Neuroprotective Effects Research Articles

Neuroprotective Effects of Metformin on Cerebral Ischemia-Reperfusion Injury: Modulation of JNK and p38 MAP Kinase Signaling Pathways.

Cerebral ischemia-reperfusion injury (CIRI) is a significant pathological process in stroke, characterized by neuronal cell death and neurological dysfunction. Metformin, commonly used for diabetes management, has been noted for its neuroprotective properties, though its effects on CIRI and the mechanisms involved remain unclear. This study explored the neuroprotective impact of metformin on CIRI, focusing on its potential to modulate the c-Jun N-terminal kinase (JNK) and p38 MAP kinase (p38) signaling pathways. Using in vitro models of oxygen-glucose deprivation/reperfusion (OGD/R) in neuronal cells and in vivo mouse models of middle cerebral artery occlusion (MCAO), the effects of metformin were assessed. Cell viability was measured with Cell Counting Kit-8 (CCK-8), protein expression via Western Blot (WB), and apoptosis through flow cytometry. The extent of brain injury in mice was evaluated using 2,3,5-triphenyltetrazolium chloride (TTC) staining, while JNK and p38 activation statuses were detected through WB and phospho-JNK (p-JNK) immunofluorescence staining. Results showed that metformin significantly improved the viability of HT22 cells post-OGD/R, reduced apoptosis, and decreased OGD/R-induced phosphorylation of JNK and p38 in vitro. In vivo, metformin treatment notably reduced brain infarct volume in MCAO mice, inhibited p-p38 and p-JNK expression, and enhanced neurological function. These findings suggest that metformin exerts neuroprotective effects against CIRI by modulating the JNK/p38 signaling pathway, highlighting its potential therapeutic value in treating cerebral ischemia-reperfusion injury and paving the way for clinical applications.

Deferiprone promoted remyelination and functional recovery through enhancement of oligodendrogenesis in experimental demyelination animal model.

Remyelination refers to myelin regeneration, which reestablishes metabolic supports to axons. However, remyelination often fails in multiple sclerosis (MS), leading to chronic demyelination and axonal degeneration. Therefore, pharmacological approaches toward enhanced remyelination are highly demanded. Recently, deferiprone (DFP) was reported to exert neuroprotective effects, besides its iron-chelating ability. Since DFP exerts protective effects through various mechanisms, which share several factors with myelin formation process, we aimed to investigate the effects of DFP treatment on remyelination. Focal demyelination was induced by injection of lysolecithin, into the optic nerve of male C57BL/6J mice. The animals were treated with DFP/vehicle, starting from day 7 and continued during the myelin repair period. Histopathological, electrophysiological, and behavioral studies were used to evaluate the outcomes. Results showed that DFP treatment enhanced remyelination, decreased g-ratio and increased myelin thickness. At the mechanistic level, DFP enhanced oligodendrogenesis and ameliorated gliosis during the remyelination period. Furthermore, our results indicated that enhanced remyelination led to functional recovery as evaluated by the electrophysiological and behavioral tests. Even though the exact molecular mechanisms by which DFP-enhanced myelin repair remain to be elucidated, these results raise the possibility of using deferiprone as a therapeutic agent for remyelination therapy in MS.

Palmitic acid modulation of the insulin-like growth factor system in hypothalamic astrocytes and neurons.

Insulin-like growth factor (IGF)1 and IGF2 have neuroprotective effects, but less is known regarding how other members of the IGF system, including IGF binding proteins (IGFBPs) and the regulatory proteinase pappalysin-1 (PAPP-A) and its endogenous inhibitor stanniocalcin-2 (STC2) participate in this process. Here we analyzed whether these members of the IGF system are modified in neurons and astrocytes in response to palmitic acid (PA), a fatty acid that induces cell stress when increased centrally. Primary hypothalamic astrocyte cultures from male and female PND2 rats and the pro-opiomelanocortin (POMC) neuronal cell line, mHypoA-POMC/GFP-2, were treated with PA, IGF1 or both. To analyze the role of STC2 in astrocytes, siRNA assays were employed. In astrocytes of both sexes, PA rapidly increased cell stress factors followed by increased Pappa and Stc2 mRNA levels and then a decrease in Igf1, Igf2 and Igfbp2 expression and cell number. Exogenous IGF1 did not revert these effects. In mHypoA-POMC/GFP-2 neurons, PA reduced cell number and Pomc and Igf1 mRNA levels, and increased Igfbp2 and Stc2, again with no effect of exogenous IGF1. PA increased STC2 expression, but no effect of decreasing its levels by interference assays or exogenous STC2 treatment in astrocytes were found. The response of the IGF system to PA was cell and sex specific, but no protective effects of the IGFs were found. However, the modifications in hypothalamic PAPP-A and STC2 indicate that further studies are required to determine their role in the response to fatty acids and possibly in metabolic control.

Herpotrichone A Exerts Neuroprotective Effects by Relieving Ferroptosis.

Inhibition of oxidative stress and ferroptosis is currently considered to be a promising therapeutic approach for neurodegenerative diseases. Herpotrichones, a class of compounds derived from insect symbionts, have shown potential for neuroprotective activity with low toxicity. However, the specific mechanisms through which herpotrichones exert their neuroprotective effects remain to be fully elucidated. In this study, the natural [4 + 2] adducts herpotrichone A (He-A) and its new analogues were isolated from the isopod-associated fungus Herpotrichia sp. SF09 and exhibited significantly protective effects in H2O2-, 6-OHDA-, and RSL3-stimulated PC12 cells and LPS-stimulated BV-2 cells. Moreover, He-A was able to relieve ferroptotic cell death in RSL3-stimulated PC12 cells and 6-OHDA-induced zebrafish larvae. Interestingly, He-A can activate antioxidant elements and modulate the SLC7A11 pathway without capturing oxidic free radical and chelating iron. These findings highlight He-A as a novel hit that protects against ferroptosis-like neuronal damage in the treatment of neurodegenerative diseases.

Dihydroartemisinin promotes tau O-GlcNAcylation and improves cognitive function in hTau transgenic mice

Tauopathy is a collective term for several neurodegenerative diseases characterized by the intracellular accumulation of hyperphosphorylated microtubule-associated protein Tau (P-tau). Our recent report has revealed the neuroprotective effect of dihydroartemisinin (DHA) on mice overexpressing human Tau (hTau) in the hippocampus by enhancing O-linked-N-Acetylglucosaminylation (O-GlcNAcylation) modification. However, whether DHA can improve synaptic and cognitive function in hTau transgenic mice by specifically promoting Tau O-GlcNAcylation is still unclear. Here, we introduced hTau transgenic mice, a more optimal tauopathy model, to study the effect of DHA on Tau O-GlcNAcylation. We reported that DHA treatment alleviated the deficits of hippocampal CA1 LTP and spatial learning and memory in the Barnes maze and context fear conditioning tests in hTau transgenic mice. Mechanically, we revealed that DHA exerted a significant protective effect by upregulating Tau O-GlcNAcylation and attenuating Tau hyperphosphorylation. Through molecular docking, we found a stable binding between DHA and O-GlcNAc transferase (OGT). We further reported that DHA treatment had no effect on the expression of OGT, but it promoted OGT nuclear export, thereby enhancing OGT-mediated Tau O-GlcNAcylation. Taken together, these results indicate that DHA exerts neuroprotective effect by promoting cytoplasmic translocation of OGT and rebuilding the balance of Tau O-GlcNAcylation/phosphorylation, enhancing O-GlcNAcylation of Tau, suggesting that DHA may be a potential therapeutic agent against tauopathy.

TMEM106B Knockdown Exhibits a Neuroprotective Effect in Parkinson's Disease via Decreasing Inflammation and Iron Deposition.

Parkinson's disease (PD) is closely related to iron accumulation and inflammation. Emerging evidence indicates that TMEM106B plays an essential role in PD. But whether TMEM106B could act on neuroinflammation and iron metabolism in PD has not yet been investigated. The aim of this study was to investigate the pathological mechanisms of inflammation and iron metabolism of TMEM106B in PD. 1-methyl-4-phenylpyridinium (MPP+)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced SH-SY5Y cells and mice were treated with LV-shTMEM106B and AAV-shTMEM106B to construct PD cellular and mouse models. Pole tests and open-field test (OFT) were performed to evaluate the locomotion of the mice. Immunohistochemistry and iron staining were used to detect TH expression and iron deposition in the SN. Iron staining was used to measure the levels of iron. Western blotting was used to detect the expression of inflammatory factors (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)), NOD-like receptor protein 3 (NLRP3) inflammasome, divalent metal transporter 1 (DMT1), and Ferroportin1 (FPN1)). Knockdown of TMEM106B improved motor ability and rescued dopaminergic (DA) neuron loss. TMEM106B knockdown attenuated the increases of TNF-α, IL-6, NLRP3 inflammasome, and DMT1 expression in the MPP+ and MPTP-induced PD models. Furthermore, TMEM106B knockdown also increases the expression of FPN1. This study provides the first evidence that knockdown of TMEM106B prevents dopaminergic neurodegeneration by modulating neuroinflammation and iron metabolism.

Neuroprotective Effects Induced by Citicoline/Coenzyme Q10 Fixed Combination in Rat CTX-TNA2 Astrocytes Exposed to Oxidative Stress

Neuroprotective Effects Induced by Citicoline/Coenzyme Q10 Fixed Combination in Rat CTX-TNA2 Astrocytes Exposed to Oxidative Stress

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest

BackgroundCardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established.MethodsThis study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures.DiscussionIn vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms.Trial registrationClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Flow augmentation therapies preserve brain network integrity and hemodynamics in a canine permanent occlusion model

The acute phase of ischemic stroke presents a critical window for therapeutic intervention, where novel approaches such as hyper-acute cerebral flow augmentation offer promising avenues for neuroprotection. In this study, we investigated the effects of two such therapies, NEH (a combination of norepinephrine and hydralazine) and Sanguinate (pegylated bovine carboxyhemoglobin), on resting-state functional connectivity, global mean signal (GMS), and blood oxygen level-dependent (BOLD) time lag in a pre-clinical canine model of stroke via permanent occlusion of the middle cerebral artery (total of n = 40 IACUC-approved mongrel canines randomly split into control/natural history and two treatment groups). Utilizing group independent component analysis (ICA), we identified and examined the integrity of sensorimotor and visual networks both pre- and post-occlusion, across treatment and control groups. Our results demonstrated that while the control group exhibited significant disruptions in these networks following stroke, the treatment groups showed remarkable preservation of network integrity. Voxel-wise functional connectivity analysis revealed less pronounced alterations in the treatment groups, suggesting maintained neural connections. Notably, the treatments stabilized GMS, with only minimal reductions observed post-occlusion compared to significant decreases in the control group. Furthermore, BOLD time-lag unity plots indicated that NEH and Sanguinate maintained consistent hemodynamic response timing, as evidenced by tighter clustering around the line of unity, suggesting a potential neuroprotective effect. These findings were underscored by robust statistical analyses, including paired T-tests and Mann–Whitney U tests, which confirmed the significance of the connectivity changes observed. The correlation of BOLD time-lag variations with neuroimaging functional biomarkers highlighted the impact of stroke and the efficacy of early therapeutic interventions. Our study supports the further study of flow augmentation therapies such as NEH and Sanguinate in stroke treatment protocols and suggests flow augmentation therapies should be further explored in an effort to improve patient outcomes.

Neuroprotective effect of sea urchins (Diadema savignyi) extract in an animal model of aluminum neurotoxicity

Human exposure to heavy metals causes major health consequences. Aluminum (Al) toxicity primarily affects the brain and has been implicated in neurodegenerative disorders. Natural products offer a cheap and safe source of protective agents against heavy metal toxicity. This study investigates the neuroprotective role of the shell extract (SH) from the Sea urchin (Diadema savignyi) collected from the Red Sea in an Aluminum-induced neurotoxicity model.Aluminum (Al, 250 µg/ml) caused cell death in a dose-dependent manner on neuroblastoma (SH-SY5Y) cells. The shell extract (50, 100, and 200 µg/ml) improved cell viability of the neuroblastoma cells. In vivo, toxicity assessment showed that Aluminum administration increased the levels of blood Urea, creatinine, and liver enzymes. Treatment with Shell extract reversed the levels back to normal.Oxidative stress assessment in vitro and in vivo showed that Al caused an increase in Nitric Oxide (NO) concentration and a significant reduction in Catalase and Glutathione (GSH) activity. Treatment with Shell extract (SH) improved these changes.Microscopic examination of the cerebral cortex showed that Aluminum-treated animals had significant neuronal damage, as evidenced by the degenerated neurons and increased apoptosis marker Caspase 3. There was also an increase in glial activation seen by an increase in the expression of Glial fibrillary Acidic Protein (GFAP). Treatment with Shell extract (100 and 200 µg/kg) showed neuroprotective effects all over cortical layers with minimal neuronal degenerative changes.The current work proves the potential antitoxic and neuroprotective properties of Sea Urchins (Diadema savignyi) extract as a cheap and safe therapeutic alternative against heavy metal toxicity.

Seaweeds as Source of Bioactive Pigments with Neuroprotective and/or Anti-Neurodegenerative Activities: Astaxanthin and Fucoxanthin

The marine kingdom is an important source of a huge variety of scaffolds inspiring the design of new drugs. The complex molecules found in the oceans present a great challenge to organic and medicinal chemists. However, the wide variety of biological activities they can display is worth the effort. In this article, we present an overview of different seaweeds as potential sources of bioactive pigments with activity against neurodegenerative diseases, especially due to their neuroprotective effects. Along with a broad introduction to seaweed as a source of bioactive pigments, this review is especially focused on astaxanthin and fucoxanthin as potential neuroprotective and/or anti-neurodegenerative agents. PubMed and SciFinder were used as the main sources to search and select the most relevant scientific articles within the field.

Antioxidant and Anti-Apoptotic Neuroprotective Effects of Cinnamon in Imiquimod-Induced Lupus

Antioxidant and Anti-Apoptotic Neuroprotective Effects of Cinnamon in Imiquimod-Induced Lupus

Viscolin-mediated antiapoptotic and neuroprotective effects in cortical neurons exposed to oxygen-glucose deprivation and rats subjected to transient focal cerebral ischemia

ABSTRACT Objective Previously, we have successfully purified and synthesized viscolin, an agent derived from Viscum coloratum extract, which has shown significant potential in the treatment of stroke. Our study aimed to evaluate the neuroprotective effects of viscolin. Methods We first assessed the cytotoxicity of viscolin on primary neuronal cultures and determined its antioxidant and radical scavenging properties. Subsequently, we identified the optimal dose-response of viscolin in protecting against glutamate-induced neurotoxicity. Results Our results demonstrated that viscolin at a concentration of 10 μM effectively reduced neuronal cell death up to 6 hours after glutamate-induced neurotoxicity. Additionally, we investigated the therapeutic window of opportunity and the potential of viscolin in preventing necrotic and apoptotic damage in cultured neurons exposed to oxygen glucose deprivation-induced neurotoxicity. Our findings showed that viscolin treatment significantly reduced DNA breakage, prevented the release of cytochrome c from mitochondria to cytosol, increased the expression of anti-apoptotic protein Bcl-2, decreased the expression of pro-apoptotic protein Bax, and reduced the number of TUNEL-positive cells. Additionally, our in vivo investigation demonstrated a reduction in brain infarction following middle cerebral artery occlusion. Conclusion Viscolin has potential utility as a therapeutic agent in the treatment of stroke.

Novel 1,2,4-triazole derivatives containing the naphthalene moiety as selective butyrylcholinesterase inhibitors: Design, synthesis, and biological evaluation.

Butyrylcholinesterase (BChE) is considered a promising therapeutic target for treating Alzheimer's disease due to the increase in the levels and activity of BChE in the late stage of the disease. In this study, a series of novel 1,2,4-triazole derivatives bearing the naphthalene moiety linked to the benzothiazole, thiazole, and phenyl scaffolds via amid chain were designed and synthesized as potential and selective BChE inhibitors. The results of the inhibitory activity studies revealed that most of these compounds exhibited significant inhibitor potency on BChE. Compounds 35a (0.025 ± 0.01 μM) and 37a (0.035 ± 0.01 μM) displayed the most potent inhibitory activity, with excellent selectivity against BChE over acetylcholinesterase (SIBChE, 23,686 and 16,936, respectively) among the target compounds. The kinetics studies revealed that these compounds behaved with noncompetitive BChE inhibitors. Molecular docking studies indicated that 35a and 37a fit well into the active side of BChE. In addition, 35a and 37a also had the lowest cytotoxicity for human neuroblastoma cells (SH-SY5Y), potential antioxidant capacity, moderate inhibition potency on amyloid-β1-42 aggregation, and significant neuroprotective effect against SH-SY5Y cellinjury induced by H2O2 and amyloid-β1-42. All results suggest that these compounds might be considered as promising new lead compounds in the drug discovery process for the treatment of late-stage Alzheimer's disease.

Exploring the therapeutic potential of Aloin: unraveling neuroprotective and anticancer mechanisms, and strategies for enhanced stability and delivery

We investigate the therapeutic potential of Aloin A and Aloin B, two natural compounds derived from Aloe vera leaves, focusing on their neuroprotective and anticancer properties. The structural differences between these two epimers suggest that they may exhibit distinct pharmacological properties. Our investigations revealed that both epimers are not stable in aqueous solution and tend to degrade rapidly, with their concentration decreasing by over 50% within approximately 12 h. These results underscore the importance of addressing issues such as the need for encapsulation into effective drug delivery systems to enhance stability. ThT fluorescence experiments showed that neither compound was able to inhibit Aβ amyloid aggregation, indicating that other mechanisms may be responsible for their neuroprotective effects. Next, an equimolar mixture of Aloin A and Aloin B demonstrated an ability to inhibit proteasome in tube tests, which is suggestive of potential anticancer properties, in accordance with antiproliferative effects observed in neuroblastoma SH-SY5Y and HeLa cell lines. Higher water stability and increased antiproliferative activity were observed by encapsulation in carbon dot nanoparticles, suggesting a promising potential for further in vivo studies.

Memantine alleviates cognitive impairment and hippocampal morphology injury in a mouse model of chronic alcohol exposure

Alcohol-related cognitive impairment (ARCI) is highly prevalent among patients with alcohol abuse and dependence. The pathophysiology of ARCI, pivotal for refined therapeutic approaches, is not fully elucidated, posing a risk of progression to severe neurological sequelae such as Korsakoff's syndrome (KS) and Alcohol-Related Dementia (ARD). This study ventures into the underlying mechanisms of chronic alcohol-induced neurotoxicity, notably glutamate excitotoxicity and cytoskeletal disruption, and explores the therapeutic potential of Memantine, a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor known for its neuroprotective effect against excitotoxicity. Our investigation centers on the efficacy of Memantine in mitigating chronic alcohol-induced cognitive and hippocampal damages in vivo. Male C57BL/6J mice were subjected to 30 % (v/v, 6.0 g/kg) ethanol via intragastric administration alongside Memantine co-treatment (10 mg/kg/day, intraperitoneally) for six weeks. The assessment involved Y maze, Morris water maze, and novel object recognition tests to evaluate spatial and recognition memory deficits. Histopathological evaluations of the hippocampus were conducted to examine the extent of alcohol-induced morphological changes and the potential protective effect of Memantine. The findings reveal that Memantine significantly improves chronic alcohol-compromised cognitive functions and mitigates hippocampal pathological changes, implicating a moderating effect on the disassembly of actin cytoskeleton and microtubules in the hippocampus, induced by chronic alcohol exposure. Our results underscore Memantine's capability to attenuate chronic alcohol-induced cognitive and hippocampal morphological harm may partly through regulating cytoskeleton dynamics, offering valuable insights into innovative therapeutic strategies for ARCI.

ARL13B promotes cell cycle through the sonic hedgehog signaling pathway to alleviate nerve damage during cerebral ischemia/reperfusion in rats

Cerebral ischemia/reperfusion (CIRI) is a leading cause of death worldwide. A small GTPase known as ADP-ribosylation factor-like protein 13B (ARL13B) is essential in several illnesses. The role of ARL13B in CIRI remains unknown, though. A middle cerebral artery occlusion/reperfusion (MCAO/R) in rats as well as an oxygen-glucose deprivation/reoxygenation (OGD/R) models in PC12 cells were constructed. The neuroprotective effects of ARL13B against MCAO/R were evaluated using neurological scores, TTC staining, rotarod testing, H&E staining, and Nissl staining. To detect the expression of proteins associated with the SHH pathway and apoptosis, western blotting and immunofluorescence were employed. Apoptosis was detected using TUNEL assays and flow cytometry. There was increased expression of ARL13B in cerebral ischemia/reperfusion models. However, ARL13B knockdown aggravated CIRI nerve injury by inhibiting the sonic hedgehog (SHH) pathway. In addition, the use of SHH pathway agonist (SAG) can increased ARL13B expression, reverse the effects of ARL13B knockdown exacerbating CIRI nerve injury. ARL13B alleviated cerebral infarction and pathological injury and played a protective role against MCAO/R. Furthermore, ARL13B significantly increased the expression of SHH pathway-related proteins and the anti-apoptotic protein BCL-2, while decreased the expression of pro-apoptotic protein BAX, thus reducing apoptosis. The results from the OGD/R model in PC12 cells were consistent with those obtained in vivo. Surprisingly, we demonstrated that ARL13B regulates the cell cycle to protect against CIRI nerve injury. Our findings indicate that ARL13B protects against CIRI by reducing apoptosis through SHH-dependent pathway activation, and suggest that ARL13B plays a crucial role in CIRI pathogenesis.

Alpha-lipoic acid alleviates cognitive deficits in transgenic APP23/PS45 mice through a mitophagy-mediated increase in ADAM10 α-secretase cleavage of APP

BackgroundAlpha-lipoic acid (ALA) has a neuroprotective effect on neurodegenerative diseases. In the clinic, ALA can improve cognitive impairments in patients with Alzheimer’s disease (AD) and other dementias. Animal studies have confirmed the anti-amyloidosis effect of ALA, but its underlying mechanism remains unclear. In particular, the role of ALA in amyloid-β precursor protein (APP) metabolism has not been fully elucidated.ObjectiveTo investigate whether ALA can reduce the amyloidogenic effect of APP in a transgenic mouse model of AD, and to study the mechanism underlying this effect.MethodsALA was infused into 2-month-old APP23/PS45 transgenic mice for 4 consecutive months and their cognitive function and AD-like pathology were then evaluated. An ALA drug concentration gradient was applied to 20E2 cells in vitro to evaluate its effect on the expression of APP proteolytic enzymes and metabolites. The mechanism by which ALA affects APP processing was studied using GI254023X, an inhibitor of A Disintegrin and Metalloproteinase 10 (ADAM10), as well as the mitochondrial toxic drug carbonyl cyanide m-chlorophenylhydrazone (CCCP).ResultsAdministration of ALA ameliorated amyloid plaque neuropathology in the brain tissue of APP23/PS45 mice and reduced learning and memory impairment. ALA also increased the expression of ADAM10 in 20E2 cells and the non-amyloidogenic processing of APP to produce the 83 amino acid C-terminal fragment (C83). In addition to activating autophagy, ALA also significantly promoted mitophagy. BNIP3L-knockdown reduced the mat/pro ratio of ADAM10. By using CCCP, ALA was found to regulate BNIP3L-mediated mitophagy, thereby promoting the α-cleavage of APP.ConclusionsThe enhanced α-secretase cleavage of APP by ADAM10 is the primary mechanism through which ALA ameliorates the cognitive deficits in APP23/PS45 transgenic mice. BNIP3L-mediated mitophagy contributes to the anti-amyloid properties of ALA by facilitating the maturation of ADAM10. This study provides novel experimental evidence for the treatment of AD with ALA.Graphical abstract

An Overview of the Natural Neuroprotective Agents for the Management of Cognitive Impairment Induced by Scopolamine in Zebrafish (Danio rerio).

Alzheimer's Disease (AD) is a neurodegenerative disorder mainly characterized by dementia and cognitive decline. AD is essentially associated with the presence of aggregates of the amyloid-β peptide and the hyperphosphorylated microtubule-associated protein tau. The available AD therapies can only alleviate the symptoms; therefore, the development of natural treatments that exhibit neuroprotective effects and correct the behavioral impairment is a critical requirement. The present review aims to collect the natural substances that have been evaluated for their neuroprotective profile against AD-like behaviors induced in zebrafish (Danio rerio) by scopolamine. We focused on articles retrieved from the PubMed database via preset searching strings from 2010 to 2023. Our review assembled 21 studies that elucidated the activities of 28 various natural substances, including bioactive compounds, extracts, fractions, commercial compounds, and essential oils. The listed compounds enhanced cognition and showed several mechanisms of action, namely antioxidant potential, acetylcholinesterase's inhibition, and reduction of lipid peroxidation. Additional studies should be achieved to demonstrate their preventive and therapeutic activities in cellular and rodent models. Further clinical trials would be extremely solicited to support more insight into the neuroprotective effects of the most promising drugs in an AD context.

Healthy Plasma Exosomes Exert Potential Neuroprotective Effects against Methylmalonic Acid-Induced Hippocampal Neuron Injury.

Exosomes have shown good potential for alleviating neurological deficits and delaying memory deterioration, but the neuroprotective effects of exosomes remain unknown. Methylmalonic acidemia is a metabolic disorder characterized by the accumulation of methylmalonic acid (MMA) in various tissues that inhibits neuronal survival and function, leading to accelerated neurological deterioration. Effective therapies to mitigate these symptoms are lacking. The purpose of this study was to explore the neuroprotective effects of plasma exosomes on cells and a mouse model of MMA-induced injury. We evaluated the ability of plasma exosomes to reduce the neuronal apoptosis, cross the blood-brain barrier, and affect various parameters related to neuronal function. MMA promoted cell apoptosis, disrupted the metabolic balance, and altered the expression of B-cell lymphoma-2 (Bcl-2), Bcl2-associated X (Bax), and synaptophysin-1 (Syp-1), and these changes may be involved in MMA-induced neuronal apoptosis. Additionally, plasma exosomes normalized learning and memory and protected against MMA-induced neuronal apoptosis. Our findings indicate that neurological deficits are linked to the pathogenesis of methylmalonic acidemia, and healthy plasma exosomes may exert neuroprotective and therapeutic effects by altering the expression of exosomal microRNAs, facilitating neuronal functional recovery in the context of this inherited metabolic disease. Intravenous plasma-derived exosome treatment may be a novel clinical therapeutic strategy for methylmalonic acidemia.