Potential Neuroprotective Properties Research Articles

Uric acid, cognitive disorders, neurodegeneration

This article examines the role of uric acid (UA) in cognitive changes and neurodegeneration, focusing on its functions as an antioxidant and prooxidant. Research suggests that changes in serum UA levels may be associated with the development or delay of cognitive impairment, especially in the context of neurodegenerative diseases such as Alzheimer's disease. It was revealed that there is a relationship between the level of UA and the dynamics of cognitive functions, indicating the potential neuroprotective properties of UA. Particular attention is paid to the balance between the antioxidant and prooxidant properties of UA, which may play a key role in protecting neurons from damage. However, research results are not clear-cut, highlighting the need for further research to more fully understand the role of UA in cognitive processes. Determining the optimal serum UA level may be an important step in developing strategies for the prevention and treatment of cognitive impairment associated with neurodegeneration. Overall, these studies advance the understanding of the mechanisms underlying the interaction between uric acid metabolism and brain health.

Environmental enrichment and the combined interventions of EE and metformin enhance hippocampal neuron survival and hippocampal-dependent memory in type 2 diabetic rats under stress through the BDNF-TrkB signaling pathways

BackgroundType 2 diabetes (T2D) with depression causes severe cognitive impairments. The devastating conditions will further compromise the overall quality of life. The overconsumption of high-fat and high-sucrose (HFS) diet is one of the modifiable risk factors for T2D, depression, and cognitive impairments. Thus, it is essential to identify effective therapeutic strategies to overcome the cognitive impairments in T2D with depression. We proposed environmental enrichment (EE) which encompasses social, cognitive, and physical components as the alternative treatment for such impairments. We also investigated the potential neuroprotective properties of the antidiabetic drug metformin. This study aimed to investigate the effects of EE and metformin interventions on hippocampal neuronal death, and hippocampal-dependent memory impairment in T2D rats under stress. MethodsThirty-two male rats (200–250 g) were divided into four groups: C group (standard diet + conventional cage), DS group [HFS-induced T2D + restraint stress (RS)], DSE group [HFS-induced T2D + RS + EE] and DSEM group [HFS + RS + EE + metformin]. Serum corticosterone (CORT) was measured to evaluate stress levels. The serum Free Oxygen Radicals Testing (FORT) and Free Oxygen Radicals Defence Test (FORD) were measured to evaluate the systemic oxidative status (OS). Serum brain-derived neurotrophic factor (BDNF) and T-maze tasks were performed to evaluate cognitive functions. Rats were humanely sacrificed to collect brains for histological, morphometric, and hippocampal gene expression studies. ResultsThe CORT and the serum FORT levels in the DSE and DSEM groups were lower than in the DS group. Meanwhile, the serum BDNF, T-maze scores, histological, and morphometric analysis were improved in the DSE and DSEM groups than in the DS group. These findings supported that EE and the combined interventions of EE and metformin had neuroprotective properties. The hippocampal gene expression analysis revealed that the DSE and DSEM groups showed improved regulation of BDNF-TrkB signalling pathways, including the BDNF/TrkB binding, PI3K – Akt pathway, Ras–MAPK pathway, PLCγ–Ca2+ pathway, and CREB transcription. ConclusionEE and the combined interventions of EE and metformin improved hippocampal neuron survival and hippocampal-dependent memory in T2D rats under stress by enhancing gene expression regulation of neurogenesis and synaptic plasticity.

Silybin mitigated liver and brain damage after difenoconazole exposure: Crosstalk between oxidative stress, inflammation, ferroptosis and apoptosis

Long-term residue of difenoconazole (DFZ) in the environment caused multiple organ damage to aquatic organisms. Due to the potential hepatoprotective and neuroprotective properties of silybin (SIL), we hypothesized that SIL could alleviate growth inhibition, liver, and brain damage in carp induced by DFZ exposure. The in vivo experiments were divided into the Control group, the SIL group, the DFZ group and the DFZ + SIL group. The exposure concentration of DFZ was 0.39 mg/L, and the therapeutic dose of SIL was 400 mg/kg. The whole experiment lasted for 30 days. SIL was also found to reduce hepatic injury and lipid metabolism based on H&E staining, oil red O staining, and measurement of serum and liver tissue levels of ALT, AST, LDH, TG, and TC. Similarly, SIL reduced brain damage after DFZ exposure, according to H&E staining and detection transcription level of the ZO-1, ZO-2, occludin, and Claudin7 in carp brain. In terms of mechanism, the results showed that SIL inhibited the excessive production of ROS in liver and brain tissues, increased the activity of antioxidant enzymes (T-AOC, SOD, CAT) and resist oxidative stress. Also, SIL promoted the production of anti-inflammatory factors (TGF-β1 and IL-10) and inhibited the expression of pro-inflammatory factors (TNF-α and IL-6) to reduce the inflammatory response in liver and brain tissues caused by DFZ. ln terms of ferroptosis, by lowering iron levels, upregulating ferroptosis-related genes (GPX4, SIC7A11, GCLC), and downregulating the expression of NCOA4, STEAP3, COX2, and P53, SIL was able to inhibit ferroptosis of liver and brain tissues of carp. In addition, SIL restored the reduced mitochondrial membrane potential (MMP) level and inhibited apoptosis as measured by MMP level detection, TUNEL staining, and apoptosis gene transcript levels. In this study, we analyzed the interactions between genes and proteins associated with oxidative stress, inflammation, ferroptosis and apoptosis using the String database and ranked the nodes in the network using the Cytoscape plugin Cytohubba, and found that P53, Caspase3, TNF-α, IL-6 and Bcl-2 were the key hub genes. Our study not only revealed the multiple pharmacological activities of SIL, but also provided a reference for the prevention and reduction pesticide hazards to aquatic organisms.

Nicotine inhalant via E-cigarette facilitates sensorimotor function recovery by upregulating neuronal BDNF-TrkB signalling in traumatic brain injury.

Traumatic brain injury (TBI) causes lifelong physical and psychological dysfunction in affected individuals. The current study investigated the effects of chronic nicotine exposure via E-cigarettes (E-cig) (vaping) on TBI-associated behavioural and biochemical changes. Adult C57/BL6J male mice were subjected to controlled cortical impact (CCI) followed by daily exposure to E-cig vapour for 6 weeks. Sensorimotor functions, locomotion, and sociability were subsequently evaluated by nesting, open field, and social approach tests, respectively. Immunoblots were conducted to examine the expression of mature brain-derived neurotrophic factor (mBDNF) and associated downstream proteins (p-Erk, p-Akt). Histological analyses were performed to evaluate neuronal survival and neuroinflammation. Post-injury chronic nicotine exposure significantly improved nesting performance in CCI mice. Histological analysis revealed increased survival of cortical neurons in the perilesion cortex with chronic nicotine exposure. Immunoblots revealed that chronic nicotine exposure significantly up-regulated mBDNF, p-Erk and p-Akt expression in the perilesion cortex of CCI mice. Immunofluorescence microscopy indicated that elevated mBDNF and p-Akt expression were mainly localized within cortical neurons. Immunolabelling of Iba1 demonstrated that chronic nicotine exposure attenuated microglia-mediated neuroinflammation. Post-injury chronic nicotine exposure via vaping facilitates recovery of sensorimotor function by upregulating neuroprotective mBDNF/TrkB/Akt/Erk signalling. These findings suggest potential neuroprotective properties of nicotine despite its highly addictive nature. Thus, understanding the multifaceted effects of chronic nicotine exposure on TBI-associated symptoms is crucial for paving the way for informed and properly managed therapeutic interventions.

Curcumin attenuates brain aging by reducing apoptosis and oxidative stress.

Brain aging is a physiological event, and oxidative stress and apoptosis are involved in the natural aging process of the brain. Curcumin is a natural antioxidant with potent anti-aging and neuroprotective properties. Therefore, we investigated the protective effects of curcumin on brain apoptosis and oxidative stress, brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) in aged rats. Old female Wistar rats were randomly divided into three groups (n = 7); as follows: (1) control; (2); saline and (3) curcumin (received 30mg/kg of curcumin, 5 days/week for 8 weeks, intraperitoneally). Our results indicated that treatment with curcumin in aged rats attenuates brain lipid peroxidation, which was accompanied by a significant increase in the BDNF, VEGF, superoxide dismutase (SOD) activity, and anti-apoptotic protein BCl-2. No significant change in brain anti-apoptotic Bax protein levels was observed after curcumin treatment. The study indicates that curcumin could alleviate brain aging which may be due to attenuating oxidative stress, inhibiting apoptosis, and up-regulating SOD activity, which in turn enhances VEGF and BDNF. Therefore, curcumin has potential therapeutic value in the treatment of neurological apoptosis, neurogenesis, and angiogenesis changes caused by brain aging.

Unveiling the Molecular Interactions Between Human Transferrin and Limonene: Natural Compounds in Alzheimer's Disease Therapeutics.

Neurodegeneration is a term describing an irreversible process of neuronal damage. In recent decades, research efforts have been directed towards deepening our knowledge of numerous neurodegenerative disorders, with a particular focus on conditions such as Alzheimer's disease (AD). Human transferrin (htf) is a key player in maintaining iron homeostasis within brain cells. Any disturbance in this equilibrium gives rise to the emergence of neurodegenerative diseases and associated pathologies, particularly AD. Limonene, a natural compound found in citrus fruits and various plants, has shown potential neuroprotective properties. In this study, our goal was to unravel the binding of limonene with htf, with the intention of comprehending the interaction mechanism of limonene with htf. Binding was scrutinized using fluorescence quenching and UV-Vis spectroscopic analyses. The binding mechanism of limonene was further investigated at the atomic level through molecular docking and extensive 200 ns molecular dynamic simulation (MD) studies. Molecular docking uncovered that limonene interacted extensively with the deep cavity located within the htf binding pocket. MD results indicated that binding of limonene to htf did not induce substantial structural alterations, ultimately forming stable complex. The findings from fluorescence binding indicated a pronounced interaction between limonene and htf, limonene binds to htf with a binding constant (K) of 0.1×105 M-1. UV spectroscopy also advocated stable htf-limonene complex formation. The study deciphered the binding mechanism of limonene with htf, providing a platform to use limonene in AD therapeutics in context of iron homeostasis.

Neuroprotective effect of acetoxypachydiol against oxidative stress through activation of the Keap1-Nrf2/HO-1 pathway

BackgroundExcessive oxidative stress in the brain is an important pathological factor in neurological diseases. Acetoxypachydiol (APHD) is a lipophilic germacrane-type diterpene extracted as a major component from different species of brown algae within the genus Dictyota. There have been no previous reports on the pharmacological activity of APHD. The present research aims to explore the potential neuroprotective properties of APHD and its underlying mechanisms.MethodsThe possible mechanism of APHD was predicted using a combination of molecular docking and network pharmacological analysis. PC12 cells were induced by H2O2 and oxygen–glucose deprivation/reoxygenation (OGD/R), respectively. Western blot, flow cytometry, immunofluorescence staining, and qRT-PCR were used to investigate the antioxidant activity of APHD. The HO-1 inhibitor ZnPP and Nrf2 gene silencing were employed to confirm the influence of APHD on the signaling cascade involving HO-1, Nrf2, and Keap1 in vitro.ResultsAPHD exhibited antioxidant activity in both PC12 cells subjected to H2O2 and OGD/R conditions by downregulating the release of LDH, the concentrations of MDA, and ROS, and upregulating SOD, GSH-Px, and GSH concentrations. APHD could potentially initiate the Keap1-Nrf2/HO-1 signaling cascade, according to the findings from network pharmacology evaluation and molecular docking. Furthermore, APHD was observed to increase Nrf2 and HO-1 expression at both mRNA and protein levels, while downregulating the protein concentrations of Keap1. Both Nrf2 silencing and treatment with ZnPP reversed the neuroprotective effects of APHD.ConclusionsAPHD activated antioxidant enzymes and downregulated the levels of LDH, MDA, and ROS in two cell models. The neuroprotective effect is presumably reliant on upregulation of the Keap1-Nrf2/HO-1 pathway. Taken together, APHD from brown algae of the genus Dictyota shows potential as a candidate for novel neuroprotective agents.

γ-Oryzanol from Rice Bran Antagonizes Glutamate-Induced Excitotoxicity in an In Vitro Model of Differentiated HT-22 Cells.

The excessive activation of glutamate in the brain is a factor in the development of vascular dementia. γ-Oryzanol is a natural compound that has been shown to enhance brain function, but more research is needed to determine its potential as a treatment for vascular dementia. This study investigated if γ-oryzanol can delay or improve glutamate neurotoxicity in an in vitro model of differentiated HT-22 cells and explored its neuroprotective mechanisms. The differentiated HT-22 cells were treated with 0.1 mmol/L glutamate for 24 h then given γ-oryzanol at appropriate concentrations or memantine (10 µmol/L) for another 24 h. Glutamate produced reactive oxygen species and depleted glutathione in the cells, which reduced their viability. Mitochondrial dysfunction was also observed, including the inhibition of mitochondrial respiratory chain complex I activity, the collapse of mitochondrial transmembrane potential, and the reduction of intracellular ATP levels in the HT-22 cells. Calcium influx triggered by glutamate subsequently activated type II calcium/calmodulin-dependent protein kinase (CaMKII) in the HT-22 cells. The activation of CaMKII-ASK1-JNK MAP kinase cascade, decreased Bcl-2/Bax ratio, and increased Apaf-1-dependent caspase-9 activation were also observed due to glutamate induction, which were associated with increased DNA fragmentation. These events were attenuated when the cells were treated with γ-oryzanol (0.4 mmol/L) or the N-methyl-D-aspartate receptor antagonist memantine. The results suggest that γ-oryzanol has potent neuroprotective properties against glutamate excitotoxicity in differentiated HT-22 cells. Therefore, γ-oryzanol could be a promising candidate for the development of therapies for glutamate excitotoxicity-associated neurodegenerative diseases, including vascular dementia.

Synthesis of naringenin-betaine cocrystal by gas antisolvent technique and cell models for in vitro permeation studies

Naringenin (NRG) is a flavanone characterized by potential neuroprotective properties, even if low water solubility and poor oral bioavailability limit the ability of this compound to target the central nervous system. As an attempt to overcome these limitations, it is here described the synthesis and characterization of a cocrystal obtained with NRG and betaine (BTN) using gas antisolvent (GAS) technique. The ability of NRG, its cocrystal and the parent physical mixture to permeate across the intestinal and the blood-brain (BBB) barriers was simulated in vitro by using monolayers obtained by IEC-6 cells and a model established by ECV 304, respectively. It is evidenced that the NRG: BTN cocrystal improves both the solubility and dissolution rate of NRG, potentially allowing to enhance its oral bioavailability. Moreover, the results of viability studies performed on IEC-6 cells suggest that low doses of cocrystal frequently administered are required for absorption to be efficient and safe. The study also suggests a synergistic effect of NRG and BTN for the cocrystal and physical mixture in enhancing NRG permeation through the BBB. These results indicate that the NRG:BTN cocrystal is potentially useful for the brain targeting of NRG, following its oral administration.

Phytocannabinoids: Exploring Pharmacological Profiles and Their Impact on Therapeutical Use.

Phytocannabinoids, a diverse group of naturally occurring compounds extracted from the Cannabis plant, have attracted interest due to their potential pharmacological effects and medicinal uses. This comprehensive review presents the intricate pharmacological profiles of phytocannabinoids while exploring the diverse impacts these substances have on biological systems. From the more than one hundred cannabinoids which were identified in the Cannabis plant so far, cannabidiol (CBD) and tetrahydrocannabinol (THC) are two of the most extensively studied phytocannabinoids. CBD is a non-psychoactive compound, which exhibits potential anti-inflammatory, neuroprotective, and anxiolytic properties, making it a promising candidate for a wide array of medical conditions. THC, known for its psychoactive effects, possesses analgesic and antiemetic properties, contributing to its therapeutic potential. In addition to THC and CBD, a wide range of additional phytocannabinoids have shown intriguing pharmacological effects, including cannabichromene (CBC), cannabigerol (CBG), and cannabinol (CBN). The endocannabinoid system, made up of the enzymes involved in the production and breakdown of endocannabinoids, cannabinoid receptors (CB1 and CB2), and endogenous ligands (endocannabinoids), is essential for preserving homeostasis in several physiological processes. Beyond their effects on the endocannabinoid system, phytocannabinoids are studied for their ability to modify ion channels, neurotransmitter receptors, and anti-oxidative pathways. The complex interaction between phytocannabinoids and biological systems offers hope for novel treatment approaches and lays the groundwork for further developments in the field of cannabinoid-based medicine. This review summarizes the state of the field, points out information gaps, and emphasizes the need for more studies to fully realize the therapeutic potential of phytocannabinoids.

Uncovering potential neuroprotective flavonoids for Alzheimer's disease using cutting-edge molecular simulation and in vitro SHSY-5Y analysis

Context: Alzheimer's disease (AD) is a debilitating neurodegenerative condition primarily afflicting the elderly, causing a progressive decline in cognitive function. It is marked by the presence of beta-amyloid protein plaques that trigger inflammation and neuronal death. Unfortunately, effective treatments for Alzheimer's remain elusive. One promising approach involves targeting the mitochondrial cascade to shield neurons from inflammation-induced cell death, and flavonoids have been identified for their potential neuroprotective properties. Aims: To investigate the most potential bioactive compound that has neuroprotective effects, especially for Alzheimer's, through molecular simulation and in vitro studies. Methods: The study employed molecular simulations to identify apigenin as a potential neuroprotective compound. Quercetin and donepezil were selected as control compounds. The MTT assay was conducted to evaluate the neuroprotective activity of apigenin, quercetin, and donepezil on the SHSY5Y cell line induced by beta-amyloid protein. Results: The MTT assay demonstrated the neuroprotective activity of apigenin and reference compounds quercetin and donepezil against beta-amyloid-induced damage in the SHSY5Y cell line. Conclusions: These findings suggest that apigenin could hold promise as a neuroprotective treatment for AD. However, further research is essential to elucidate its mechanism of action and evaluate its efficacy in more complex organisms. This study underscores the crucial role of bioinformatics tools and experimental validation in the quest for potential neuroprotective compounds for the treatment of AD.

Spirulina platensis and Phaeodactylum tricornutum as sustainable sources of bioactive compounds: Health implications and applications in the food industry

AbstractThe exponential growth of the global population, coupled with issues of insufficient and imbalanced nutrition, as well as a surge in health‐related problems, has compelled individuals to seek innovative and alternative food sources while optimizing existing resources. Microalgae have been a staple source of livelihood and essential nourishment for people in various regions worldwide. Their rich content of proteins, essential amino acids, carbohydrates, lipids, vitamins, and minerals necessary for nutrition, has made them a fundamental source of sustenance. Spirulina platensis (S. platensis), a single‐celled, filamentous, prokaryotic microalgae, has long been recognized as a valuable natural food source, with historical usage dating back to ancient times. On the other hand, Phaeodactylum tricornutum (P. tricornutum), although a freshwater species, belongs to the Pennateae group of single‐celled eukaryotic diatoms and exhibits adaptability to marine environments. S. platensis and P. tricornutum have recently gained attention due to their abundant bioactive compounds, including carotenoids and phenolic acids. These bioactive compounds are known for their potential health benefits, including anticancer, antioxidant, anti‐inflammatory, neuroprotective, hepatoprotective, and hypocholesterolemic properties. This review examines the bioactive compounds produced by S. platensis and P. tricornutum, their impacts on human health, and their promising applications within the food industry.

Role of SIRT1 in Potentially Toxic Trace Elements (Lead, Fluoride, Aluminum and Cadmium) Associated Neurodevelopmental Toxicity.

The formation of the central nervous system is a meticulously planned and intricate process. Any modification to this process has the potential to disrupt the structure and operation of the brain, which could result in deficiencies in neurological growth. When neurotoxic substances are present during the early stages of development, they can be exceptionally dangerous. Prenatally, the immature brain is extremely vulnerable and is therefore at high risk in pregnant women associated with occupational exposures. Lead, fluoride, aluminum, and cadmium are examples of possibly toxic trace elements that have been identified as an environmental concern in the aetiology of a number of neurological and neurodegenerative illnesses. SIRT1, a member of the sirtuin family has received most attention for its potential neuroprotective properties. SIRT1 is an intriguing therapeutic target since it demonstrates important functions to increase neurogenesis and cellular lifespan by modulating multiple pathways. It promotes axonal extension, neurite growth, and dendritic branching during the development of neurons. Additionally, it contributes to neurogenesis, synaptic plasticity, memory development, and neuroprotection. This review summarizes the possible role of SIRT1 signalling pathway in potentially toxic trace elements -induced neurodevelopmental toxicity, highlighting some molecular pathways such as mitochondrial biogenesis, CREB/BDNF and PGC-1α/NRF1/TFAM.

Effect of prothymosin α on neuroplasticity following cerebral ischemia‑reperfusion injury.

Prothymosin α (ProT), a highly acidic nuclear protein with multiple cellular functions, has shown potential neuroprotective properties attributed to its anti‑necrotic and anti‑apoptotic activities. The present study aimed to investigate the beneficial effect of ProT on neuroplasticity after ischemia‑reperfusion injury and elucidate its underlying mechanism of action. Primary cortical neurons were either treated with ProT or overexpressing ProT by gene transfection and exposed to oxygen‑glucose deprivation for 2h invitro. Immunofluorescence staining for ProT and MAP‑2 was performed to quantify ProT protein expression and assess neuronal arborization. Mice treated with vehicle or ProT (100µg/kg) and ProT overexpression in transgenic mice received middle cerebral artery occlusion for 50min to evaluate the effect of ProT on neuroplasticity‑associated protein following ischemia‑reperfusion injury. The results demonstrated that in cultured neurons ProT significantly increased neurite lengths and the number of branches, accompanied by an upregulation mRNA level of brain‑derived neurotrophic factor. Furthermore, ProT administration improved the protein expressions of synaptosomal‑associated protein, 25kDa and postsynaptic density protein 95 after ischemic‑reperfusion injury invivo. These findings suggested that ProT can potentially induce neuroplasticity effects following ischemia‑reperfusion injury.

Abstract 29: Neuroprotective Potential of Nitroglycerin (GTN) in Ischemic Stroke: Insights Into Glucose Metabolism and ER Stress Inhibition Through NO-CGMP-PKG Signaling

Background: While Nitroglycerin (GTN) is predominantly recognized as a vasodilator for ischemic heart disease, its potential neuroprotective properties in acute ischemic stroke (AIS) remain under exploration. This investigation sought to discover the therapeutic advantages of GTN post-recanalization in AIS and underlying mechanisms. Methods: Adult male Sprague Dawley rats were categorized into sham, MCAO with or without GTN treatment, and MCAO treated with both GTN and KT5823, an inhibitor of cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG). AIS was induced by MCAO for 2 hours followed by 6 or 24 hours of reperfusion (tMCAO). A 28-hour MCAO without reperfusion was defined as the permanent MCAO group (pMCAO). The study assessed infarct volumes, neurological impairments, glucose metabolism metrics (lactate and ROS levels), nitric oxide (NO) and cGMP levels (via ELISA). mRNA and protein expressions of hyperglycolysis (GLUT1, GLUT3, PFK, LDH), gluconeogenesis (PCK1, PCK2), ER stress (BIP, PERK, EIF2α, ATF4, CHOP) as well as signaling molecules (PKG, AMPK), were measured with RT-PCR and Western blotting. Apoptotic cell death was evaluated using TUNEL. Results: GTN significantly reduced cerebral infarct volumes, neurological deficits, apoptotic cell death, lactate and ROS levels and decreased the expression of NO and cGMP levels and key glucose metabolism and ER stress-related genes and proteins, including GLUT1, GLUT3, PFK1, LDH, PCK1, PCK2, BIP, PERK, EIF2α, ATF4, CHOP and phosphorylated AMPK, while boosting PKG expression only in tMCAO. The coadministration of GTN and KT5823 reversed the observed GTN benefits. Conclusion: Our findings illuminate that GTN showcases neuroprotective properties in tMCAO (but not pMCAO) by enhancing glucose metabolism (hyperglycolysis and gluconeogenesis), controlling ER stress, and working through the NO-CGMP-PKG signaling cascade to inhibit AMPK phosphorylation.

Azilsartan Attenuates 3-Nitropropinoic Acid-Induced Neurotoxicity in Rats: The Role of IĸB/NF-ĸB and KEAP1/Nrf2 Signaling Pathways

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by motor, psychiatric and cognitive symptoms. Injection of 3-nitropropionic acid (3-NP) is a widely used experimental model for induction of HD. The current study aimed to inspect the potential neuroprotective properties of azilsartan (Azil), an angiotensin II type 1 receptor blocker (ATR1), in 3-NP-induced striatal neurotoxicity in rats. Rats were randomly allocated into five groups and treated for 14 days as follows: group I received normal saline; group II received Azil (10 mg/kg, p.o.); group III received 3-NP (10 mg/kg, i.p); group IV and V received Azil (5 or 10 mg/kg, p.o, respectively) 1 h prior to 3-NP injection. Both doses of Azil markedly attenuated motor and behavioural dysfunction as well as striatal histopathological alterations caused by 3-NP. In addition, Azil balanced striatal neurotransmitters levels as evidenced by the increase of striatal gamma-aminobutyric acid content and the decrease of glutamate content. Azil also amended neuroinflammation and oxidative stress via modulating IĸB/NF-ĸB and KEAP1/Nrf2 downstream signalling pathways, as well as reducing iNOS and COX2 levels. Moreover, Azil demonstrated an anti-apoptotic activity by reducing caspase-3 level and BAX/BCL2 ratio. In conclusion, the present study reveals the neuroprotective potential of Azil in 3-NP-induced behavioural, histopathological and biochemical changes in rats. These findings might be attributed to inhibition of ATR1/NF-κB signalling, modulation of Nrf2/KEAP1 signalling, anti-inflammatory, anti-oxidant and anti-apoptotic properties.Graphical

Cath-KP, a novel peptide derived from frog skin, prevents oxidative stress damage in a Parkinson's disease model.

Parkinson's disease (PD) is a neurodegenerative condition that results in dyskinesia, with oxidative stress playing a pivotal role in its progression. Antioxidant peptides may thus present therapeutic potential for PD. In this study, a novel cathelicidin peptide (Cath-KP; GCSGRFCNLFNNRRPGRLTLIHRPGGDKRTSTGLIYV) was identified from the skin of the Asiatic painted frog ( Kaloula pulchra). Structural analysis using circular dichroism and homology modeling revealed a unique αββ conformation for Cath-KP. In vitro experiments, including free radical scavenging and ferric-reducing antioxidant analyses, confirmed its antioxidant properties. Using the 1-methyl-4-phenylpyridinium ion (MPP +)-induced dopamine cell line and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, Cath-KP was found to penetrate cells and reach deep brain tissues, resulting in improved MPP +-induced cell viability and reduced oxidative stress-induced damage by promoting antioxidant enzyme expression and alleviating mitochondrial and intracellular reactive oxygen species accumulation through Sirtuin-1 (Sirt1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation. Both focal adhesion kinase (FAK) and p38 were also identified as regulatory elements. In the MPTP-induced PD mice, Cath-KP administration increased the number of tyrosine hydroxylase (TH)-positive neurons, restored TH content, and ameliorated dyskinesia. To the best of our knowledge, this study is the first to report on a cathelicidin peptide demonstrating potent antioxidant and neuroprotective properties in a PD model by targeting oxidative stress. These findings expand the known functions of cathelicidins, and hold promise for the development of therapeutic agents for PD.

Notoginsenoside R1 attenuates brain injury in rats with traumatic brain injury: Possible mediation of apoptosis via ERK1/2 signaling pathway.

Traumatic brain injury (TBI) occurs worldwide and is associated with high mortality and disability rate. Apoptosis induced by TBI is one of the important causes of secondary injury after TBI. Notoginsenoside R1 (NGR1) is the main phytoestrogen extracted from Panax notoginseng. Many studies have shown that NGR1 has potent neuroprotective, anti-inflammatory, and anti-apoptotic properties and is effective in ischemia-reperfusion injury. Therefore, we investigated the potential neuroprotective effects of NGR1 after TBI and explored its molecular mechanism of action. A rat model of TBI was established using the controlled cortical impact (CCI) method. The expression levels of Bcl-2, Bax, caspase 3, and ERK1/2-related molecules in the downstream pathway were also detected by western blotting. The expression levels of pro-inflammatory cytokines were detected by real-time quantitative PCR. Nissl staining was used to clarify the morphological changes around the injury foci in rats after TBI. Fluoro-Jade B (FJB) and terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) fluorescence staining were used to detect the apoptosis of neural cells in each group of rats. The results showed that NGR1 administration reduced neurological deficits after TBI, as well as brain edema and brain tissue apoptosis. It also significantly inhibited the expression of pro-inflammatory cytokines. Furthermore, NGR1 decreased the expression levels of extracellular signal-regulated kinase (ERK) and p-RSK1, which are phosphorylated after trauma. This study suggests that NGR1 can improve neuronal apoptosis in brain injury by inhibiting the ERK signaling pathway. NGR1 is a potential novel neuroprotective agent for the treatment of secondary brain injury after TBI.

Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders.

Metformin, a widely prescribed medication for type 2 diabetes, has garnered increasing attention for its potential neuroprotective properties due to the growing demand for treatments for Alzheimer's, Parkinson's, and motor neuron diseases. This review synthesizes experimental and clinical studies on metformin's mechanisms of action and potential therapeutic benefits for neurodegenerative disorders. A comprehensive search of electronic databases, including PubMed, MEDLINE, Embase, and Cochrane library, focused on key phrases such as "metformin", "neuroprotection", and "neurodegenerative diseases", with data up to September 2023. Recent research on metformin's glucoregulatory mechanisms reveals new molecular targets, including the activation of the LKB1-AMPK signaling pathway, which is crucial for chronic administration of metformin. The pleiotropic impact may involve other stress kinases that are acutely activated. The precise role of respiratory chain complexes (I and IV), of the mitochondrial targets, or of the lysosomes in metformin effects remains to be established by further research. Research on extrahepatic targets like the gut and microbiota, as well as its antioxidant and immunomodulatory properties, is crucial for understanding neurodegenerative disorders. Experimental data on animal models shows promising results, but clinical studies are inconclusive. Understanding the molecular targets and mechanisms of its effects could help design clinical trials to explore and, hopefully, prove its therapeutic effects in neurodegenerative conditions.

An Appraisal of the Oleocanthal-Rich Extra Virgin Olive Oil (EVOO) and Its Potential Anticancer and Neuroprotective Properties.

Dietary consumption of olive oil represents a key pillar of the Mediterranean diet, which has been shown to exert beneficial effects on human health, such as the prevention of chronic non-communicable diseases like cancers and neurodegenerative diseases, among others. These health benefits are partly mediated by the high-quality extra virgin olive oil (EVOO), which is produced mostly in Mediterranean countries and is directly made from olives, the fruit of the olive tree (Olea europaea L.). Preclinical evidence supports the existence of antioxidant and anti-inflammatory properties exerted by the polyphenol oleocanthal, which belongs to the EVOO minor polar compound subclass of secoiridoids (like oleuropein). This narrative review aims to describe the antioxidant and anti-inflammatory properties of oleocanthal, as well as the potential anticancer and neuroprotective actions of this polyphenol. Based on recent evidence, we also discuss the reasons underlying the need to include the concentrations of oleocanthal and other polyphenols in the EVOO's nutrition facts label. Finally, we report our personal experience in the production of a certified organic EVOO with a "Protected Designation of Origin" (PDO), which was obtained from olives of three different cultivars (Rotondella, Frantoio, and Leccino) harvested in geographical areas located a short distance from one another (villages' names: Gorga and Camella) within the Southern Italy "Cilento, Vallo di Diano and Alburni National Park" of the Campania Region (Province of Salerno, Italy).