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Hypoxic ischemic encephalopathy (HIE) is the leading cause of neonatal mortality and disability, but its treatment options are very limited and there is an urgent need to further improve treatment outcomes. The present study aims to reveal the therapeutic effects, action pattern, and potential mechanisms of Cerebroprotein hydrolysate-I (CH-I), a mixture of hydrolyzed peptides and amino acids, for the management of HIE. To simulate the complex pathogenesis of HIE more accurately, we innovatively constructed a "triple hit" neonatal HIE rat model. The efficacy of CH-1 was examined in this model, and it was found that CH-I treatment not only significantly improved the behavior and small molecule metabolism disorders of neonatal HIE rats, but also reduced intracerebral neuronal apoptosis, neuroinflammation, and oxidative stress levels. In addition, the neuroprotective effect of CH-I was also confirmed in the hypoxic oligodendrocyte precursor cell model. We innovatively found that CH-I could reverse myelin damage induced by HIE modeling via activating the Wnt/β-catenin signaling pathway. More importantly, a robust quantitative analysis assay for the main peptides in CH-I was developed based on LC-MS/MS system combining Skyline software. Then the pharmacokinetics of the main peptides was studied based on 'relative exposure approach' combining 'mixed calibration curves' strategy. The transient exposure of peptides in vivo indicated that CH-I should exert neuroprotective effects through the "hit and run" pattern., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: GLP-1 receptor agonists, traditionally used for treating type 2 diabetes mellitus and obesity, have demonstrated anti-inflammatory properties. However, their potential neuroprotective effects in neurodegenerative disorders remain unclear., Objective: To evaluate the impact of GLP-1 receptor agonists on the risk of developing various neurodegenerative conditions in obese patients., Methods: This comprehensive retrospective cohort study analyzed data from 5,307,845 obese adult patients across 73 healthcare organizations in 17 countries. Propensity score matching was performed, resulting in 102,935 patients in each cohort. We compared the risk of developing neurodegenerative disorders between obese patients receiving GLP-1 receptor agonist therapy and those who were not., Results: Obese patients treated with GLP-1 receptor agonists showed significantly lower risks of developing Alzheimer's disease (RR = 0.627, 95 %CI = 0.481-0.817), Lewy body dementia (RR = 0.590, 95 %CI = 0.462-0.753), and vascular dementia (RR = 0.438, 95 %CI = 0.327-0.588). The risk reduction for Parkinson's disease was not statistically significant overall (RR = 0.784, 95 %CI = 0.580-1.058) but was significant for semaglutide users (RR = 0.574, 95 %CI = 0.369-0.893). Semaglutide consistently showed the most pronounced protective effects across all disorders. Additionally, a significant reduction in all-cause mortality was observed (HR = 0.525, 95 %CI = 0.493-0.558)., Conclusion: This study provides evidence that the effects of GLP-1 receptor agonists may extend beyond their known metabolic and cardioprotective benefits to include neuroprotection, associated with a decreased risk of developing various neurodegenerative disorders. These findings suggest the potential for expanding the therapeutic applications of GLP-1 receptor agonists to improve neurocognitive outcomes. Further research is warranted to elucidate the mechanisms underlying these neuroprotective effects and to explore their clinical applications in neurodegenerative disease prevention and treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Dysregulation of Th17 and Treg cells contributes to the pathophysiology of cerebral ischemia. Metabolic changes of peripheral CD4 + T cells lead to the imbalance of Treg/Th17 polarization, which represents a promising strategy for post-stroke therapy. Polyphyllin VII (PVII), a steroidal saponin extracted from traditional Chinese herb Rhizoma Paridis, has multiple bioactivities, but the potential function of PVII in cerebral ischemia-reperfusion injury is not elucidated yet. In our study, a mouse transient middle cerebral artery occlusion (MCAO) model was constructed. TTC staining, H&E staining, TUNEL staining, ELISA assay, flow cytometry, western blot, RT-qPCR, Open-field test, Morris water maze test, hanging wire test, rotarod test and foot-fault test were performed to evaluate the potential function of PVII in MCAO mice. We found that PVII showed protective effects on cerebral ischemia-reperfusion injury by reducing infarct volume, ameliorating brain injury and neuroinflammation, and improving long-term functional recovery of MCAO mice. PVII promoted Treg infiltration and suppressed infiltration of Th1/Th17 cells in ischemic brain in vivo. Moreover, PVII impaired peripheral CD4 + T cell activation and modulated Treg/Th17 differentiation in vitro. Mechanistically, PVII suppressed mTORC1 activation to influence glycolytic metabolism and ROS generation of T cells, thus leads to the imbalance of Treg/Th17 polarization towards Treg skewed. Furthermore, reactivation of mTORC1 by MHY1485 abolished the influence of PVII on brain injury and neuroinflammation in MCAO mice. Our data provided a novel role of PVII in cerebral ischemia-reperfusion injury via manipulating Treg/Th17 imbalance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Oxidative stress is critically involved in the cognitive dysfunction and neuronal progressive degeneration in the vascular cognitive impairment (VCI). The natural lignan molecular isoamericanin A (ISOA) containing multiple hydroxyl groups has great potential for suppressing oxidative stress in VCI. The primary objective of this study was to delve into the pharmacological properties of ISOA against VCI, as well as to elucidate the mechanisms driving this effect from the perspective of antioxidative stress. Transient bilateral common carotid arteries occlusion (tBCCAO) mice model and hydrogen peroxide (H 2 O 2 ) treated N2a cells were employed in vivo and in vitro, respectively. Behavioral tests showed that ISOA (5, 10 mg/kg) treatment alleviated learning, memorizing, and recognition in tBCCAO model mice. ISOA alleviated the neuronal damages by increasing the number of NeuN-positive cells, decreasing the TUNEL-positive cells density, up-regulating MAP-2 expression, lighting the damage of neuronal nucleus and synapse. Mechanistically, we found that ISOA reduced the oxidative stress in neurons, which manifested by reduction on the expressions of superoxide, H 2 O 2 , intercellular reactive oxygen species (ROS) and malondialdehyde (MDA) level, and up-regulations on the expressions of anti-oxidant enzymes superoxide dismutase, heme oxygenase-1, glutathione peroxidase 4, glutathione, and NAD(P)H: quinone oxidoreductase 1. Further investigation showed that ISOA activated nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by downregulating the expression of kelch-like ECH-associated protein 1, upregulating the nuclear translocation and expression of Nrf2, and augmenting antioxidant response elements (ARE) promotor activity. The ISOA-mediated promotion on ARE promotor activity and anti-oxidant enzymes expressions, and suppression on superoxide and ROS expressions and MDA levels were weakened by pharmacological inhibition or genetic knockdown of Nrf2. These effects were enhanced after knockdown Keap1 in H 2 O 2 -treated cells. Our study demonstrates that ISOA alleviates the cognitive impairments and neuronal loss in VCI by attenuating oxidative stress through promoting the activation of Nrf2 pathway., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: Depression, a prevalent mental disorder, significantly impairs the quality of life and social functioning. Targeting neuroinflammation is a promising therapeutic approach, highlighting the need for natural neuroprotective agents. Gypenosides (Gyp) from Gynostemma pentaphyllum exhibit anxiolytic and antidepressant effects, yet the underlying mechanisms remain unclear. We investigated whether Gyp, isolated and purified by our laboratory, can exert neuroprotective effects by modulating neuroinflammation in the hippocampus and prefrontal cortex (PFC) of mice with LPS-induced anxiety and depression, thereby ameliorating behavioral phenotypes., Methods: LPS (1 mg/kg, i.p.) was used to induce anxiety and depression-like behaviors. Gyp was administered at 50, 100, or 200 mg/kg in pretreatment, with fluoxetine hydrochloride (Flu) as a positive control, for 10 consecutive days., Results: Gyp, especially at 100 mg/kg, significantly ameliorated LPS-induced anxiety and depression in mice, normalizing cytokine expression in the hippocampus and PFC, with IL-1β showing the most pronounced regulation (Hippocampus: Ratio Gyp-100/LPS  = 30.73 %, PFC: Ratio Gyp-100/LPS  = 55.89 %). Gyp also reversed LPS-induced neuronal loss and necrosis, reduced glial cell activation, and prevented the transition of microglia to the M1 phenotype. Mechanistically, Gyp suppressed the activation of the NLRP3 inflammasome in the PFC, and modulated hippocampal synaptic protein loss, thereby mediating neuroinflammation., Conclusions: Gyp improved anxiety and depression in LPS-induced mice, which may be achieved by balancing systemic inflammatory levels, regulating glial cell activation and phenotypic polarization, regulating hippocampal synaptic plasticity, and suppressing the NLRP3/Caspase-1/ASC signaling pathway in the PFC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Ischemic stroke is the leading cause of death and long-term disability worldwide. After stroke, microglia exhibit not only pro-inflammatory phenotype to aggravate the neuroinflammation, but also anti-inflammatory phenotype to play a neuroprotective role. Studies on the spatial and temporal changes in microglia and the underlying mechanisms help to elucidate the inflammatory cascade after stroke. The regulation of microglia polarization provides new insights for the intervention of post-stroke inflammation., Objective: We aimed to investigate the phenotypic change of microglia in the acute phase of ischemic stroke and the effects of Dl-3-n-butylphthalide (NBP) on microglia. TSPO-PET was used to image microglia and evaluate the efficacy of NBP., Methods: We constructed an MCAO model in rats and administered NBP daily. The infarct volumes in the NBP-treated and control groups were measured. TSPO-PET/CT was used to demonstrate the activation of microglia and the effects of NBP. Additionally, we investigated the effects of NBP on TSPO expression. In vitro, microglia were exposed to glucose oxygen deprivation, and the effects of NBP on microglia and TSPO expression were verified., Results: NBP improved neurological severity scores and reduced infarct volume in the acute phase of ischemic stroke. NBP facilitated microglia to adopt the anti-inflammatory phenotype and reduce the pro-inflammatory phenotype. NBP decreased the expressions of inflammatory cytokines. TSPO-PET/CT observed increase in uptake in the infarct lesion, and this uptake was reduced in response to NBP. NBP reduced TSPO expression in microglia after stroke. In vitro experiments further verified that NBP facilitated the transition of microglia towards the anti-inflammatory phenotype, and inhibited inflammatory cytokine secretion and TSPO expression., Conclusion: We illustrated that NBP fosters the shift of microglia towards the anti-inflammatory phenotype while diminishing their inclination towards the pro-inflammatory phenotype, thereby exerting neuroprotective effects. NBP reduces TSPO expression in microglia, which can be observed by TSPO-PET/CT imaging., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The purpose of this work was to investigate how curcumin (Cur) might enhance cognitive function and to gain a better understanding of the molecular mechanisms behind Cur's impacts on neurogenesis deficits brought on by intermittent hypoxia (IH). Using network pharmacology, we explored possible targets for Cur's obstructive sleep apnea (OSA) therapy. We established an IH model using C57BL/6 mice and c17.2 cells, and we assessed the influence of Cur on treatment outcomes as well as the effect of IH on cognitive function. Hippocampal damage and neurogenesis, as well as expression of core targets, were then examined. Network pharmacology analysis revealed that Cur has the potential for multi-target, multi-pathway therapy, with CTNNB1 and MYC as core target genes. The Morris water maze test showed that Cur (100 mg/kg, intragastrically) significantly improved cognitive dysfunction induced by IH. The hematoxylin and eosin (H&E) and Nissl staining indicated that Cur could alleviate damage to the hippocampus caused by IH. Immunohistochemistry, immunofluorescence, and western blotting results showed that Cur might promote neurogenesis and upregulate the expression of β-catenin and c-myc. In vitro, Cur (0.5 μM) has a protective effect on IH-induced neural stem cells (NSCs) injury and apoptosis and can restore the Wnt/β-catenin. Cur significantly increased the neurogenesis via the Wnt/β-catenin pathway, providing the scientific groundwork for the development of new treatment strategies for neurological damage linked to OSA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neurodegenerative disorders such as Alzheimer's disease (AD) are age-related and are fatal in advanced cases. There is a limited efficacy of drugs used for the management of these diseases. Herein, the neurotherapeutic efficacy of a benzofuran-derivative-7 (BF-7) was investigated. Aluminum chloride (AlCl 3 ) was employed to induce AD-like brain toxicity in rats. The rats were divided into four groups: Negative control, AlCl 3 -induced AD rats (100 mg/kg body weight, orally), AlCl 3 -AD induced rats treated with BF-7 (10 mg/kg body weight, orally), AlCl 3 -AD-induced rats treated with the standard drug "Donepezil" (10 mg/kg body weight, orally). The behavioral performance was tested using a beam-balance test. Brain and serum acetylcholinesterase (AChE) activities and the brain levels of norepinephrine, dopamine (DA), and serotonin (5-HT) were measured. The genetic expression of Bcl-2, Bax, caspase-3, and insulin 1 were assayed. The histopathological imaging and the immunohistochemical evaluation of Glial Fibrillary Acidic Protein (GFAP) were investigated in the cerebral cortex. Treatment of AD-rats with BF-7 mitigated AlCl 3 -induced neurotoxicity by improving motor functions, counteracting apoptosis, and exerting cholinergic functions. In addition, the genetic expression of Insulin 1 was upregulated significantly in AD-induced rats treated with BF-7. This compound could be used as a promising candidate for neurotherapeutic drug discovery against AD or any other toxic brain disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The progressive degeneration of dopaminergic neurons in the substantia nigra region of the brain leads to a deficiency of dopamine and, ultimately, the onset of Parkinson's disease (PD). Since there is currently no cure for PD, patients all around the world are dealing with symptomatic management. PD progression is influenced by multiple elements, such as environmental, biological, chemical, genetic, and epigenetic factors. Epigenetics is gaining increased attention due to its role in controlling the expression of genes that contribute to PD. Recent advancements in our understanding of the brain network and its related conditions have shown that alterations in gene expression may occur independently of genetic abnormalities. Therefore, a thorough investigation has been carried out to explore the significance of epigenetics in all degenerative disorders. Epigenetic modifications are essential for regulating cellular homeostasis. Therefore, a deeper understanding of these modifications might provide valuable insights into many diseases and potentially serve as targets for therapeutic interventions. This review article focuses on diverse epigenetic alterations linked to the progression of PD. These abnormalities are supported by numerous research on the control of gene expression and encompass all the epigenetic processes. The beginning of PD is intricately associated with aberrant DNA methylation mechanisms. DNA methyltransferases are the enzymes that create and preserve various DNA methylation patterns. Integrating epigenetic data with existing clinical methods for diagnosing PD may aid in discovering potential curative medicines and novel drug development approaches. This article solely addresses the importance of epigenetic modulators in PD, primarily the mechanisms of DNMTs, their roles in the development of PD, and their therapeutic approaches; it bypasses other PD therapies., Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The progressive decline of dopaminergic neurons in Parkinson's disease (PD) has been linked to an imbalance in energy and the failure of mitochondrial function. AMP-activated protein kinase (AMPK), the major intracellular energy sensor, regulates energy balance, and damage to nigral dopaminergic neurons induced by 6-hydroxydopamine (6-OHDA) is exacerbated in the absence of AMPK activity. This study aimed to examine the potential therapeutic advantages of AdipoRon, an AMPK activator, on motor function and mitochondrial homeostasis in a 6-OHDA-induced PD model. Male Wistar rats were subjected to unilateral injection of 6-OHDA (10 μg) into the left medial forebrain bundle at two points, and after 7 days, they were treated with intranasal AdipoRon (0.1, 1, and 10 μg) or Levodopa (10 mg/kg, p. o.) for 21 successive days. Following the last treatment day, motor behavior was evaluated through the Murprogo's test, bar test, beam walking test, and apomorphine-induced rotation test. After euthanasia, the left substantia nigra (SN) was separated for evaluation of ATP, mitochondrial membrane potential (MMP), and protein expressions of AMPK, p-AMPK, and mitochondrial dynamics markers (Mfn-2 and Drp-1). Moreover, the number of tyrosine hydroxylase-positive (TH + ) cells was quantified in the left substantia nigra. Intranasal AdipoRon effectively reversed muscle rigidity, akinesia, bradykinesia, and rotation caused by 6-OHDA. Moreover, AdipoRon increased the phospho-AMPK/AMPK ratio, mitigated mitochondrial dysfunction, and improved mitochondrial dynamics in the SN. Furthermore, AdipoRon increased the number of TH + cells in the SN of PD animals. These findings suggest that AdipoRon could protect dopaminergic neurons by activating the AMPK pathway and improving mitochondrial dysfunction., Competing Interests: Declaration of competing interest The authors declare they have no financial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Methods: This study seeks to identify the bioactive compounds within Rhododendron dauricum and explore potential mechanisms for treating cerebral I/R injury through a comprehensive analysis employing network pharmacology, complemented by experimental validation., Results: The core targets associated with quercetin in the treatment of cerebral I/R injury are TNF-α, IL-6, IL-1β, and AKT1. Notably, we propose for the first time that its mode of action primarily involves the inhibition of the TNF-α/RhoA/ROCK2 pathway., Conclusion: Our findings reveal that quercetin emerges as a pivotal bioactive component of Rhododendron dauricum in the context of cerebral I/R injury treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neurodegenerative diseases, mostly occurring in the elderly population, are the significant cause of disability and death worldwide. The pathogenesis of neurodegenerative diseases is still largely unknown yet, although they have been continuously explored. Thus, there is still a lack of safe, effective, and low side effect drugs in clinical practice for the treatment of neurodegenerative diseases. Pieces of accumulating evidence have demonstrated that licorice played neuroprotective roles in various neurodegenerative diseases. In the past two decades, increasing studies have indicated that glycyrrhizic acid (GL), the main active ingredient from traditional Chinese medicine licorice (widely used in the food industry) and a triterpenoid saponin with multiple pharmacological effects (such as anti-oxidant, anti-inflammatory, and immune regulation), and its metabolites (glycyrrhetinic acid and carbenoxolone) play a neuroprotective role in a range of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and epilepsy. This review will elaborate on the multiple neuroprotective mechanisms of GL and its metabolites in this series of diseases, aiming to provide a basis for further research on these protective drugs for neurodegenerative diseases and their clinical application. In summary, GL may be a promising candidate drug for the therapy of neurodegenerative diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Oxidative stress plays a pivotal role in multiple sclerosis (MS), triggering demyelination predominantly through excessive peroxide production and the depletion of antioxidants. The accumulation of oxidative damage can be caused by dysregulation of astrocytes, which are the brain's main regulators of oxidative homeostasis. Calycosin, an essential bioactive component extracted from Astragalus, is recognized for its neuroprotective properties. Although recent research has highlighted calycosin's neuroprotective capabilities, its role in demyelinating conditions like MS remains unclear. In this work, we examined the possible molecular mechanism of calycosin's neuroprotective effect on cuprizone (CPZ)-induced demylination in mice. According to our research, calycosin successfully reduced demyelination and behavioral dysfuction in CPZ mice. Calycosin also decreased the production of oxidative stress and enhanced the expression of antioxidants in CPZ mice and in astrocytes induced by hydrogen peroxide (H 2 O 2 ). Furthermore, both in vivo and in vitro experiments demonstrated that calycosin promoted the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) along with the upregulation of heme oxygenase 1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), and superoxide dismutase (SOD). Importantly, the application of all-trans retinoic acid (ATRA), a specific inhibitor of Nrf2, effectively reversed the myelin-protective and antioxidant effects conferred by calycosin. This study suggested that calycosin might exert neuroprotection by inhibiting oxidative stress and reducing demyelination via the activation of astrocyte Nrf2 signaling. These findings indicated that calycosin might be a potential candidate for treating MS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Aims: Calcitonin gene-related peptide (CGRP) is a pluripotent neuropeptide crucial for maintaining vascular homeostasis, yet its full therapeutic potential remains incompletely exploited. Within the brain, CGRP demonstrates a distinct bimodal effect, contributing to neuroprotection in ischemic conditions while inducing neuronal sensitization and inflammation in non-ischemic settings. Despite extensive research on CGRP, the absence of a definitive determinant for this observed dichotomy has limited its potential for therapeutic applications in the brain. This review examines the effects of CGRP in both physiological and pathological conditions, aiming to identify a unifying factor that could enhance its therapeutic applicability., Materials and Methods: This comprehensive literature review analyzes the molecular pathways associated with CGRP and the specific cellular responses observed in these contexts. Additionally, the review investigates the psychological implications of CGRP in relation to cerebral perfusion levels, aiming to elucidate its underlying factors., Key Findings: Reviewing the literature reveals that, elevated levels of CGRP in non-ischemic conditions exert detrimental effects on brain function, while they confer protective effects in the context of ischemia. These encompass anti-oxidative, anti-inflammatory, anti-apoptotic, and angiogenic properties, along with behavioral normalization. Current findings indicate promising therapeutic avenues for CGRP beyond the acute phases of cerebral injury, extending to neurodegenerative and psychological disorders associated with cerebral hypoperfusion, as well as chronic recovery following acute cerebral injuries., Significance: Improved understanding of CGRP's bimodal properties, alongside advancements in CGRP delivery methodologies and brain ischemia detection technologies, paves the way for realizing its untapped potential and broad therapeutic benefits in diverse pathological conditions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chunyan Li reports financial support was provided by National Institute of Neurological Disorders and Stroke. Chunyan Li reports financial support was provided by US Army Medical Research and Development Command. Chunyan Li reports financial support was provided by Northwell Health Feinstein Institutes for Medical Research. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Status epilepticus (SE) is a neurologic emergency characterized by prolonged or rapidly recurring seizures. Increased intracellular calcium concentration ([Ca 2+ ] i ) occurring after SE is a key mediator of excitotoxicity that contributes to the brain damage associated with the development of epilepsy. Accumulated evidence indicates that dantrolene, a ryanodine receptor (RyR) blocker may have protective effects against the SE-induced damage. We evaluated whether dantrolene (10 mg/kg, i.p.) administered twice, 5 min and 24 h after the lithium-pilocarpine-induced SE in rats, had neuroprotective effects. Dantrolene by itself had no effects on control rats. However, it exacerbated the signs of damage in rats that underwent SE, increasing brain glucose hypometabolism as measured by PET neuroimaging 3 days after SE. Likewise, the neurohistochemical studies revealed that dantrolene aggravated signs of hippocampal neurodegeneration, neuronal death and microglia-induced neuroinflammation. Besides, the damaging effects were reflected by severe body weight loss. Overall, our results point towards a deleterious effect of dantrolene in the lithium-pilocarpine-induced SE model. Nonetheless, our results are in opposition to the reported neuroprotective effects of dantrolene. Whether the mechanisms underlying [Ca 2+ ] i increase might significantly differ depending on the particularities of the model of epilepsy used and general experimental conditions need further studies. Besides, it is yet to be determined which isoform of RyRs significantly contributes to Ca 2+ -induced excitotoxicity in the lithium-pilocarpine SE rat model., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Irisin is a glycosylated protein formed from the hydrolysis of fibronectin type III domain-containing protein 5 (FNDC5). Irisin is widely involved in the regulation of glucose and lipid metabolism. In addition, recent studies have demonstrated that Irisin can inhibit inflammation, restrain oxidative stress and have neuroprotective effects, which suggests that Irisin may have a good therapeutic effect on central nervous system diseases. Therefore, this review summarizes the role of Irisin in central nervous system diseases, including its signal pathways and possible mechanisms, etc. Irisin may be a potential candidate drug for the treatment of central nervous system diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

This study aimed to evaluate the cognitive-enhancing and neuroprotective effects of cardamonin in the 5XFAD transgenic mouse model of Alzheimer's disease (AD). We treated six-month-old female 5XFAD mice with cardamonin at 5 mg/kg, 10 mg/kg, and 20 mg/kg. Cognitive function was assessed using the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests. ELISA, western blot, and PCR analyses evaluated amyloid-beta (Aβ) levels, neuroinflammation markers, and apoptosis-related factor expression. All animals survived without toxicity. Cardamonin treatment significantly improved spatial learning and memory retention in MWM and NOR tests, with the 20 mg/kg dose showing the most pronounced effects. Additionally, cardamonin reduced soluble and insoluble Aβ levels in the frontal cortex and hippocampus. The treatment also significantly decreased neuroinflammatory markers, with IL-1β, IL-6, and TNF-α levels dropping substantially at higher doses. Cardamom treatment also normalizes cleaved caspase 3, GFAP, Iba-1, PSD-95, and synaptophysin, which aids in restoring synaptic integrity. Furthermore, cardamonin led to a marked reduction in apoptosis-related gene expression, indicating its potential to mitigate neurodegeneration. Cardamonin demonstrates significant cognitive-enhancing and neuroprotective properties in the 5XFAD mouse model, suggesting its potential as a therapeutic agent for AD. These findings support further investigation into cardamonin's mechanisms and applicability in treating neurodegenerative disorders., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra that primarily affects movement control. Neuroinflammation plays a pivotal role in driving the disease's progression. The persistent inflammatory state in the brain exacerbates neuronal damage, creating a cycle that perpetuates the neurodegenerative process. Glucocorticoids, such as dexamethasone, have potent anti-inflammatory properties and have been studied for their neuroprotective potential in different neurodegenerative diseases. However, their specific impact on PD remains unclear. This study aimed to evaluate the impact of dexamethasone on a neuromelanin (NM)-driven model of PD. We demonstrated that dexamethasone administration significantly improved motor function and preserved dopaminergic neuron compared to untreated controls in our study. These neuroprotective effects were mediated, at least in part, by suppressing reactive microglia and reducing the infiltration of peripheral immune cells into the brain. Our findings underscore the potential therapeutic benefits of dexamethasone in mitigating neuroinflammation and maintaining neuronal integrity in a NM-driven model of PD. These results advocate for further investigation into glucocorticoid-based therapies as adjunctive treatments for PD, particularly in scenarios where neuroinflammation contributes prominently to disease progression., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background & Aims: Gait disturbances are commonly observed in patients with neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and higher-level gait disorders, which are associated with cholinergic deficits. We conducted a systematic review and meta-analysis to investigate the effects of rivastigmine on improvement in gait., Methods: A comprehensive literature search was conducted using Medical Subject Heading (MeSH) terms and text keywords related to gait and falls after rivastigmine treatment for neurodegenerative disorders. The intervention (rivastigmine), comparison (control or no treatment), and outcomes of improvement in gait speed and fall were assessed from database inception to April 2024. References and collected data were meticulously reviewed to ensure the integrity of the included studies. Standardized mean differences (SMDs) and Hedges'g, along with their 95% confidence intervals (Cls), were calculated for gait speed and number of falls., Results: A total of 222 articles were identified during the initial search across different electronic databases, 50 including PubMed (n = 23), Cochrane (n = 19), Embase (n = 139), Scopus (n = 38), and a manual search (n = 3). Finally, we conducted a systematic review and meta-analysis focusing on the final four studies, encompassing 286 participants. The pooled SMD for the overall gait speed without a comparison group was 0.761 (95% CI: -1.165 to 2.688), indicating no significant improvement in gait speed. For the overall number of falls between the rivastigmine treatment and control groups, the pooled SMD was -0.366 (95% CI: -0.650 to -0.083). A statistically significant reduction in the number of falls was observed in the rivastigmine group than in the control group., Conclusion: Rivastigmine treatment in patients with neurodegenerative disorders tend to improve gait speed and significantly reduces fall incidence. Given the limited efficacy of current treatments for gait disturbances and falls, dual cholinesterase inhibitors like rivastigmine could be a promising therapeutic option., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Shim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A sharp increase in intramedullary pressure after spinal cord injury (SCI) can aggravate secondary injury and lead to severe neurological deficits. Unfortunately, effective treatment options are currently lacking. The mechanosensitive ion channel Piezo1 plays an important role in the pathological process of SCI by transducing mechanical stress. The Piezo1 inhibitor GsMTx4 has been shown to have neuroprotective effects and may hold therapeutic potential for SCI. Given that single drug treatment strategy has limited effect on functional recovery after SCI, we explored the efficacy of combining GsMTx4 with exercise training in treating SCI in rats and investigated the underlying mechanisms. We used the T10 SCI rat model, administered GsMTx4 immediately after injury, and performed 4 weeks of body weight supported treadmill training starting (BWSTT) 2 weeks post injury. Subsequently, HE and LFB staining were used to observe the morphology of spinal cord tissue, WB was used to detect autophagy and apoptosis-related proteins, biochemical detection of calcium ion concentration and CTSD activity, IHC detection of LAMP1 expression, immunofluorescence labeling of NeuN and ChAT-positive motor neurons, as well as MBP and GFAP, and BBB scores were used to evaluate rat motor function. We found that the combined treatment of GsMTx4 drug and exercise training was more effective than single treatment alone. The combined treatment reduced calcium ion concentration, improved lysosomal function, enhanced autophagic flux, reduced cell apoptosis, and significantly improved the motor function of rats. This combined treatment regimen may pave the way for developing more comprehensive treatment strategies for SCI in the future., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Motor neuron disease (MND) is a devastating neurodegenerative disease characterized by progressive muscle weakness., Sources of Data: PubMed, MEDLINE, and Cochrane databases were searched for articles to March 2024. Searches involved the terms 'motor neuron disease' or 'amyotrophic lateral sclerosis' and 'epidemiology', 'diagnosis', 'clinical', 'genetic', 'management', 'treatment', or 'trial'., Areas of Agreement: Evidence-based management involves riluzole, multidisciplinary care, provision of noninvasive ventilation and gastrostomy, and symptomatic treatments. Tofersen should be offered to treat SOD1-MND., Areas of Controversy: Edaravone and Relyvrio are approved treatments in the USA, but insufficient evidence was found to support approval in the UK and Europe., Growing Points: The discovery of neurofilaments as MND biomarkers, growth of platform trials and development of novel therapies provide optimism for more powerful neuroprotective therapies., Areas Timely for Developing Research: Further work should focus on the elucidation of environmental causes of MND, gene-environment interactions, and advanced cellular models of disease., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aluminum exposure has been widely demonstrated to cause cognitive impairment and neuronal damage, which are significant factors in many neurodegenerative diseases. Ginger root extract (GRE) has attracted researchers' attention in recent years due to its antioxidant and neuroprotective properties, as a potential therapeutic intervention to mitigate aluminum-induced neural damage.To evaluate the effects of GRE on cognitive impairment and the expression of Nrf2, GPX4, and SLC7A11 in aluminum (Al)-exposed rats. In this study, a total of 60 male Sprague-Dawley (SD) rats were randomly assigned to 6 groups: Control, Al exposure (Al), Clinical Drug, low-dose GRE (Al + L-GRE), medium-dose GRE (Al + M-GRE), and high-dose GRE (Al + H-GRE). All groups, except Control, received 10 mg/ml AlCl₃ in drinking water for three months. Post-exposure treatments included saline for Control and Al groups, 0.5 mg/kg donepezil hydrochloride for the Clinical Drug group, and 100, 200, and 400 mg/kg GRE for the respective GRE groups. Treatments were administered once daily, five days a week, for a duration of one month. Cognitive and spatial abilities were assessed using the Morris water maze and Y-maze tests. Neuronal damage and mitochondrial structure in the hippocampus were evaluated via Nissl staining and transmission electron microscopy. Serum levels of SOD, GSH, MDA, and Fe²⁺ were measured, and Nrf2/GPX4/SLC7A11 mRNA and protein levels in hippocampal tissues were analyzed using real-time PCR and Western blotting. The Al group demonstrated compromised cognitive function, diminished neuronal integrity, disrupted mitochondrial structure, and an imbalance in serum antioxidant levels compared to the Control group.GRE treatment appeared to have a positive effect on cognitive function, potentially contributing to the maintenance of neuronal integrity, possibly aiding in the preservation of mitochondrial structure, and potentially assisting in the regulation of antioxidant levels. Notably, the Al + M-GRE and Al + H-GRE groups demonstrated encouraging enhancements in escape latency, platform crossings, novel arm entries, and time spent in the novel arm. Additionally, these groups showed elevated levels of SOD and GSH, reduced levels of MDA and Fe²⁺, and increased expression of Nrf2, GPX4, and SLC7A11, suggesting a potential beneficial impact of GRE treatment.GRE mitigated cognitive impairment in Al-exposed rats, likely through the Nrf2/GPX4/SLC7A11 signaling pathway, demonstrating its potential neuroprotective effects., Competing Interests: Declarations. Ethical approval: The animal experiments were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. This study was approved by the Experimental Animal Use and Management Committee of the Guangxi Zhuang Autonomous Region Institute for Occupational Disease Prevention and Control, approval number: 2022-07. Consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Due to the complex pathophysiology of AD (Alzheimer's Disease), there are currently no effective clinical treatments available, except for acetylcholinesterase inhibitors. However, CREB (cyclic AMP-responsive element binding protein) has been identified as the critical factor for the transcription in memory formation. Understanding the effect of potential drugs on the CREB pathway could lead to the development of new therapeutic molecules. Rufinamide has shown promise in improving memory in animal models, and these effects may be associated with modulation of the CREB pathway, however, this has not been previously reported. Thus, the present study aimed to determine the involvement of the CREB pathway in the cognitive improvement effects of rufinamide in STZ (streptozotocin) induced mouse model of dementia. Administration of STZ [3 mg/kg, i.c.v. (intracerebroventricular) bilaterally] significantly impaired cognitive performance in step-down passive avoidance and Morris water maze tests in animals, reduced brain endogenous antioxidant levels (GSH, superoxide dismutase, and catalase), and increased marker of brain oxidative stress [TBARS (thiobarbituric acid reactive substances)] and inflammation [IL-1β (Interleukin-1 beta), IL-6 (Interleukin-6), TNF-α (Tumor necrosis factor alpha) and NF-κB (Nuclear factor kappa B)], along with neurodegeneration. These effects were markedly reversed by rufinamide (50 and 100 mg/kg) when administered to STZ animals. However, the pre-treatment with the CREB inhibitor (666-15) in STZ and rufinamide-administered animals neutralized the beneficial influence of rufinamide. Our data suggest that rufinamide, acting via CREB signaling, reduced oxidative stress and inflammatory markers while elevating anti-oxidant levels. Our study has established that rufinamide may act through CREB signaling in an investigational AD model, which could be crucial for developing new treatments beneficial in progressive neurological disorders., Competing Interests: Declarations. Competing interests: The authors have no relevant financial or non-financial interests to disclose. Ethical Approval: The experiments followed the international guidelines for animal care and handling. The study was performed in accordance with the guidelines of the Committee for Control and Supervision of Experimentation on Animals (CCSEA), Government of India on animal experimentation. Consent to Participate: Not applicable. Consent to Publish: Not applicable., (© 2024. The Author(s).)

Introduction: Memory impairment is a critical challenge in neurodegenerative disorders, particularly in Alzheimer's disease, Parkinson's disease, and age-related cognitive decline. This research explores the molecular mechanisms by which curcumin, a polyphenolic compound derived from Curcuma longa, exerts neuroprotective effects that may ameliorate cognitive deficits associated with these conditions., Results and Conclusion: Evidence from both preclinical studies and emerging clinical trials indicates that curcumin enhances neuronal signaling and synaptic plasticity, primarily through the modulation of pathways such as NF-κB and PI3K/Akt. Specifically, curcumin has been shown to reduce neuroinflammation and oxidative stress, thereby promoting synaptic integrity and function. For instance, studies demonstrate that curcumin treatment increases the density of dendritic spines in the hippocampus, which correlates with improved spatial learning and memory performance in animal models. Despite promising findings, significant gaps remain in our understanding of curcumin's efficacy in humans. Most existing research is derived from animal studies, with limited large-scale clinical trials to substantiate its therapeutic potential. Furthermore, challenges such as curcumin's low bioavailability and inconsistencies in dosing complicate its clinical application. This review underscores the need for future research focused on enhancing curcumin's bioavailability, establishing optimal dosages, and conducting comprehensive human trials to validate its effectiveness. By addressing these issues, we aim to clarify curcumin's role as a potential therapeutic agent for memory impairment in neurodegenerative disorders, paving the way for innovative treatment strategies., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: Not applicable (this paper was provided based on researching in global databases)., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The plant Cissus tuberosa Moc is abundant in phenolics, has been documented to have neuroprotective properties. The study seeks to determine the neuroprotective effects of C. tuberosa ethanolic extract (CTE) against Parkinson's disease by evaluating its impact on motor dysfunction, cognitive deficits, neuroinflammation, and neurodegeneration in paraquat-induced Parkinson's disease models. The research hypothesizes that CTE can modulate key biomarkers involved in Parkinson's pathology, including α-synuclein, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), assessed through qRT-PCR, as well as interleukin-6 (IL-6) and TNF-α, evaluated through ELISA. Parkinson disease was induced by using paraquat intraperitoneally. The study was designed by considering various groups with their respective treatments, control group treated normally, disease control receiving paraquat (1 mg/kg, i.p.), standard treated grabbed with (levodopa+carbidopa), and three treatment groups received plant extract (150, 300, 600 mg/kg) respectively for 21 days study period. Both behavioral, and biochemical analysis were performed. HPLC analysis revealed the presence of several phenolic compounds. CTE significantly improved motor function and cognitive performance in rats, showing a dose-dependent reduction in paraquat-induced neurotoxicity (150 < 300 < 600 mg/kg, P<0.001). CTE significantly restored antioxidant enzyme levels (P<0.001), contributing to the alleviation of oxidative stress. Neurotransmitter levels were significantly improved in a dose-dependent manner (P<0.001), while acetylcholinesterase (AChE) levels were significantly reduced (P<0.001). CTE treatment showed significant restoration of brain tissue, reducing neuroinflammation and neurodegeneration, thereby preserving normal brain structure. ELISA testing demonstrated a significant (P<0.001) downregulation of IL-6 and TNF-α levels in CTE-treated groups. qRT-PCR results showed significant downregulation of α-synuclein, IL-1β, and TNF-α mRNA expression in CTE-treated groups compared to the diseased group, suggesting neuroprotective effects. The study concludes that CTE has potential therapeutic effects in alleviating Parkinson's disease symptoms, primarily through its antioxidant, anti-inflammatory, and neuroprotective properties., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Saadullah et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Triolein, a symmetric triglyceride exhibiting anti-inflammatory and antioxidant properties, has demonstrated potential in mitigating cellular damage. However, its therapeutic efficacy in ischemic stroke (IS) and underlying molecular mechanisms remain elusive. Given the critical roles of inflammation and autophagy in IS pathogenesis, this study aimed to elucidate the effects of triolein in IS and investigate its mechanism of action., Methods: We evaluated the impact of triolein using both in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) and in vivo middle cerebral artery occlusion (MCAO/R) models. Neurological function and cerebral infarct volume were assessed 72 h post-reperfusion. Autophagy was quantified through monodansyl cadaverine (MDC) labeling of autophagic vesicles and Western blot analysis of autophagy-related proteins. Microglial activation was visualized via immunofluorescence, while inflammatory cytokine expression was quantified using RT-qPCR. The cytoprotective effect of triolein on OGD/R-induced HT22 cells was evaluated using Cell Counting Kit-8 and lactate dehydrogenase release assays. The involvement of the Protein kinase B/Mechanistic target of rapamycin kinase (AKT/mTOR) pathway was assessed through Western blot analysis., Results: Triolein administration significantly reduced infarct volume, enhanced neurological recovery, and attenuated M1 microglial activation and inflammation in MCAO/R-induced mice. Western blot analysis and MDC labeling revealed that triolein exerted an inhibitory effect on post-IS autophagy. Notably, in the BV2-induced OGD/R model, triolein demonstrated an autophagy-dependent suppression of the inflammatory response. Furthermore, triolein inhibited the activation of the AKT/mTOR signaling pathway, consequently attenuating autophagy and mitigating the post-IS inflammatory response., Conclusions: This study provides novel evidence that triolein exerts neuroprotective effects by inhibiting post-stroke inflammation through an autophagy-dependent mechanism. Moreover, the modulation of the AKT/mTOR signaling pathway appears to be integral to the neuroprotective efficacy of triolein. These findings elucidate potential therapeutic strategies for IS management and warrant further investigation., Competing Interests: Declarations. Ethics approval and consent to participate: The animal study underwent thorough review and received approval from the Ethics Committee of Renmin Hospital of Wuhan University. Consent for publication: All authors have approved the manuscript and consent to publication. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Ketone bodies, or ketones, are an alternative energy source and have several nonmetabolic signaling actions, such as inhibiting inflammation. Because of this, exogenous ketone supplementation has been used to help treat various diseases. β-hydroxybutyrate (βHB) is the major ketone body that has reduced neurological injury and brain edema in animal models of ischemic stroke and traumatic brain injury. However, the therapeutic potential of βHB in intracerebral hemorrhage (ICH) has not yet been determined. Here we investigated the effects of exogenous βHB treatment following ICH on inflammation, edema, injury size, and functional outcomes. To do this, we administered 250 mg/kg of βHB (subcutaneously every 12 hours) starting 2 hours after collagenase-induced ICH in rats over 3 experiments. First, we observed that βHB-treated rats had significant reductions in transcript expression of pro-inflammatory markers Il1b (p = 0.0210), Tnfa (p = 0.0108), and Mcp1 (p = 0.0473) 3 days post-ICH. Second, βHB significantly improved neurological deficits measured by the neurological deficit scale on day 3 (p = 0.0416) in another cohort of rats, despite no treatment effect on edema (p = 0.2110). To test whether the effects of acute βHB treatment (for 7 days post-ICH) were chronically sustained, the third experiment used serial behavioural testing which confirmed that βHB significantly improved neurological deficit scores (p = 0.0459) 3 days post-ICH. These effects were not sustained at 7, 14, and 28 days post-ICH (all p≥0.1546). Similarly, βHB treatment did not yield differences in forelimb use asymmetry (all p>0.45) or brain lesion volume (p = 0.3381), the primary endpoint of this study. Thus, our studies show that an acute βHB treatment post-ICH can provide some early signs of functional benefit without evidence of lasting effects or neuroprotection. However, it remains to be tested whether other βHB dosing regimens may favorably affect these and other neurological, behavioral, and biochemical parameters, particularly given the early signals of reduced striatal inflammation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sander et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Neurotrophic factors are endogenous proteins that promote the survival of various neuronal cells. Increasing evidence has suggested a key role for brain-derived neurotrophic factor (BDNF) in the dopaminergic neurotoxicity associated with Parkinson's Disease (PD). This study explores the therapeutic potential of filbertone, a bioactive compound found in hazelnuts, in neurodegeneration, focusing on its effects on neurotrophic factors and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. In our study, filbertone markedly elevated the expression of neurotrophic factors, including BDNF, Glial cell line-Derived Neurotrophic Factor (GDNF), and Nerve Growth Factor (NGF), in human neuroblastoma SH-SY5Y cells, mouse astrocyte C8-D1A cells, and mouse hypothalamus mHypoE-N1 cells. Moreover, filbertone effectively countered neuroinflammation and reversed the decline in neurotrophic factors and Nrf2 activation induced by a high-fat diet (HFD) in neurodegeneration models. The neuroprotective effects of filbertone were further validated in models of neurotoxicity induced by palmitic acid (PA) and the neurotoxin MPTP/MPP + , where it was observed to counteract PA and MPTP/MPP + -induced decreases in cell viability and neuroinflammation, primarily through the activation of Nrf2 and the subsequent upregulation of BDNF and heme oxygenase-1 expression. Nrf2 deficiency negated the neuroprotective effects of filbertone in MPTP-treated mice. Consequently, our finding suggests that filbertone is a novel therapeutic agent for neurodegenerative diseases, enhancing neuronal resilience through the Nrf2 signaling pathway and upregulation of neurotrophic factors., Competing Interests: Declarations. Ethical Approval: All experimental procedures were approved by the Ethics Committee of the University of Ulsan University (HTC-22-010) in accordance with the National Institutes of Health guidelines. Efforts were made to minimize animal suffering, and all sample sizes for the assessment parameters were calculated to minimize the number of animals used. Consent to Paricipate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Protein aggregation occurs as a consequence of dysfunction in the normal cellular proteostasis, which leads to the accumulation of toxic fibrillar aggregates of certain proteins in the cell. Enhancing the activity of proteolytic pathways may serve as a way of clearing these aggregates in a cell, and consequently, autophagy has surfaced as a promising target for the treatment of neurodegenerative disorders. Several strategies involving small molecule compounds that stimulate autophagic pathway of cell have been discovered. However, despite many compounds having demonstrated favorable outcomes in experimental disease models, the translation of these findings into clinical benefits for patient's remains limited. Consequently, alternative strategies are actively being explored to effectively target neurodegeneration via autophagy modulation. Recently, newer approaches such as modulation of expression of autophagic genes have emerged as novel and interesting areas of research in this field, which hold promising potential in neuroprotection. Similarly, as discussed for the first time in this review, the use of autophagy-inducing nanoparticles by utilizing their physicochemical properties to stimulate the autophagic process, rather than relying on their role as drug carriers, offers a completely fresh avenue for targeting neurodegeneration without the risk of drug-associated adverse effects. This review provides fresh perspectives on developing autophagy-targeted therapies for neurodegenerative disorders. Additionally, it discusses the challenges and impediments of implementing these strategies to alleviate the pathogenesis of neurodegenerative disorders in clinical settings and highlights the prospects and directions of future research in this context., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Inhibition of COX and LOX could contribute to memory formation and prevention of neurodegeneration, by alleviation of neuroinflammation and improvement of mitochondrial homeostasis. We aimed to assess the effect of licofelone, a dual COX and 5-LOX inhibitor on memory formation, neural apoptosis, neural regeneration, and mitophagy in acute and chronic dosages, given that licofelone could regulate nitric oxide levels. Y-maze and Passive Avoidance tests were used to evaluate memory function in NMRI mice using the EthoVision setting, following scopolamine administration (1 mg/kg, i.p.) as an acute amnestic drug. Hippocampi were used to evaluate the levels of apoptosis via TUNEL assay, neural regeneration via immunohistochemistry method detecting doublecortin and nestin, and mitophagy via Western blot of mitophagy proteins Parkin and ATG5. While acute high-dose licofelone (20 mg/kg) could reverse amnestic effects of scopolamine in passive avoidance test (p = 0.0001), Chronic licofelone (10 mg/kg for 10 consecutive days) could improve performance in Y-maze (p = 0.0007). Molecular analysis revealed that the chronic form of the drug could enhance neural regeneration in CA1 and SGZ regions, reset mitophagy levels as much as the healthy state, and reduce apoptosis rate. Licofelone appears to show a desirable anti-amnestic profile in a low dose chronically; it is hence recommended for future clinical studies on the prevention of neuroinflammation and memory deficit., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The increasing attention towards age-related diseases has generated significant interest in the concept of cognitive dysfunction associated with Alzheimer's disease (AD). Certain limitations are associated with the current therapies, and flavonoids have been reported to exhibit multiple biological activities and anti-AD effects in several AD models owing to their antioxidative, anti-inflammatory, and anti-amyloidogenic properties. In this study, we performed an initial in silico predictions of the pharmacokinetic properties of three flavonoids (rhoifolin, baicalein 5,6-dimethyl ether and agathisflavone). Subsequently, we evaluated the antiamnesic and antioxidant potential of flavonoids in concentrations of 1, 3, and 5 μg/L in scopolamine (100 μM)-induced amnesic zebrafish (Danio rerio) model. Zebrafish behavior was analyzed by novel tank diving test (NTT), Y-maze, and novel object recognition test (NOR). Acetylcholinesterase (AChE) activity, brain antioxidant status and the expression of bdnf, npy, egr1, nrf2α, creb1 genes, and CREB-1 protein level was measured to elucidate the underlying mechanism of action. Our flavonoids improved memory and decreased anxiety-like behavior of scopolamine-induced amnesia in zebrafish. Also, the studied flavonoids reduced AChE activity and brain oxidative stress and upregulated the gene expression, collectively contributing to neuroprotective properties. The results of our study add new perspectives on the properties of flavonoids to regulate the evolution of neurodegenerative diseases, especially AD, by modulating the expression of genes involved in the regulation of synaptic plasticity, axonal growth, and guidance, sympathetic and vagal transmission, the antioxidant response and cell proliferation and growth., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ferroptosis, characterized by iron-dependent accumulation of lipid peroxides, plays an important role in spinal cord injury (SCI). Berberine (BBR), as a lipid peroxide scavenger, has been widely used in treating other diseases; however, its role in ferroptosis has not been fully elucidated. Therefore, here, to test our hypothesis that BBR can reduce the severity of SCI and promote motor function recovery by inhibiting neuronal ferroptosis, we evaluated the changes in ferroptosis-related indicators after BBR administration by establishing a cellular ferroptosis model and an SCI contusion model. We found that BBR administration significantly reduces lipid peroxidation damage, maintains normal mitochondrial function, reduces excessive accumulation of iron ions, enhances antioxidant capacity, and activates the ferroptosis defense system in vivo and in vitro. Mechanistically, BBR alleviates neuronal ferroptosis by inducing adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and up-regulating nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1) protein expression to promote glutathione production. BBR administration also significantly improves motor function recovery in SCI rats. Meanwhile, applying the AMPK inhibitor Compound C blocks the neuroprotective and all other effects of BBR. Collectively, our findings demonstrate that BBR can attenuate neuronal ferroptosis after SCI by activating the AMPK-NRF2-HO-1 pathway., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Obstructive sleep apnea (OSA) is a common clinical condition linked to cognitive impairment, mainly characterized by chronic intermittent hypoxia (CIH). GLP-1 receptor agonist, known for promoting insulin secretion and reducing glucose levels, has demonstrated neuroprotective effects in various experimental models such as stroke, Alzheimer's disease, and Parkinson's disease. This study aims to investigate the potential role and mechanisms of the GLP-1 receptor agonist liraglutide in ameliorating OSA-induced cognitive deficits. CIH exposure, a well-established and mature OSA pathological model, was used both in vitro and in vivo. In vitro, CIH significantly activated oxidative stress, inflammation, and apoptosis in SH-SY5Y cells. Liraglutide enhanced the nuclear translocation of Nrf2, activating its downstream pathways, thereby mitigating CIH-induced injury in SH-SY5Y cells. Additionally, liraglutide modulated the MAPK/NF-κB signaling pathway, reducing the expression of inflammatory factors and proteins. In vivo, we subjected mice to an intermittent hypoxia incubator to mimic the pathogenesis of human OSA. The Morris water maze test revealed that CIH exposure substantially impaired spatial memory. Subsequent western blot analyses and histopathological examinations indicated that liraglutide could activate the Nrf2/HO-1 axis and inhibit the MAPK/NF-κB signaling pathway, thereby alleviating OSA-associated cognitive dysfunction in mice. These findings suggest that GLP-1 receptor agonists may offer a promising preventive strategy for OSA-associated cognitive impairment. By refining these findings, we provide new insights into GLP-1's protective mechanisms in combating cognitive deficits associated with CIH, underscoring its potential as a therapeutic agent for conditions linked to OSA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: The novel phthalein component QBT, extracted from Ligusticum chuanxiong, shows promising biological activity against cerebrovascular diseases. This study focused on ferroptosis and pyroptosis to explore the effects of QBT on nerve injury, cognitive dysfunction, and related mechanisms in a rat model of vascular dementia (VaD)., Methods: We established a rat model of VaD and administered QBT as a treatment. Cognitive dysfunction in VaD rats was evaluated using novel object recognition and Morris water maze tests. Neuronal damage and loss in the brain tissues of VaD rats were assessed with Nissl staining and immunofluorescence. Furthermore, we investigated the neuroprotective mechanisms of QBT by modulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/cystine-glutamate antiporter (xCT)/glutathione peroxidase 4 (GPX4) and Nod-like receptor family pyrin domain-containing 3 (NLRP3)/cysteine-requiring aspartate protease-1 (Caspase-1)/Gasdermin D (GSDMD) pathways to inhibit ferroptosis and pyroptosis both in vivo and in vitro., Results: Our findings indicated that QBT significantly ameliorated neuronal damage and cognitive dysfunction in VaD rats. Additionally, QBT reversed abnormal changes associated with ferroptosis and pyroptosis in the brains of VaD rats, concurrently up-regulating the Nrf2/xCT/GPX4 pathway and down-regulating the NLRP3/Caspase-1/GSDMD pathway to inhibit ferroptosis and pyroptosis in neuronal cells, thereby exerting a neuroprotective role., Conclusion: In summary, QBT effectively mitigated neuronal damage and cognitive dysfunction in VaD rats, demonstrating a neuroprotective effect by inhibiting ferroptosis and pyroptosis in neuronal cells. This study offers a novel perspective and theoretical foundation for the future development of drugs targeting VaD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Parkinson's Disease (PD) is a degenerative disease driven by neuroinflammation. Nuclear receptor subfamily 1 group H member 4 (NR1H4), a nuclear receptor involved in metabolic and inflammatory regulation, is found to be widely expressed in central nervous system. Previous studies suggested the protective role of NR1H4 in various diseases related to inflammation, whether NR1H4 participates in PD progression remains unknown. To investigate the role of NR1H4 in neuroinflammation regulation, especially astrocyte activation during PD, siRNA and adenovirus were used to manipulate Nr1h4 expression. RNA-sequencing (RNA-seq), quantitative real-time PCR, enzyme-linked immunosorbent assay, Chromatin immunoprecipitation and western blotting were performed to further study the underlying mechanisms. We identified that NR1H4 was down-regulated during PD progression. In vitro experiments suggested that Nr1h4 knockdown led to inflammatory response, reactive oxygen species generation and astrocytes activation whereasNr1h4 overexpressionhad the opposite effects. The results of RNA-seq on astrocytes revealed that NR1H4 manipulated neuroinflammation in a CEBPβ/NF-κB dependent manner. Additionally, pharmacological activation of NR1H4 via Obeticholic acid ameliorated neuroinflammation and promoted neuronal survival. Our study first proved the neuroprotective effects of NR1H4against PD via inhibiting astrocyte activation and neuroinflammation in a CEBPβ/NF-κB dependent manner., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Sophora flavescens , the source of oxymatrine, is gaining popularity due to its potential in neuroprotection and treatment of various neurological conditions like epilepsy, depression, Parkinson's, Alzheimer's and multiple sclerosis. Its natural occurrence and promising preliminary research highlight its ability to reduce nerve cell damage and inflammation, attributed to its antiapoptotic, antioxidant and anti-inflammatory properties. However, challenges like solubility, potential adverse effects and limited bioavailability hinder its full therapeutic utilization. Current strategies, including formulation optimization and innovative drug delivery systems, aim to enhance its efficacy and safety. Despite its potential, further research is necessary to overcome these obstacles and maximize its clinical effectiveness. Conclusively, oxymatrine demonstrates distinct neuroprotective properties, offering unique advantages over other agents currently being studied or used in clinical practice for neurological disorders. nevertheless, additional study is necessary to surmount current obstacles and maximize its effectiveness for clinical settings. This study provides a comprehensive overview of oxymatrine's neuroprotective mechanisms and therapeutic potential while emphasizing the need for continued investigation and development for practical clinical application.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. When the CAG repeat exceeds 36, it results in the accumulation of the mutant HTT (mHTT) protein in neurons and glial cells. Key pathological mechanisms in HD include excitotoxicity, energy dysfunction, impaired mitochondrial function, increased oxidative stress, and neuroinflammation. The NLRP3 inflammasome is a multimeric protein complex element of NLRP3, ASC, and caspase-1, which regulates interleukin (IL)-1β and IL-18 secretion. The NLRP3 inflammasome plays an important role in inflammatory reactions and is involved in the pathogenesis of several neurodegenerative diseases. We have previously demonstrated high NLRP3 inflammasome expression levels in the striatum of R6/2 mice (a transgenic HD mouse model). Systematic administration of an NLRP3 inhibitor (MCC950) to R6/2 mice suppressed the NLRP3 inflammasome, decreased IL-1β and reactive oxygen species production, and reduced neuronal toxicity, suggesting protective effects against HD. Antrodia cinnamomea is an indigenous medicinal fungus in Taiwan, which shows diverse medicinal and pharmacological activities, but its effects in HD are not well understood. Herein, we report that systematic administration of Antcin-H isolated from A. cinnamomea to R6/2 mice suppressed the NLRP3 inflammasome, IL-1β production, and reduced neuronal toxicity. Most importantly, oral administration of Antcin-H reduced disease progression by increasing neuronal survival, reducing neuroinflammation during an extended lifespan, and improving motor dysfunction in R6/2 mice. Taken together, our data suggest that Antcin-H has therapeutic potential for treating HD., Competing Interests: Declarations. Ethics Approval and Consent to Participate: Not applicable. Consent for Publication: All the authors mentioned agreed to the publication of the manuscript. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuroprotective drugs as adjunctive therapy for adults with acute ischemic stroke (AIS) remains contentious. This study summarizes the latest evidence regarding the benefits of neuroprotective agents combined with intravenous recombinant tissue plasminogen activator (rt-PA) intravenous thrombolysis. This study conducted a structured search of PubMed, the Cochrane Library, EMBASE, Wanfang Data, and CNKI databases from their inception to March 2024. Grey literature was also searched. The outcomes included efficacy (National Institutes of Health Stroke Scale (NIHSS) score and Barthel Index (BI) score) and safety (rate of adverse reactions). A total of 70 randomized controlled trials were selected for this network meta-analysis (NMA), encompassing 4,140 patients with AIS treated using different neuroprotective agents plus RT-PA, while 4,012 patients with AIS were in control groups. The top three treatments for NIHSS scores at the 2-week follow-up were Edaravone Dexborneo with 0.9 mg/kg rt-PA, Edaravone with 0.9 mg/kg rt-PA, and HUK with 0.9 mg/kg rt-PA. HUK with 0.9 mg/kg rt-PA, Dl-3n-butylphthalide with 0.9 mg/kg rt-PA, and Edaravone Dexborneo with 0.9 mg/kg rt-PA were ranked the top three for BI scores at the 2-week follow-up. The top three treatments with the lowest adverse effect rates were 0.6 mg/kg rt-PA, HUK with 0.9 mg/kg rt-PA, and Edaravone Dexborneo with 0.9 mg/kg rt-PA due to their excellent safety profiles. Compared to rt-PA alone, the combination treatments of Edaravone+rt-PA, Edaravone Dexborneol+rt-PA, HUK+rt-PA, Dl-3n-butylphthalide+rt-PA, and Ganglioside GM1+rt-PA have shown superior efficacy. This NMA suggest that combination therapies of neuroprotective agents and rt-PA can offer better outcomes for patients with AIS. The results support the potential integration of these combination therapies into standard AIS treatment, aiming for improved patient outcomes and personalized therapeutic approaches., Competing Interests: The authors have declared that no competing interests exist, (Copyright: © 2024 Dang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Ischemic stroke is a devastating disease that causes neuronal death, neuroinflammation, and other cerebral damage. However, effective therapeutic strategies for ischemic stroke are still lacking. Histone deacetylase 6 (HDAC6) has been implicated in the pathogenesis of ischemic stroke, and the pharmacological inhibition of HDAC6 has shown promising neuroprotective effects. In this study, we utilized positron emission tomography (PET) imaging with the HDAC6-specific radioligand [ 18 F]PB118 to investigate the dynamic changes of HDAC6 expression in the brain after ischemic injury. The results revealed a significant decline in [ 18 F]PB118 uptake in the ipsilateral hemisphere on the first day after ischemia, followed by a gradual increase on days 4 and 7. To evaluate the therapeutic potential of HDAC6 inhibitors, we developed a novel brain-permeable and potent HDAC6 inhibitor, PB131, and assessed its neuroprotective effects in an ischemic stroke mouse model. PET imaging studies demonstrated that PB131 treatment alleviated the decline in [ 18 F]PB118 uptake and reduced the infarct size in middle cerebral artery occlusion mice. Furthermore, PET imaging with the TSPO-specific radioligand [ 18 F]FEPPA revealed that PB131 significantly suppressed neuroinflammation in the ischemic brain. These findings provide insights into the dynamic changes of HDAC6 in ischemic stroke and the potential of HDAC6 inhibitors as novel therapeutic agents for this condition.

Background: Alzheimer's disease (AD) as a neurodegenerative disease can cause behavioral impairments due to oxidative stress. Aging and oxidative conditions are some AD risk factors., Objective: We assessed the influence of geraniol (GR), an acyclic monoterpene alcohol, on behavioral functions, hippocampal oxidative status, and histological alterations in AD rats induced by amyloid-β (Aβ)., Methods: Male Wistar rats (n = 70) were randomly allocated to the control, sham, AD, control-GR (100 mg/kg; per oral: P.O.), AD-GR (100 mg/kg; P.O.; treatment), GR-AD (100 mg/kg; P.O.; pretreatment), and GR-AD-GR (100 mg/kg; P.O.; pretreatment + treatment) groups. GR administration was done for four continuous weeks. After treatments, novel object recognition (NOR) and Morris water maze (MWM) tests assessed the animals' behavior. Then, hippocampal specimens were collected for biochemical assessment. Finally, the number of intact neurons was identified in the hippocampus using hematoxylin and eosin staining., Results: Aβ microinjection increased learning and memory deficits in both NOR and MWM tests, oxidative stress status, and neuronal loss. Oral GR administration improved behavioral deficits and reduced oxidative stress status and neuronal loss in the Aβ-infused animals., Conclusions: GR ameliorates behavioral impairments through a decrease in neuronal degeneration and oxidative stress., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.Alireza Komaki is an Editorial Board Member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review.

Background: This study aimed to investigate whether exposure to Sunset Yellow FCF (SY) since post-weaning can lead to hippocampal structural changes and memory impairment in adult rat and whether the Coenzyme Q10 (CoQ10) can protect against these adverse effects., Methods: The weanling rats were randomly divided into six groups and were treated daily by oral gavage for 6 weeks, as follows: (I) control group, administered distilled water (0.3 mL/100 g/day); (II) CoQ10 group, received 10 mg/kg/day CoQ10; (III) low SY group, received 2.5 mg/kg/day SY; (IV) high SY group, received 70 mg/kg/day SY; (V) low SY + CoQ10 group; and (VI) high SY + CoQ10 group. At the end of the sixth week, the novel object recognition (NOR) test was conducted to evaluate memory. Then, after sacrificing animals, the cerebral hemispheres were removed for stereological study and evaluation of MDA levels., Results: The low and high doses of SY led to significant neuronal loss and a decrease in the volume of the hippocampus (CA1 and DG subregions), as well as increased the MDA level, which was associated with short- and long-term memory impairment. Although, administration of CoQ10 prevented the hippocampal neural loss and volume, and caused a reduction in MDA and improved memory in the low and high SY groups., Conclusion: It seems that CoQ10 could prevent the neuronal loss and hippocampal atrophy caused by post-weaning exposure to SY through preventing oxidative stress, ultimately improving memory impairment in rats., (© 2024 International Society for Developmental Neuroscience.)

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and Multiple sclerosis (MS), pose a significant global health challenge due to their intricate pathology and limited therapeutic interventions. Natural products represent invaluable reservoirs for combating these neurodegenerative diseases by targeting key pathological hallmarks such as protein aggregation, synaptic dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, inflammation, and neuronal cell death. This review provides an in-depth analysis of the mechanisms and therapeutic targets of natural products for their neuroprotective effects. Furthermore, it elucidates the current progress of clinical trials investigating the potential of natural products in delaying neurodegeneration. The objective of this review is to enhance the comprehension of natural products in the prevention and treatment of neurodegenerative diseases, offering new insights and potential avenues for future pharmaceutical research., Competing Interests: Declaration of competing interest All of the authors declared there are no conflicts of interest for this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neurodegenerative diseases (NDDs), as a neurological disorder characterised by neuronal degeneration and death, are a serious threat to human health and have long attracted attention due to their complex pathogenesis and the ineffectiveness of therapeutic drugs. Existing studies have shown that Polygonatum Sibiricum polysaccharides (PSP) have immunoregulatory, antioxidant, anti-inflammatory and other pharmacological effects, and their neuroprotective effects have been demonstrated in several scientific studies. This paper reviews the main pharmacological effects and mechanisms of PSP in the protection and treatment of NDDs, to provide a reference for the clinical application and basic research of PSP in NDDs., Competing Interests: Declaration of competing interest Since 2016, Polygonatum sibiricum polysaccharides (PSP) as one of the most important active compounds in PS have gradually become a hot research topic of the moment, which has a sweet taste, low toxicity, rich bioactivity, is more suitable for long-term administration and is widely used in cardiovascular and diabetic treatments. Recent studies have demonstrated the great potential of PSP in neuroprotective effects and its obvious role in improving behavioral deficits caused by cerebral nerve damage, but the current state of knowledge in sorting out the progress and mechanisms of its intervention in Neurodegenerative Disease (NDDs) still lacks adequate theoretical support. This study reviews the pathogenesis of NDDs, the composition, safety and bioactivity of PSP, and the interventional effects and mechanisms of PSP on NDDs to provide a research basis for the discovery and development of potential neuroprotective agents and the clinical prevention and treatment of NDDs., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is a neurodegenerative disorder that is the fifth most common cause of mortality worldwide and the second most common cause of death in developed countries. The etiology of AD remains poorly understood; however, it is correlated with the accumulation of proteins in the brain, ultimately leading to cellular damage. Multiple factors, including genetic and environmental factors such as chemicals or food, have been linked to protein aggregation and cell death in AD. Boron is a vital micronutrient that is necessary for plant growth and is abundantly present in various fruits and nuts. Prior research has emphasized the importance of boron as a neuroprotective agent and necessary component for the preservation of brain health and function. However, the precise function of boron in the brain remains poorly understood. This review elucidates the molecular role of boron in the brain by examining existing information about its impact on neurodegenerative diseases and may provide a deeper understanding of the etiology of AD and, ultimately, lead to the development of novel approaches for its treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for [Journal name] and was not involved in the editorial review or the decision to publish this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Adherence is critical in patients with Alzheimer's disease (AD) in order to achieve optimal benefit from therapy. However, patient compliance with the treatment remains a challenge., Objective: To evaluate, in a real-world clinical setting, caregiver preference and treatment compliance with twice-weekly versus daily transdermal rivastigmine patch in mild-to-moderate AD., Methods: 92 patients who had been treated with daily rivastigmine patch for at least six months prior to switching to twice-weekly patch were evaluated. The change in therapeutic regimen was decided by the treating physician in accordance with standard practice. Caregivers' satisfaction with daily rivastigmine patch was assessed at study entry. Caregiver's preference and satisfaction with twice-weekly patch as well as patient compliance were evaluated at weeks 12 and 24 using the Alzheimer's Disease Caregiver Preference Questionnaire., Results: A significantly higher proportion of caregivers expressed a preference for the twice-weekly patch over the daily patch ( p  < 0.001), and this preference was found to be associated with ease of use ( p  < 0.001), ease of following the schedule ( p  < 0.001), and ease of compliance ( p  < 0.001). Furthermore, caregivers were more satisfied with the twice-weekly patch ( p  < 0.0001). At 24 weeks, patient compliance was significantly better with the twice-weekly patch than with the daily patch ( p  = 0.002). Caregiver burden significantly improved at the end of the treatment ( p  = 0.003). No serious adverse events were reported., Conclusions: The twice-weekly rivastigmine patch offers a convenient and straightforward dosing regimen for caregivers, with potential to enhance adherence with treatment in AD patients without causing serious adverse events., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Parkinson's disease (PD) is a neurodegenerative disorder triggered by the loss of dopaminergic neurons in the substantia nigra (SN). Recent studies have demonstrated that necroptosis is involved in dopaminergic neuronal cell death and the resulting neuroinflammation. During the process of necroptosis, a necrosome complex is formed consisting of the proteins receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL). Although the neuroprotective effects of the RIPK1-specific inhibitor necrostatin-1, as well as RIPK3 and MLKL knockout in mice, have been described, the effects of RIPK3 pharmacological inhibitors have not yet been reported in animal models of PD. In the present study, we investigated the neuroprotective effects of GSK872, a specific RIPK3 inhibitor, in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. GSK872 rescued MPTP-induced motor impairment and inhibited tyrosine hydroxylase-positive dopaminergic cell death in the SN and striatum. Additionally, GSK872 inhibited the MPTP-induced increase in the expression of p-RIPK3 and p-MLKL in both the dopaminergic neurons and microglia, as assessed by biochemical and histological analyses. GSK872 further inhibited microglial activation and the expression of inflammatory mediators including NLRP3, interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha, and inducible nitric oxide synthase in the SN region of MPTP mice. Using in vitro experiments, we validated the effects of GSK872 on necroptosis in SH-SY5Y neuronal and BV2 microglial cells. Overall, our results suggest that GSK872 exerts neuroprotective and anti-inflammatory effects, and may thus have therapeutic potential for PD., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ocular neurodegenerative diseases, particularly glaucoma, represent a significant global cause of blindness, with current therapies inadequately addressing the degeneration of the retina and optic nerve. Recent research has identified the sigma-2 receptors as a potential druggable target to offer neuroprotection in managing ocular neurodegenerative disorders. This study investigates the neuroprotective potential of CT2074, a sigma-2 receptor modulator, in a mouse model of primary open-angle glaucoma. Male mice were subjected to unilateral magnetic bead-induced elevation of intraocular pressure (IOP) and received daily oral administration of CT2074, commencing three days prior to ocular hypertension (OHT) induction, and continuing for three weeks. Mice received bilateral intraocular injections of cholera toxin B-488 (CTB) to assess retinal ganglion cell (RGC) anterograde transport. Retina, optic nerve, and brain tissues were collected three weeks post OHT induction for quantification of RGC and axon number, with contralateral retinas and cerebelli preserved for assessment of drug exposure. CT2074 was observed in the retina at levels exceeding the 95% receptor occupancy concentration. RGC quantification showed a significant reduction in the Vehicle group compared to Naïve and CT2074 groups. Notably, the CT2074 treatment group exhibited significantly higher RGC density than the Vehicle (p < 0.0001) and was no different than Naïve. Analysis of RGC axons in optic nerve cross-sections revealed significant axonal loss in both the Vehicle and CT2074 groups compared to Naïve, though the CT2074-treated group had significantly higher axon number compared to the Vehicle. Anterograde transport in the Vehicle and CT2074 groups did not differ. This study underscores the potential of CT2074 administered orally to protect RGCs exposed to elevated IOP, as evidenced by substantial preservation of RGCs and their axons compared to Vehicle-treated mice. These findings signify a promising avenue for the development of sigma-2 receptor-targeted therapeutics in glaucoma and related neurodegenerative diseases, addressing a critical unmet need in the field of ocular neuroprotection., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Metabotropic glutamate receptor 7 (mGluR7) belongs to the family of type III mGluR receptor, playing an important part in the central nervous system (CNS) through response to neurotransmitter regulation, reduction of excitatory toxicity, and early neuronal development. Drugs targeting mGluR7 (mGluR7 agonists, antagonists, and allosteric modulators) may be among the most promising agents for the treatment of CNS disorders, such as psychiatric disorders, neurodegenerative diseases, and neurodevelopmental impairments, though these potential therapies are at early stages and the data are still limited. In this review, we summarized the structure and function of mGluR7 and discussed recent progress on mGluR7 agonists and antagonists. A deeper understanding of mGluR7 will contribute to uncovering the molecular mechanisms of neuroprotection and providing a theoretical basis for the formulation of therapeutic strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Stroke is one of the most common causes of death and disability. In addition, most neuroprotective agents fail to rescue neurons from cerebral ischemic insults due to their poor ability to penetrate the blood-brain barrier (BBB). Here, the tailored engineered nanoenzyme has been successfully synthesized by coordination-driven co-assembly of dopamine (DA) and iron ion (Fe 3+ ), which is subsequently camouflaged by neuron-specific rabies viral glycoprotein (RVG) peptide to scavenge reactive oxygen species (ROS) and inhibit inflammatory response in damaged neuron for the efficient therapy of ischemic stroke. The resulting nanoenzyme with good biocompatibility, core-shell structure, and suitable diameter can nondestructively cross the BBB and then internalize into the damaged neuron through the camouflaging and homologous targeted strategy of neuron-specific RVG peptide. After intravenous injection into transient middle cerebral artery occlusion (tMCAO) mouse models, nanoenzyme exerted a significant neuroprotective effect, resulting in a 50 % reduction in neurological scores and an approximate 33 % decrease in cerebral infarction volume. Interestingly, such nanoenzyme can eliminate free radicals, reduce neuroinflammation, enhance BBB integrity, improve mitochondrial function, and inhibit neuronal ferroptosis. Taken together, this well-designed nanoenzyme with its excellent biocompatibility and well-understood mechanisms holds promise a robust therapy for ischemic stroke., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Objectives: Loss of supraspinal cardiovascular control and secondary damage following spinal cord injury (SCI) lead to cardiovascular dysfunction, where autonomic dysreflexia (AD), triggered by stimuli below the injury, can cause uncontrolled blood pressure (BP) surges, posing severe health risks such as stroke and seizures. While anti-inflammatory neuroprotective agents have been studied for motor recovery, their impact on cardiovascular function remains under investigated. The objective was to assess the efficacy of four clinically approved neuroprotective agents in promoting cardiovascular recovery following SCI., Methods: Male Wistar rats received contusion at the third thoracic spinal segment (T3). Fluoxetine, Glyburide, Valproic acid, and Indomethacin were first administered at 1 h or 6 h post-SCI, and every 12 h for two weeks thereafter. Four weeks following SCI, hemodynamics were measured at rest and during colorectal distension. Locomotor function was assessed prior to SCI and weekly for four weeks after SCI, using the Basso-Beattie-Bresnahan (BBB) locomotor scale. Quantitative comparisons of lesion area were performed., Results: Contrary to the published literature, Indomethacin and Valproic acid resulted in high morbidity and mortality rates 60 % and 40 % respectively) within 2-3 days of administration. Fluoxetine, and Glyburide were well-tolerated. There were no differences in change in systolic BP with colorectal distension compared to control i.e., all experimental groups experienced severe episodes of AD [F(6, 67) = 0.94, p = 0.47]. There was no significant difference in BBB scores in any experimental group compared to control [F(18, 252) = 0.3, p = 0.99]. No between-group differences were observed in tissue sparing at the lesion epicentre [F(6, 422) = 6.98, p = 0.29]., Discussion: Despite promising beneficial effect reported in previous studies, none of the drugs demonstrated improvement in cardiovascular or motor function. Indomethacin and Valproic acid exhibited unexpected high mortality at doses deemed safe in the literature. This emphasizes the necessity for reproducibility studies in pre-clinical research and underscores the importance of publishing null findings to guide future investigations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)