Neuroprotective Effects Research Articles

Evaluating the nutrient composition and antioxidant properties of orange (Citrus sinensis) peels through Penicillium camemberti-based solid-substrate fermentation

Citrus by-products, especially orange peels, are a significant global waste issue, driving research into management solutions. Solid-substrate fermentation is a promising method to convert this waste into valuable resources, enhancing its medicinal and nutritional potential while addressing environmental and economic concerns in food waste management. Therefore, this study was carried out to evaluate the impact of solid-substrate fermentation (SSF) with Penicillium camemberti on the nutrient profile, antioxidative properties, and potential neuroprotective effects of orange peels in AlCl3 (Al)-induced neurotoxicity in fruit fly (Drosophila melanogaster) model. Orange peels were collected, air-dried to a constant weight, and subjected to a 10-day SSF process with Penicillium camemberti. Post-fermentation, in vitro nutritional profiling, and antioxidant assays were conducted, alongside in vivo assessments of the neuroprotective effects on survival rate, memory index, monoamine oxidase (MAO) activity, and endogenous antioxidant markers on Al-induced fruit flies were determined. The results showed that fermentation with Penicillium camemberti significantly enhanced the nutritional composition of the orange peels compared to their unfermented counterparts. The antioxidant properties of fermented orange peels were significantly (p < 0.05) increased, as evidenced by increased DPPH scavenging activity (81.68 ± 0.18) and ferric reducing antioxidant power (10.77 ± 0.27). Additionally, biochemical assays in vivo revealed a significant improvement in survival rates and memory indices in Al-induced flies. Also, monoamine oxidase (MAO) levels were significantly reduced, while glutathione S-transferase (GST) levels were significantly (p < 0.05) elevated in the induced flies fed with the fermented samples. Conclusively, this study highlights the capability of Penicillium camemberti fermentation in converting waste into valuable resources, enhancing the nutrient profile of citrus peels for applications in livestock feed and potential therapeutic interventions for degenerative disorders.

Polyphenols and Diets as Current and Potential Nutrition Senotherapeutics in Alzheimer's Disease: Findings from Clinical Trials.

Cellular senescence, a hallmark of aging, plays an important role in age-related conditions among older adults. Targeting senescent cells and its phenotype may provide a promising strategy to delay the onset or progression of Alzheimer's disease (AD). In this review article, we investigated efficacy and safety of nutrition senotherapy in AD, with a focus on the role of polyphenols as current and potential nutrition senotherapeutic agents, as well as relevant dietary patterns. Promising results with neuroprotective effects of senotherapeutic agents such as quercetin, resveratrol, Epigallocatechin-gallate, curcumin and fisetin were reported from preclinical studies. However, in-human trials remain limited, and findings were inconclusive. In future, nutrition senotherapeutic agents should be studied both individually and within dietary patterns, through the perspective of cellular senescence and AD. Further studies are warranted to investigate bioavailability, dosing regimen, long term effects of nutrition senotherapy and provide better understanding of the underlying mechanisms. Collaboration between researchers needs to be established, and methodological limitations of current studies should be addressed.

A Randomized-Controlled Trial Targeting Cognition in Early Alzheimer's Disease by Improving Sleep with Trazodone (REST).

Alzheimer's disease (AD) is a leading cause of mortality and morbidity among aging populations worldwide. Despite arduous research efforts, treatment options for this devastating neurodegenerative disease are limited. Sleep disturbances, through their link to changes in neural excitability and impaired clearance of interstitial abnormal protein aggregates, are a key risk factor for the development of AD. Research also suggests that the neuroprotective effects of sleep are particularly active during slow wave sleep. Given the strong link between sleep disturbance and AD, targeting sleep in the prodromal stages of AD, such as in mild cognitive impairment (MCI), represents a promising avenue for slowing the onset of AD-related cognitive decline. In efforts to improve sleep in older individuals, several pharmacologic approaches have been employed, but many pose safety risks, concern for worsening cognitive function, and fail to effectively target slow wave sleep. Trazodone, a safe and widely used drug in the older adult population, has shown promise in inducing slow wave sleep in older adults, but requires more rigorous research to understand its effects on sleep and cognition in the prodromal stages of AD. In this review, we present the rationale and study design for our randomized, double-bind, placebo-controlled, crossover trial (NCT05282550) investigating the effects of trazodone on sleep and cognition in 100 older adults with amnestic MCI and sleep complaints.

Neuroprotective Effect of Artemisinin in an Animal Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease in older people, characterized by the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of aggregated of hyperphosphorylated tau protein, which normally helps stabilize microtubules in neurons. Nowadays, artemisinin (ART) as well as its semisynthetic derivatives (ARTs) are seen as potential neuroprotectors. The goal of the present study is the assessment of neuroprotective, antibacterial activity of ART, as well as in silico studies of ART affinity to Aβ-peptides and the search of potential targets for ART. The study is referring to explores the impact of ART on an animal model of AD that is induced by the aggregated amyloidogenic peptide Aβ1-42 by electrophysiology and morphology analysis. Specifically, the focus is on the activation of the entorhinal cortex (ENT) as synaptic potentiation. Electrophysiological and histochemical have demonstrated that therapeutic injection of ART or its derivatives acts as a neuroprotective This treatment appears to prevent or slow down damage to brain tissue, and it promotes the restoration of neurons and their surrounding environment. The protective effects of ART may involve various mechanisms, including antioxidant activity, anti-inflammatory effects, and the inhibition of apoptosis. in silico studies revealed a direct, strong interaction of ART with the amyloidogenic peptides 5Aβ17-42, 12Aβ9-40, and 18Aβ9-40. in silico screening revealed several protein targets for ART, including cytochrome P-450 2B6 (CYP2B6). The highest binding affinity was found on the active site of CYP2B6. ART has great potential for discovering new drugs using combined therapies.

Enantiomerically Pure Indazole Bioisosteres of Ifenprodil and Ro 25-6981 as Negative Allosteric Modulators of NMDA Receptors with the GluN2B Subunit.

Administration of negative allosteric modulators of GluN2B subunit-containing NMDA receptors such as Ro 25-6981 (1) and ifenprodil (2) results in neuroprotective effects. In this study, the phenol of 1 and 2 was replaced bioisosterically by an indazole to inhibit glucuronidation. The γ- and β-aminoalcohols 10 and 11 were prepared without installing a protective group at the indazole ring using the ketone 6 as a common intermediate. All four stereoisomeric γ- and β-aminoalcohols 10 and 11 were obtained by diastereoselective reduction of ketones 7 and 9 followed by separation of enantiomers. The analogously structured γ-aminoalcohol (1S,2S)-10c (Ro 25-6981 bioisostere) and β-aminoalcohol (1R,2R)-11c (ifenprodil bioisostere) exhibited high GluN2B affinity (Ki = 50 and 66 nM, respectively) and high to moderate inhibitory activity in two-electrode voltage clamp experiments. The indazole bioisosteres 10 and 11 showed higher metabolic stability than 1. In the presence of uridinyldiphosphate activated glucuronic acid, glucuronidation of 10 and 11 was not observed.

Scoliidines: Neuroprotective Peptides in Solitary Scoliid Wasp Venoms.

A comprehensive LC-MS study examined the venom components of the solitary scoliid wasp Scolia oculata. Online mass fingerprinting showed that crude venom contains 25 small molecules (amino acids, biogenic amines, and nucleosides/nucleotides) and 45 peptides with MW 400-2700. The small molecules were identified by elemental composition analysis, and peptide sequences were determined by ESI-MS/MS and MALDI-TOF/TOF MS analyses. As major peptide components, a known peptide, β-scoliidine (DYVTVKGFSPLRKA), and three new peptides, γ-scoliidine (YVTVKGFSPLR), δ-scoliidine (YVTVKGFSPLREP) and ε-scoliidine (DYVTVKGFSPLREP) were identified, all of which are closely homologous to each other. Once the neuroprotective effects of β-scoliidine have already been described, the other three new scoliidine peptides were analyzed against oxidative stress-induced toxicity in PC12 neuronal cells by mitochondrial metabolism assay, and the structure-activity relationship was evaluated. Interestingly, pre-treatment with ε-scoliidine increased the mitochondrial metabolism of PC12 cells (106 ± 3.6%; p = 0.007) exposed to H2O2-induced oxidative stress in contrast to γ- and δ-scoliidines (77.6 ± 4.8 and 68.5 ± 4.1%, respectively) in compared to cells treated only H2O2 (75.8 ± 2.4%). These new peptides were also analyzed for enzyme inhibitor/substrate assays with angiotensin-converting enzyme (ACE), neprilysin (NEP), and acetylcholinesterase (AChE). In these assays, only δ- and ε-scoliidines increased the AChE activity (128.7 ± 3.8%; p = 0.01; and 116.8 ± 3.8% p = 0.03; respectively) in relation to basal activity (100.1 ± 1.6%). In addition, the four peptides were analyzed through in silico analysis, and none of them demonstrated possible hemolytic and toxic activities. In our study, the comprehensive LC-MS and MS/MS analyses of Scolia oculate venom identified four major peptide components of the venom β-, γ-, δ- and ε-scoliidines, and small differences in their primary structures are important to their neuroprotective properties.

Angiotensin-(1-7) relieves behavioral defects and α-synuclein expression through NEAT1/miR-153-3p axis in Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, whose characteristic pathology involves progressive deficiency of dopaminergic neurons and generation of Lewy bodies (LBs). Aggregated and misfolded α-synuclein (α-syn) is the major constituent of LBs. As the newly discovered pathway of renin-angiotensin system (RAS), Angiotensin-(1-7) (Ang-(1-7)) and receptor Mas have attracted increasing attentions for their correlation with PD, but underlying mechanisms remain not fully clear. Based on above, this study established PD models of mice and primary dopaminergic neurons with AAV-hα-syn(A53T), then discussed the effects of Ang-(1-7)/Mas on α-syn level and neuronal apoptosis for these models combined with downstream long non-coding RNA (lncRNA) and microRNA (miRNA). Results showed that Ang-(1-7) alleviated behavioral impairments, rescued dopaminergic neurons loss and lowered α-syn expression in substantia nigra of hα-syn(A53T) overexpressed PD mice. We also discovered that Ang-(1-7) decreased level of α-syn and apoptosis in the hα-syn(A53T) overexpressed dopaminergic neurons through lncRNA NEAT1/miR-153-3p axis. Moreover, miR-153-3p level in peripheral blood is found negatively correlated with that of α-syn. In conclusion, our work not only showed neuroprotective effect and underlying mechanisms for Ang-(1-7) on α-syn in vivo and vitro, but also brought new hope on miR-153-3p and NEAT1 for diagnosis and treatment in PD.

Anti-cholinesterase profile of Murraya koenigii (L.) Spreng essential oil and its chemical constituents

Traditionally, Murraya koenigii (L.) Spreng has been used as an ingredient in medicinal formulations. Several studies have reported on the potential of M. koenigii leaves to enhance learning and memory functions in animal models. This study aimed to identify the chemical constituents and evaluate the anti-cholinesterase activity of the essential oil extracted from M. koenigii leaves. The essential oil extracted via hydrodistillation was analyzed using gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). A total of 41 constituents were identified, with β-phellandrene (35.42%), β-caryophyllene (16.79%) and α-pinene (17.75%) predominating in the essential oil. Using Ellman’s colorimetric method, the M. koenigii essential oil demonstrated potent inhibitory activity against acetylcholinesterase (AChE), with an IC50 value of 36.89 μg/mL. Interestingly, a mixture of the three major constituents (β-phellandrene, β-caryophyllene, and α-pinene) was more effective than the individual constituents (β-caryophyllene and α-pinene). In conclusion, the study on the neuroprotective effects of M. koenigii essential oil has yielded promising results.

Empagliflozin modulates seizure activity and oxidative stress in rats with epilepsy

Drug-resistant epilepsy, a commonly devastating condition, affects more than 50 million people globally. Type 2 diabetes mellitus (T2DM) is associated with an increased risk of neurological disorders, and a potential association between epilepsy and subsequent T2DM has emerged. Inhibiting sodium-glucose linked transporters (SGLTs), which are differentially expressed in the brain, has been shown to reduce epileptic episode activity. This study aimed to evaluate the anticonvulsive effect of empagliflozin in rats with seizures induced by maximal electric shock (MES) and pentylenetetrazol (PTZ). Generalized tonic‒clonic seizures were induced in the rats using an electroconvulsive meter, and pentylenetetrazol was injected to induce absence seizures. The duration of all the stages of seizure and Racine stage scoring (RSS) were performed. Malondialdehyde (MDA), nitric oxide (NO) and reduced glutathione (GSH) levels in the brain tissues were determined. Histopathological analysis of the brain tissues was carried out. A significant (p &amp;lt;0.01) decrease in the duration of tonic hind limb extension (THLE), a significant decrease in the levels of pro-oxidants such as MDA and NO, and an increase in the levels of antioxidants such as GSH were observed in the low dose 10 mg/kg and high dose 20 mg/kg empagliflozin groups compared to the disease control group. Histopathological analysis revealed a greater number of healthy neurons with few dark-stained cells in the treatment groups, suggesting the neuroprotective effect of empagliflozin. The present study showed that empagliflozin modulates epileptic activity. Empagliflozin has a potential role in the management of epilepsy in diabetic patients.

Metal Ruthenium Complexes Treat Spinal Cord Injury By Alleviating Oxidative Stress Through Interaction With Antioxidant 1 Copper Chaperone Protein.

Oxidative stress is a major factor affecting spinal cord injury (SCI) prognosis. A ruthenium metal complex can aid in treating SCI by scavenging reactive oxygen species via a protein-regulated mechanism to alleviate oxidative stress. This study aimed to introduce a pioneering strategy for SCI treatment by designing two novel half-sandwich ruthenium (II) complexes containing diverse N^N-chelating ligands. The general formula is [(η6-Arene)Ru(N^N)Cl]PF6, where arene is either 2-phenylethanol-1-ol (bz-EA) or 3-phenylpropanol-1-ol (bz-PA), and the N^N-chelating ligands are fluorine-based imino-pyridyl ligands. This study shows that these ruthenium metal complexes protect neurons by scavenging reactive oxygen species. Notably, η6-Arene substitution from bz-PA to bz-EA significantly enhances reactive oxygen species scavenging ability and neuroprotective effect. Additionally, molecular dynamics simulations indicate that the ruthenium metal complex increases Antioxidant 1 Copper Chaperone protein expression, reduces oxidative stress, and protects neurons during SCI treatment. Furthermore, ruthenium metal complex protected spinal cord neurons and stimulated their regeneration, which improves electrical signals and motor functions in mice with SCI. Thus, this treatment strategy using ruthenium metal complexes can be a new therapeutic approach for the efficient treatment of SCI.

Anti-Inflammatory Potential of Costus speciosus rhizome Bioactive Phytochemicals: A Combined GC-MS and Computational Approach Targeting TLR-4 Signaling.

Plants represent a rich reservoir of bioactive compounds with established therapeutic value in diverse diseases. Notably, the Toll-like receptor-4 (TLR-4) signaling pathway plays a pivotal role in inflammation. Upon engagement with pro-inflammatory ligands like lipopolysaccharide, TLR-4 triggers downstream cascades involving nuclear factor ĸappa B and mitogen- activated protein kinases. This signaling cascade ultimately dictates the onset and progression of inflammatory diseases. Therefore, targeting TLR-4 signaling offers a promising therapeutic approach for managing inflammatory disorders. This study investigated the potential of Costus speciosus rhizome phytocompounds, a traditional medicinal plant, as novel as modulators of TLR-4 signaling, highlighting their mechanisms of action and potential clinical applications. In the present study, 18 phytocompounds isolated from the rhizome of Costus speciosus, were studied against TLR-4/AP-1 signaling, which is implicated in the inflammatory process using a computational approach. The compounds exhibited binding affinities ranging from -4.087 to -8.93 kcal/mol with the TLR-4 protein due to the formation of multiple intermolecular interactions. Benzenepropanoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, methyl ester (compound 7) exhibited exceptional binding energy (-8.93 kcal/mol), indicating strong affinity for the TLR-4 protein. Additionally, compound 7 displayed favorable ADMET properties, suggesting promising drug development potential. Molecular dynamics simulations confirmed the stability of the compound 7-TLR4 complex, further supporting its ability to modulate TLR-4 signaling. These findings highlight the therapeutic potential of Costus speciosus phytocompounds, particularly compound 7, as potent anti-inflammatory modulators. Further research is warranted to validate their anti-inflammatory and neuroprotective effects in pre-clinical models, paving the way for their development as novel therapeutic agents for inflammatory diseases.

Citrus extraction provides neuroprotective effect in optic nerve crush injury mice through P53 signaling pathway

Optic nerve injury induces the loss of retinal ganglion cells and optic nerve atrophy. Our previous study demonstrated the neuroprotective effects of Citrus in the optic nerve crush (ONC) injury model. To explore the underlying neuroprotective mechanism, we focus on the changes in gene expression profile pre- and post-Citrus treatment in the ONC injury model. The results suggested that the Citrus regulated the chemokine signaling pathway and P53 signaling pathway, etc. Four genes were identified as potential target genes (Melk, Mki67, Ccnb1, and Cenpf). Subsequent qRT-PCR and western blot confirmed that Citrus regulated cell apoptosis and inflammation-related gene expression, and inhibited P53 activation-induced cell death. The present study demonstrated that the neuroprotective effect of Citrus was achieved through the regulation of the P53/BCL-2/BAX pathway and the expression regulation of four critical genes, which provide novel therapeutic targets for the therapy of optic nerve injury.

Glycosylation of chrysin with β-d-glucose tetraacetate (LQFM280) enhances its in vitro and in vivo neuroprotective effects against the toxicity induced by 3-nitropropionic acid.

Chrysin (CHR) is a naturally occurring flavonoid found in the human diet, recognized for its potential in preventing neurodegenerative diseases. However, its limited water solubility restricts its bioavailability and therapeutic applications. To address this issue and bolster the neuroprotective properties of CHR for potential nutraceutical or medicinal use, we investigated a novel compound, LQFM280, formed by conjugating CHR with β-d-glucose tetraacetate. We conducted both in vitro (using SH-SY5Y cells, mutant STHdhQ111/Q111 cells, and wild-type STHdhQ7/Q7 cells), and in vivo (mice) neurotoxicity experimental model induced by 3-nitropropionic acid, which mimic biological changes akin to Huntington's disease in humans. Compared to non-glycosylated CHR, LQFM280 showed superior in vitro effects in preventing neurotoxicity caused by increased mitochondrial vulnerability due to mutant huntingtin. In vivo findings demonstrated that LQFM280 has heightened efficacy in mitigating weight loss, memory and locomotor impairment, oxidative stress, and disruptions in the antioxidant defense system, as well as succinate dehydrogenase, and cholinesterase activities induced by 3-nitropropionic acid. These findings underscore the significant enhancement of chrysin's neuroprotective effects through glycosylation with β-d-glucose tetraacetate, positioning it as a promising candidate for use as a nutraceutical or food supplement to promote health benefits.

Exploration of neuroprotective and cognition boosting effects of Mazus pumilus in Alzheimer's disease model.

Mazus pumilus (MP) an Asian flowering plant, known for various reported pharmacological activities including antioxidant, anti-nociceptive, anti-inflammatory, anticancer, antibacterial, antifungal, and hepatoprotective effects. This study focused on further exploring Mazus pumilus's methanol leaf extract (MPM) for bioactive principles and investigating its neuroprotective and cognition-enhancing potential in Alzheimer's disease models. For the phytochemical screening and identification, TLC, HPLC, and Fourier transform infrared (FTIR) were employed. In-vitro antioxidant potential was assayed by DPPH Free Radical Scavenging method, followed by in-vivo neuroprotective effect of MPM (100, 200, 300 mg/kg) using Wistar-albino rats, sodium azide for induction of AD and rivastigmine as standard. Over 21days, we observed neurobehavioral changes and performed biochemical (GSH, CAT, SOD, and AchE activity) and histopathological evaluations. Results revealed the presence of alkaloids, flavonoids, amino acids, terpenoids, glycosides, sterols, and saponins. HPLC analysis confirmed the presence of gallic acids, sinapic acid, and caffeic acid. DPPH confirmed the antioxidant effect of MPM, which served as a base for its potential neuroprotective activity. Biochemically, oxidative stress markers improved significantly post-treatment, with decreased GSH, SOD, CAT levels, and increased AchE activity, indicating a reversal of AD-induced changes. Behavioral assessments showed improvements in locomotion, memory, spatial learning, and cognition. Histologically, there was a dose-dependent reduction in neurodegenerative features like neurofibrillary tangles and amyloid beta plaques. Hence, this study concluded MPM is a promising candidate for prophylaxis and treatment of behavioral deficits and cognitive dysfunction in Alzheimer's disease.

Correction: Viveros-Paredes et al. Neuroprotective Effects of β-Caryophyllene against Dopaminergic Neuron Injury in a Murine Model of Parkinson’s Disease Induced by MPTP. Pharmaceuticals 2017, 10, 60

In the original publication [...]

Adiponectin deficiency is a critical factor contributing to cognitive dysfunction in obese mice after sevoflurane exposure

BackgroundThe number of major operations performed in obese patients is expected to increase given the growing prevalence of obesity. Obesity is a risk factor for a range of postoperative complications including perioperative neurocognitive disorders. However, the mechanisms underlying this vulnerability are not well defined. We hypothesize that obese subjects are more vulnerable to general anaesthesia induced neurotoxicity due to reduced levels of adiponectin. This hypothesis was tested using a murine surgical model in obese and adiponectin knockout mice exposed to the volatile anaesthetic agent sevoflurane.MethodsObese mice were bred by subjecting C57BL/6 mice to a high fat diet. Cognitive function, neuroinflammatory responses and neuronal degeneration were assessed in both obese and lean mice following exposure to 2 h of sevoflurane to confirm sevoflurane-induced neurotoxicity. Thereafter, to confirm the role of adiponectin deficiency in, adiponectin knockout mice were established and exposed to the sevoflurane. Finally, the neuroprotective effects of adiponectin receptor agonist (AdipoRon) were examined.ResultsSevoflurane triggered significant cognitive dysfunction, neuroinflammatory responses and neuronal degeneration in the obese mice while no significant impact was observed in the lean mice. Similar cognitive dysfunction and neuronal degeneration were also observed in the adiponectin knockout mice after sevoflurane exposure. Administration of AdipoRon partially prevented the deleterious effects of sevoflurane in both obese and adiponectin knockout mice.ConclusionsOur findings demonstrate that obese mice are more susceptible to sevoflurane-induced neurotoxicity and cognitive impairment in which adiponectin deficiency is one of the underlying mechanisms. Treatment with adiponectin receptor agonist ameliorates this vulnerability. These findings may have therapeutic implications in reducing the incidence of anaesthesia related neurotoxicity in obese subjects.

GlyT1 inhibition promotes neuroprotection in the middle cerebral artery occlusion model through the activation of GluN2A-containing NMDAR

Glycine Transporter Type 1 (GlyT1) inhibition confers neuroprotection against different forms of cerebral damage. This effect occurs through the elevation of synaptic glycine concentrations, which enhances N-methyl-d-aspartate receptor (NMDAR) activation by glutamate. To investigate the neuroprotective mechanism of GlyT1 inhibition, we used the Middle Cerebral Artery Occlusion (MCAO) model in male C57BL/6 mice, aged 10–12 weeks. We administered N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl] sarcosine (NFPS), a GlyT1 inhibitor, 24 h prior to ischemia induction. NFPS pretreatment provided significant neuroprotection in the MCAO model, associated with modulation of pathways related to long-term potentiation. Specifically, GluN2A subunit expression was upregulated, while GluN2B subunit expression was downregulated in cortical areas, correlating with enhanced phosphorylation of CaMKIV and CREB proteins. Coadministration with the GluN2B antagonist Eliprodil or the CREB inhibitor C646 did not affect the neuroprotective effects of NFPS pretreatment, but TCN-201, a specific GluN2A antagonist, disrupted these effects. These findings suggest that GlyT1 inhibition mediates neuroprotection through activation of GluN2A-containing NMDARs and the GluN2A/CaMKIV/CREB signaling cascade, thereby modulating the balance between GluN2A and GluN2B subunits.

Deciphering the mechanisms underlying the neuroprotective potential of kaempferol: a comprehensive investigation.

Neurodegenerative disorders are characterized by neuronal degradation, dysfunction, or death within the CNS. Oxidative and inflammatory stress play crucial roles in the pathogenesis of various neurodegenerative diseases. The interplay between these stressors and dysregulated cellular signaling pathways contributes to neurodegeneration. Downregulation of NRF-2 compromises antioxidant defense, exacerbating neuronal damage, while increased TLR-4/MAPK and TLR-4/NF-κB signaling promotes neuroinflammation. Excessive ROS production by NADPH oxidase leads to oxidative damage and neuronal apoptosis. The strategies targeting NRF-2, TLR-4-mediated inflammatory stress, and NADPH oxidase activity promise to mitigate neuronal damage and halt the progression of the disease. Kaempferol is a flavonoid polyphenol antioxidant found abundantly in various fruits and vegetables, including apples, grapes, tomatoes, and broccoli. It is widely found in medicinal plants including Equisetum spp., Sophora japonica, Ginkgo biloba, and Euphorbia pekinensis (Rupr.). A substantial body of in vitro and in vivo evidences have demonstrated the neuroprotective potential of kaempferol against neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Kaempferol demonstrates multifaceted potential in mitigating neuroinflammation, apoptosis, and oxidative stress in different neurodegenerative diseases through the modulation of various pathways including NRF-2, NADPH oxidase, TLR-4/MAPK, and TLR-4/NF-κB. This review article was developed through a comprehensive analysis and interpretation of research published between 2009 and 2024, sourced from multiple scientific databases, including PubMed, Scopus, ScienceDirect, and Web of Science. This review aims to provide an in-depth overview of the neuroprotective effects of kaempferol, focusing on its underlying molecular mechanisms. A total of 24 research evidence were included to elucidate the molecular pathways by which kaempferol exerts its protective effects against neurodegenerative diseases.

Identification of Astragalus Polysaccharide as a Neuroprotective Agent via Activating Klotho-mediated Nrf2 Pathway

Background Neurodegenerative diseases (NDs) have become a significant public health problem, and oxidative stress (OS) serves as a pivotal factor in the pathological progression of NDs. Pharmacological research indicates that Astragalus polysaccharide (APS, extract of Astragalus membranaceus) has antioxidant and antiaging effects, closely related to NDs. Purpose The potential of APS in treating NDs remains uncertain. Herein, the neuroprotective effect of APS was evaluated. Methods The H2O2-induced PC12 cell damage model was established to assess the neuroprotection of APS. Cell viability was determined by MTT. Cell images were observed using ImageXpress Micro Confocal analysis. Apoptosis of the cells and intracellular levels of reactive oxygen species (ROS) were detected using flow cytometry. The expression of Klotho, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), thioredoxin reductase 1 (TrxR1), and NAD(P)H quinone oxidoreductase 1 (NQO1) was determined by Western blot (WB). Results APS exerted significant protection against H2O2-caused cell death dose-dependently, and APS could significantly reduce the intracellular ROS and relieve cell apoptosis. Furthermore, we found that APS could upregulate the expression of Klotho and Nrf2 dose-dependently, and the expression levels of Nrf2-mediated antioxidant proteins increased significantly, including HO-1, TrxR1, and NQO1. Moreover, we found that APS upregulated Klotho and Nrf2-mediated antioxidant proteins time-dependently. The expression of klotho peaked at 6 hours after treatment with APS (400 mg/L). Subsequently, the protein level of Nrf2 reached the maximum at 12 hours, and the downstream NQO1, HO-1, and TrxR1 levels peaked at 24 hours. Conclusion This study demonstrates that APS is promising for further development against oxidative stress-related NDs.

Pirfenidone mitigates demyelination and electrophysiological alterations in multiple sclerosis: Targeting NF-κB, sirt1, and neurotrophic genes.

Multiple sclerosis (MS) is a demyelinating disease affecting thecentral nervous system associated with progressive neurodegeneration. Pirfenidone (Pir) is a well-known antifibrotic agent; however, Pir's function in MS is little explored. We evaluated the neuroprotective effects of Pir in MS and its possible underlying mechanisms. Forty male Swiss mice were divided equally into control, cuprizone (CPZ), Pir, and CPZ + Pir groups. Assessment of motor function was conducted using neurobehavioral tests, EMG, and nerve conduction velocity (NCV). Mice's brains were extracted to measure oxidative stress, neuroinflammatory markers, and the expression of neurotrophic genes. The corpus callosum and the sciatic nerve were subjected to histopathological and immunohistochemical studies. The CPZ group was associated with significant reductions in muscle power, frequency of contraction, sciatic NCV, SOD, IL-10, SIRT1, NGF, and neuregulin-1. Significant increases in MDA, TNF-α, INF-γ, IL-17, TGF-β, and NF-κB were also detected. Multiple areas of partially demyelinated nerve fibers in the corpus callosum, the loss of oligodendrocyte nuclei, and increased microglia and astrocytes were also observed. The sciatic nerve revealed partial demyelination with significantly reduced myelin basic protein (MBP) expression. Pir significantly restored motor function, demyelination, and neurodegenerative changes induced by CPZ. Besides the antifibrotic action of Pir, we concluded that it improves motor function in MS by alleviating the demyelinating process and neurodegeneration. Its potential anti-inflammatory, antioxidant, and antifibrotic properties could be contributing factors. These effects could be mediated by modulating the NF-κB, SIRT1, NGF, and neuregulin-1 pathways. Pir is a promising agent for treating MS.