pMCAO rat brain. We further demonstrated that caffeic acid down-regulated TFR1 and ACSL4, and up-regulated glutathione production through Nrf2 signaling pathway to resist ferroptosis in pMCAO rat brain and in oxygen glucose deprivation/reoxygenation (OGD/R)-treated SK-N-SH cells in vitro. Application of ML385, an Nrf2 inhibitor, blocked the neuroprotective effects of caffeic acid in both in vivo and in vitro models, evidenced by excessive accumulation of iron ions and inactivation of the ferroptosis defense system. In conclusion, caffeic acid inhibits oxidative stress-mediated neuronal death in pMCAO rat brain by regulating ferroptosis via Nrf2 signaling pathway. Caffeic acid might serve as a potential treatment to relieve brain injury after cerebral ischemia. Caffeic acid significantly attenuated cerebral ischemic injury and resisted ferroptosis both in vivo and in vitro. The regulation of Nrf2 by caffeic acid initiated the transcription of downstream target genes, which were shown to be anti-inflammatory, antioxidative and antiferroptotic. The effects of caffeic acid on neuroinflammation and ferroptosis in cerebral ischemia were explored in a primary microglia-neuron coculture system. Caffeic acid played a role in reducing neuroinflammation and resisting ferroptosis through the Nrf2 signaling pathway, which further suggested that caffeic acid might be a potential therapeutic method for alleviating brain injury after cerebral ischemia.

Cdk1 protects against oxygen-glucose deprivation and reperfusion-induced Golgi fragmentation and apoptosis through mediating GM130 phosphorylation.

Increasing evidence has indicated that the Golgi apparatus (GA) is involved in the development of cerebral ischemia-reperfusion (IR) injury. Finding effective neuroprotective agents targeting GA has become a priority in the treatment of ischemic stroke. GM130, a key structural protein present on the cis-face of the GA, maintains its structure through its phosphorylation and dephosphorylation. However, the molecular mechanisms by which GM130 regulates IR-induced neuronal apoptosis are not well elucidated. Mouse neuroblastoma Neuro2a (N2A) cells were subjected to oxygen-glucose deprivation and reperfusion (OGDR) insult. Cell proliferation and apoptosis were determined using MTT assay, TUNEL staining, and flow cytometry. GA morphology was detected by immunocytochemical staining and immunofluorescence microscopy. GA-related protein and mRNA levels were detected by WB and qPCR, respectively. Treatment with Purvalanol A, an effective Cdk1 inhibitor, and transfection of Cdk1-shRNA were carried out to inhibit OGDR-induced Cdk1 elevation. The results demonstrated that OGDR induced Golgi fragmentation, neuronal apoptosis, GM130 phosphorylation, and p115 cleavage in N2A cells. Cdk1 elevation after OGDR was closely correlated with GM130 phosphorylation, not p115. Inhibition of Cdk1 significantly attenuated OGDR-induced Golgi fragmentation and cell apoptosis. Cdk1 interacted with GM130 and decreased its phosphorylation on the serine 25 site in N2A cells exposed to OGDR. The present findings reveal that Cdk1 protects against IR-induced GA fragmentation and apoptosis, likely through the mediation of GM130 phosphorylation. This neuroprotective potential of Cdk1 against IR insult and the underlying mechanism will pave the way for potential clinical applications targeting the GA organelle for cerebral IR-related disorders.

Therapeutic potentialities of green tea (Camellia sinensis) in ischemic stroke: biochemical and molecular evidence.

Ischemic stroke is a leading cause of disability and death in patients. Despite considerable recent advances in the treatment of ischemic stroke, only a limited number of effective neuroprotective agents are available for stroke. Green tea (Camellia sinensis) is a popular herbal plant, and numerous studies have indicated its health benefits for several diseases. Green tea is of interest due to its high content of catechin derivatives, including epicatechin, gallocatechin, epicatechin gallate, epigallocatechin, and epigallocatechin-3-gallate. This review tried to develop a feasible background for the potential effects of green tea and its bioactive derivatives concerning protection against ischemic stroke. Green tea's antioxidants, anti-inflammatory, anti-apoptotic, and neuroprotective effects are believed to be efficacious in stroke treatment. Evidence supports the idea that green tea can be used to assist in treating ischemic stroke.

Nose-to-brain delivery of hesperidin nanoparticles loaded in-situ gel for neuroprotective action

Major depressive disorder (also known as depression) is a serious mental health condition that has a detrimental impact on a person's mood, thoughts, and behaviour. The presence of oxidative stress is associated with an increased risk of developing depression. A flavonoid called hesperidin (HSP) has been proven to be helpful in experimental depression because of its powerful antioxidant properties. However, due to its limited bioavailability, gastrointestinal degradation, inadequate permeability, and low water solubility, the clinical development of HSP has been impeded. The objective of the present research was to develop HSP Nanoparticles (NPs) loaded in-situ gel for nose-to-brain delivery to provide neuroprotective action. HSP NPs were prepared by nanoprecipitation technique and were tailored to the size by using ultrasonication technique. Optimization of NPs was conducted using the Central Composite Design. Prepared particles were analysed by FTIR, DSC, and UV technique. Forced swim test was conducted as a behavioural assessment to gauze the neuroprotective antidepressant activity of the prepared formulation. The particle size was found to be in the range of 76.5 ± 0.86 nm to 239.2 + 0.31 nm, zeta potential in the range of -8.37 ± 0.6 mV to 22.4 ± 1.37 mV, and entrapment efficiency in the range of 54.92 ± 1.36% to 74.53 ± 1.28%. Pharmacodynamic study showed formulation significantly decreased the immobility time in experimental animals. This study showed the potential of HSP NPs to be an effective neuroprotective agent.

Ruthenium Dioxide Nanoparticles Treat Alzheimer’s Disease by Inhibiting Oxidative Stress and Alleviating Neuroinflammation

Oxidative stress and neuroinflammation have received widespread attention as mechanisms of Alzheimer’s disease (AD) pathogenesis. Oxidative stress, serving as a “bridge” between various hypotheses, has been shown to interact with several pathological features (neuroinflammation, β-amyloid deposition) and forms a vicious circle that accelerates the progression of AD. Herein, we report ruthenium dioxide nanoparticles (RuO2 NPs) with diverse enzymatic activities and reactive oxygen species (ROS) elimination functions. The poly(vinylpyrrolidone) (PVP) on the surface of RuO2 NPs was used to link with borneol (Bor) to help it pass through the blood–brain barrier (BBB). In vitro and in vivo experiment results have shown that RuO2@Bor possesses good biocompatibility and multiple antioxidant-like enzymatic activities, which can scavenge ROS, protect neurons from oxidative damage, and repair impaired mitochondrial function. In addition, RuO2@Bor could also regulate microglia polarization (from pro-inflammatory M1-phenotype microglial to anti-inflammatory M2 phenotype microglial) and inhibit the release of pro-inflammatory factors (TNF-α, IL-6) to effectively relieve neuroinflammation. In vivo experiments further demonstrated that RuO2@Bor not only effectively improved the cognitive and memory abilities of AD model mice but also acted as an effective neuroprotective agent. The results suggest that RuO2@Bor would be a potential drug for the multitarget treatment of AD.

Exploring the Molecular and Genetic Mechanisms of Action of the α2-Adrenergic Agonist Mafedine in Experimental Traumatic Brain Injury in Rats

Neurological impairments due to traumatic, vascular, or neurodegenerative brain diseases have a high prevalence worldwide. Among them are motor, cognitive, and mental disorders, which have a serious negative impact on the working and social activities of the patients. This calls for the search and development of novel effective neuroprotective agents. Previous studies have shown the pyrimidine-derived α2-adrenergic agonist mafedine to be highly effective for the amelioration of neurological deficits in experimental traumatic brain injury (TBI) in rats. Despite the results of the previous works favouring the major role of the α2 adrenergic receptor activation in the mechanism of action of mafedine, the search for additional molecular targets is an important part of the development of any drug to be used in clinical practice. In this work, we evaluated the effects of 7 day-long course administration of mafedine (2.5 mg/kg b.w.) on the expression of brain-derived neurotrophic factor (BDNF), the proinflammatory cytokines interleukin (IL)-1β, -6, tumour necrosis factor (TNF)-α, and the α2A, α2B, and α2C α2-adrenergic receptor subtypes in the brain cortex of rats subjected to TBI, using the reverse-transcription real-time polymerase chain reaction method. TBI was modelled by the controlled cortical impact technique in an open area of sensorimotor cortex of the left brain hemisphere. Behavioural alterations in the injured animals were assessed in the Open field test, and the fore- and hindlimb motor function, in the Limb placing, Cylinder, and Beam walking tests. Our experiments show that TBI causes severe motor impairments as well as decreases exploration in rats. Besides, at post-TBI day 7, a reduction in the expression of all analyzed genes is seen, which is the most pronounced in the contralateral (uninjured) hemisphere. Course administration of mafedine (2.5 mg/kg b.w.) resulted in moderate stimulation of the injured rats’ behaviour, increased exploratory activity compared to controls, and improved sensorimotor deficit as assessed by the Beam walking test. Gene expression analysis results indicated that mafedine decreased α2B-adrenergic receptor, TNF-α, and IL-6 expression in the injured hemisphere. At the same time, compared to rats with TBI having received no treatment, mafedine-treated animals exhibited higher α2B-adrenergic receptor and IL-1β expression in the injured rather than the intact hemisphere. These results confirm the previously observed neuroprotective activity of mafedine and imply that it may exert its effects via suppression of α2B-adrenergic receptor and proinflammatory cytokine expression in the injured brain hemisphere, at the same time increasing their expression in the intact one.

Neuroprotective agents in acute ischemic stroke

Acute ischemic stroke (AIS) is the leading cause of disability and one of the top causes of mortality worldwide. The current standard of care is reperfusion therapy including intravenous thrombolysis (IVT) and thrombectomy. However, these treatments have limitations as they have a limited therapeutic window. Hence, there is a vital need to develop neuroprotective agents to prevent brain injury, extend the reperfusion window, improve mortality, and reduce disability in AIS patients. Neuroprotective agents work by counteracting the detrimental biochemical and molecular events that result in irreversible ischemic damage. Numerous preclinical studies and clinical trials have been done on different agents. Thus far, all have been definitively unsuccessful in large trials. Currently, there are several challenges in translation from animal studies to human trials. It is important to understand the current evidence as well as past challenges in the development of neuroprotective strategies in AIS in order for a more strategic selection of agents to be studied, improve study designs and thus contribute to the development of effective neuroprotective agents. Newer agents have shown promise in neuroprotection, and human trials are ongoing. In this review, the mechanisms of action of different families of neuroprotective agents were discussed. The evidence for the efficacy of different drugs in each family of neuroprotective agents was also evaluated and the current research landscape in neuroprotection for AIS was summarized. The past challenges and limitations in clinical trials and proposed possible ways to address these issues were highlighted.

Erythropoietin ameliorates cognitive deficits by improving hippocampal and synaptic damage in streptozotocin-induced diabetic mice

Recent studies have shown that erythropoietin (EPO) is an effective neuroprotective and neurotrophic agent for neurological disorders, such as traumatic brain injury and Alzheimer's disease. However, the effectiveness of EPO administration against diabetic cognitive impairments has rarely been examined. In this study, we investigated the effects of EPO on streptozotocin (STZ)-induced male C57BL/6 J mice. Then, we sought to clarify the mechanisms of EPO-mediated neuroprotection in high-glucose (HG)-stimulated HT22 cells. In vivo, we found that STZ-induced diabetic mice showed impaired spatial learning and memory, which was alleviated by EPO treatment. EPO also significantly lowered elevated fasting blood glucose levels, improved pancreatic and hippocampal damage, and restored oxidative stress in the STZ-induced diabetic mice. In vitro, EPO markedly increased cell viability, restrained the expression of pro-apoptotic Bax, enhanced the expression of pro-caspase 3, anti-apoptotic Bcl-2, brain-derived neurotrophic factor (BDNF) and postsynaptic density 95 (PSD-95), and attenuated the upregulation of N-methyl-d-aspartic acid (NMDA) receptor subunits NR1, NR2A and NR2B in HG-induced HT22 cells. The protective effects of EPO was obviously abolished by treatment with an NMDA receptor agonist. Our findings revealed that EPO impedes hippocampal and synaptic damage and neuronal apoptosis by regulating BDNF and PSD-95 expression through NMDA receptors, thereby ameliorating cognitive impairments in mice with T1DM.

Tenuifolin ameliorates the sleep deprivation-induced cognitive deficits.

Tenuifolin (TEN), a natural neuroprotective compound obtained from the Polygala tenuifolia Willd plant, has improved cognitive symptoms. However, the impact of TEN on memory impairments caused by sleep deprivation (SD) is unclear. Accordingly, the objective of this study was to investigate the mechanisms behind the preventative benefits of TEN on cognitive impairment caused by SD. TEN (10 and 20 mg/kg) and Huperzine A (0.1mg/kg) were given to mice through oral gavage for 28 days during the SD process. The results indicate that TEN administrations improve short- and long-term memory impairments caused by SD in the Y-maze, object identification, and step-through tests. Moreover, TEN stimulated the generation of anti-inflammatory cytokines (interleukin-10), lowered the production of pro-inflammatory cytokines (interleukin-1β, interleukin-6, and interleukin-18), and activated microglia, improving antioxidant status in the hippocampus. TEN treatments significantly boosted the expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 while considerably decreasing the expression of NOD-like receptor thermal protein domain associated protein 3 and caspase-1 p20. Additionally, TEN restored the downregulation of the brain-derived neurotrophic factor signaling cascade and the impaired hippocampal neurogenesis induced by SD. When considered collectively, our data suggest that TEN is a potentially effective neuroprotective agent for cognition dysfunction.

Edaravone for Acute Ischemic Stroke: A Systematic Review and Meta-analysis

PurposeThe management of acute stroke is challenging. The aim of this meta-analysis was to determine the efficacy and tolerability of edaravone, with or without thrombolytic therapy, in the treatment of patients with acute ischemic stroke. MethodsThe PubMed, EMBASE, and Cochrane databases were searched for randomized controlled trials (RCTs) and cohort studies. Mean differences (MD), risk ratios (RR), 95% confidence interval (CI), and heterogeneity were calculated. FindingsTotals of nine RCTs and four cohort studies were included, for a total of 2102 patients. In patients with acute ischemic stroke, edaravone monotherapy was associated with significantly improved Barthel Index of functioning in activities for daily living (MD, 23.95; 95% CI, 18.48 to 29.41; P < 0.001) and neurologic deficit, (as measured using the National Institutes of Health Stroke Scale score) (MD = –3.49; 95% CI, –5.76 to 1.22; P = 0.003), on short-term follow-up. However, edaravone was not associated with an improved rate of death or disability (RR = 0.75; 95% CI, 0.45 to 1.23; P = 0.25) on long-term follow-up.When plus to thrombolytic therapy, edaravone was associated with significant improvements in recanalization rate (RR = 1.71; 95% CI, 1.05 to 2.77; P = 0.03) and neurologic deficit (MD = 3.97; 95% CI, 5.14 to 2.79; P < 0.001), without an increase in the prevalence of bleeding events (RR = 1.11; 95% CI, 0.76 to 1.62; P = 0.59). However, edaravone did not have a significant effect on death or disability (RR = 0.85; 95% CI, 0.69 to 1.04; P = 0.12). ImplicationsBased on the findings from the present meta-analysis, edaravone was an effective and well-tolerated neuroprotective agent in these patients with ischemic stroke. With the use of edaravone, activities of daily living and neurologic deficits, along with recanalization rates, were improved on short-term follow-up, but the long-term effects still need confirmation in larger-scale clinical trials.