Good Blood-brain Barrier Permeability Research Articles

Discovery of novel cholinesterase inhibitors easily crossing the blood-brain barrier via structure-property relationship investigation: Methylenedioxy-cinnamicamides containing tertiary amine side chain.

In the present investigation, a series of dimethoxy or methylenedioxy substituted-cinnamamide derivatives containing tertiary amine moiety (N. N-Dimethyl, N, N-diethyl, Pyrrolidine, Piperidine, Morpholine) were synthesized and evaluated for cholinesterase inhibition and blood-brain barrier (BBB) permeability. Although their chemical structures are similar, their biological activities exhibit diversity. The results showed that all compounds except for those containing morpholine group exhibited moderate to potent acetylcholinesterase inhibition. Preliminary screening of BBB permeability shows that methylenedioxy substituted compounds have better brain permeability than the others. Compound 10c, containing methylenedioxy and pyrrolidine side chain, showed a better acetylcholinesterase inhibition (IC50: 1.52±0.19 μmol/L) and good blood-brain barrier permeability. Further pharmacokinetic investigation of compound 10c using ultra high performance liquid chromatography-mass/mass spectrometry (UPLC-MS/MS) in mice showed that compound 10c in brain tissue reached its peak concentration (857.72 ± 93.56 ng/g) after dosing 30 min. Its half-life in the serum is 331 min (5.52 h), and the CBrain/CSerum at various sampling points is ranged from 1.65 to 4.71(Mean: 2.76) within 24 hours. This investigation provides valuable information on the chemistry and pharmacological diversity of cinnamic acid derivatives and may be beneficial for the discovery of central nervous system drugs.

Brain-Permeable Immunoproteasome-Targeting Macrocyclic Peptide Epoxyketones for Alzheimer's Disease.

Previously, we demonstrated that linear peptide epoxyketones targeting the immunoproteasome (iP) could ameliorate cognitive deficits in mouse models of Alzheimer's disease (AD) independently of amyloid deposition. We also reported the first iP-targeting macrocyclic peptide epoxyketones, which exhibit improved metabolic stability compared with their linear counterparts. Here, we prepared additional macrocyclic peptide epoxyketones and compared them with existing macrocyclic iP inhibitors by assessing Caco2 cell-based permeability and microsomal stability, providing the four best macrocyclic iP inhibitors. We then evaluated the four compounds using the Ames test and the potency assays in BV2 cells, selecting compound 5 as our AD drug lead. When 5 was administered intravenously (40 mg/kg) or orally (150 mg/kg) into healthy BALB/c mice, we observed considerable iP inhibition in the mouse brain, indicating good blood-brain barrier permeability and target engagement. Combined results suggest that 5 is a promising AD drug lead that may need further investigation.

Discovery of novel melatonin-mydroxyquinoline hybrids as multitarget strategies for Alzheimer's disease therapy.

Alzheimer's disease (AD) is a neurodegenerative disease that seriously affects human health, and current treatment strategies are far from meeting clinical needs. Inspired by multi-target drug design strategies, a series of novel natural products-based melatonin-hydroxyquinoline hybrids were designed and synthesized, targeting anti-oxidation and metal-chelating at the same time. Most of the compounds showed significant oxygen radical absorbance capacity and Aβ1-42 aggregation inhibition. Moreover, the compounds possess good blood-brain barrier permeability. 6b and 6c have a good ability to alleviate oxidative stress induced by hydrogen peroxide. 6b and 6c possess metal-chelating properties with the chelation ratio being 2:1. Furthermore, 6b can significantly mitigate metal-induced Aβ aggregation. This work may provide a new multi-target treatment strategy for Alzheimer's disease.

High-throughput discovery of highly selective reversible hMAO-B inhibitors based on at-line nanofractionation

Human monoamine oxidase B (hMAO-B) has emerged as a pivotal therapeutic target for Parkinson's disease. Due to adverse effects and shortage of commercial drugs, there is a need for novel, highly selective, and reversible hMAO-B inhibitors with good blood-brain barrier permeability. In this study, a high-throughput at-line nanofractionation screening platform was established with extracts from Chuanxiong Rhizoma, which resulted in the discovery of 75 active compounds, including phenolic acids, volatile oils, and phthalides, two of which were highly selective novel natural phthalide hMAO-B inhibitors that were potent, selective, reversible and had good blood‒brain permeability. Molecular docking and molecular dynamics simulations elucidated the inhibition mechanism. Sedanolide (IC50 = 103 nmol/L; SI = 645) and neocnidilide (IC50 = 131 nmol/L; SI = 207) demonstrated their excellent potential as hMAO-B inhibitors. They offset the limitations of deactivating enzymes associated with irreversible hMAO-B inhibitors such as rasagiline. In SH-SY5Y cell assays, sedanolide (EC50 = 0.962 μmol/L) and neocnidilide (EC50 = 1.161 μmol/L) exhibited significant neuroprotective effects, comparable to the positive drugs rasagiline (EC50 = 0.896 μmol/L) and safinamide (EC50 = 1.079 μmol/L). These findings underscore the potential of sedanolide as a novel natural hMAO-B inhibitor that warrants further development as a promising drug candidate.

EIF4A3 targeted therapeutic intervention in glioblastoma multiforme using phytochemicals from Indian medicinal plants – an integration of phytotherapy into precision onco-medicine

Glioblastoma Multiforme (GBM), an aggressive brain tumor (grade-IV astrocytoma), poses treatment challenges. Poor prognosis results from the rapid growth, highlighting the role of EIF4A3 in regulating non-coding RNAs. EIF4A3 promotes the expression of several non-coding RNAs, viz, Circ matrix metallopeptidase 9 (MMP9), a prominent oncogene, by interacting with the upstream region of the circMMP9 mRNA transcript and acts on cell proliferation, migration, and invasion of GBM. However, research shows that EIF4A3 knockdown inhibits glioblastoma progression and increases apoptosis. In this study, we explored the efficiency of the phytochemicals from plants like Withania somnifera and Castanea sativa with potential anti-glioblastoma effects as obtained from the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT) database. Consequently, we have performed a virtual screening of the compounds against the protein EIF4A3. We further investigated the efficiency of the shortlisted compounds based on docking scores evaluated using GOLD, AutoDock4.2, LeDock, and binding free energy analyses using Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA). Among the phytochemicals studied so far, several Withania-specific compounds from Withania somnifera and a single dietary compound, viz., Thiamine from Castanea sativa, have exhibited comparatively good blood-brain barrier permeability, significant binding affinity towards the EIF4A3, and good ADMET properties. Furthermore, we have verified the interaction stability of the lead molecules with EIF4A3 using MD simulations. Thus, the present study offers an opportunity to develop drug candidates targeting glioblastoma caused by EIF4A3 over-expression, integrating phytotherapy into precision oncology to create tailored and precise natural treatment strategies for cancer. Communicated by Ramaswamy H. Sarma

Design, synthesis, and biological evaluation of novel capsaicin-tacrine hybrids as multi-target agents for the treatment of Alzheimer's disease

A series of novel hybrid compounds were designed, synthesized, and utilized as multi-target drugs to treat Alzheimer's disease (AD) by connecting capsaicin and tacrine moieties. The biological assays indicated that most of these compounds demonstrated strong inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities with IC50 values in the nanomolar, as well as good blood–brain barrier permeability. Among the synthesized hybrids, compound 5s displayed the most balanced inhibitory effect on hAChE (IC50 = 69.8 nM) and hBuChE (IC50 = 68.0 nM), and exhibited promising inhibitory activity against β-secretase-1 (BACE-1) (IC50 = 3.6 µM). Combining inhibition kinetics and molecular model analysis, compound 5s was shown to be a mixed inhibitor affecting both the catalytic active site (CAS) and peripheral anionic site (PAS) of hAChE. Additionally, compound 5s showed low toxicity in PC12 and BV2 cell assays. Moreover, compound 5s demonstrated good tolerance at the dose of up to 2500 mg/kg and exhibited no hepatotoxicity at the dose of 3 mg/kg in mice, and it could effectively improve memory ability in mice. Taken together, these findings suggest that compound 5s is a promising and effective multi-target agent for the potential treatment of AD.

Discovery of novel harmine derivatives as GSK-3β/DYRK1A dual inhibitors for Alzheimer's disease treatment.

Multitarget-directed ligands (MTDLs) have recently attracted significant interest due to their superior effectiveness in multifactorial Alzheimer's disease (AD). Combined inhibition of two important AD targets, glycogen synthase kinase-3β (GSK-3β) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), may be a breakthrough in the treatment of AD. Based on our previous work, we have designed and synthesized a series of novel harmine derivatives, investigated their inhibition of GSK-3β and DYRK1A, and evaluated a variety of biological activities. The results of the experiments showed that most of these compounds exhibited good activity against GSK-3β and DYRK1A in vitro. ZLQH-5 was selected as the best compound due to the most potent inhibitory effect against GSK-3β and DYRK1A. Molecular docking studies demonstrated that ZLQH-5 could form stable interactions with the ATP binding pocket of GSK-3β and DYRK1A. In addition, ZLQH-5 showed low cytotoxicity against SH-SY5Y and HL-7702, good blood-brainbarrierpermeability, and favorable pharmacokinetic properties. More importantly, ZLQH-5 also attenuated the tau hyperphosphorylation in the okadaic acidSH-SY5Y cell model. These results indicated that ZLQH-5 could be a promising dual-target drug candidate for the treatment of AD.

BH4 as a Therapeutic Target for ADHD: Relevance to Neurotransmitters and Stress-Driven Symptoms

Tetrahydrobiopterin (BH4) is a critical cofactor in a variety of metabolic pathways that have been linked to ADHD. There have been no previous studies utilizing BH4 as a supplement for ADHD. BH4 has been approved as a treatment for phenylketonuria (PKU). Individuals with PKU and ADHD appear to have low DA levels in common, suggesting that the hypodopaminergic state seen in both illnesses could be a relationship between the two. Clinical research involving supplementation of BH4 has shown low occurrence of adverse. In experiments, BH4 has also been found to have good blood-brain barrier permeability. BH4 also has the ability in scavenging ROS activity, which is an implication of stress and is seen in ADHD. BH4’s significance in ADHD is reviewed in this paper because of its involvement in numerous neurodevelopmental metabolic pathways, and we anticipate that exogenous BH4 can be used to treat ADHD.

Neurological potency of native plants from sub-Himalayan West Bengal through reverse pharmacology

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy, pose a growing global health challenge due to an aging population. These conditions share common processes, including protein accumulation, oxidative stress, and neuro-inflammation, making their treatment complex and costly. Network pharmacology, an innovative approach integrating systems biology and computational biology, offers insights into multi-target formulations and the repurposing of existing medications for neurodegenerative diseases. We shortlisted 730 bioactive compounds from 25 traditional Himalayan plants, assessed their drug-like properties using ADME criteria, and predicted their potential target proteins through reverse docking and pharmacophore mapping. Our study identified 287 compounds with high gastrointestinal absorption and good blood-brain barrier permeability. These compounds were subjected to target prediction, yielding a list of 171 potential target proteins. Functional annotation and pathway enrichment analysis highlighted their involvement in steroid hormone-related pathways, MAPK signaling, FOXO signaling, TNF signaling, VEGF signaling, and neurotrophin signaling. Importantly, one plant, Valeriana jatamansi, exhibited an association with beta-amyloid binding activity, a potential therapeutic approach for AD. From our study we could understand how these plants modulate our body to manage these diseases. However, further in vitro and in vivo validation is needed before commercial and public use of this data.

Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit β-amyloid self-aggregation: potential therapeutic agents for Alzheimer's disease.

We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of β-amyloid (Aβ42) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC50 = 2.90 ± 0.23µM and 3.22 ± 0.25µM, respectively). Only one acridine, 2d, an analog of dihydroacridine, 1d, was an effective BChE inhibitor (IC50 = 6.90 ± 0.55μM), consistent with docking results. Dihydroacridines inhibited Aβ42 self-aggregation; 1d and 1e were the most active (58.9% ± 4.7% and 46.9% ± 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTS•+-scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood-brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and Aβ42 self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations.

Discovery of triazole-bridged aryl adamantane analogs as an intriguing class of multifunctional agents for treatment of Alzheimer's disease

Alzheimer's disease (AD) is a progressive brain disorder associated with slow loss of brain functions leading to memory failure and modest changes in behavior. The multifactorial neuropathological condition is due to a depletion of cholinergic neurons and accumulation of amyloid-beta (Aβ) plaques. Recently, a multi-target-directed ligand (MTDL) strategy has emerged as a robust drug discovery tool to overcome current challenges. In this research work, we aimed to design and develop a library of triazole-bridged aryl adamantane analogs for the treatment of AD. All synthesized analogs were characterized and evaluated through various in vitro and in vivo biological studies. The optimal compounds 32 and 33 exhibited potent inhibitory activities against acetylcholinesterase (AChE) (32 - IC50 = 0.086 μM; 33 - 0.135 μM), and significant Aβ aggregation inhibition (20 μM). N-methyl-d-aspartate (NMDA) receptor (GluN1-1b/GluN2B subunit combination) antagonistic activity of compounds 32 and 33 measured upon heterologous expression in Xenopus laevis oocytes showed IC50 values of 3.00 μM and 2.86 μM, respectively. The compounds possessed good blood-brain barrier permeability in the PAMPA assay and were safe for SH-SY5Y neuroblastoma (10 μM) and HEK-293 cell lines (30 μM). Furthermore, in vivo behavioral studies in rats demonstrated that both compounds improved cognitive and spatial memory impairment at a dose of 10 mg/kg oral administration. Together, our findings suggest triazole-bridged aryl adamantane as a promising new scaffold for the development of anti-Alzheimer's drugs.

MDB-45. SELECTIVE B7-H3 INHIBITORS NI1 AND NI4 REDUCE AGGRESSIVENESS OF GROUP 3 MEDULLOBLASTOMA

Abstract Medulloblastoma (MB) is a primary childhood malignancy of the central nervous system (CNS). Clinically heterogenous MB are sub-grouped into four molecular subgroups, i.e. Wingless (WNT), Sonic Hedgehog (SHH), Group 3, and Group 4. Among all, Group 3 MB (G3MB) is known to be the most aggressive form, with less than 50% five-year survival. G3MB are associated with large-cell/anaplastic (LCA) histology, distinctive methylation profile, amplification of MYC, and isochromosome 17q (i17q). Targeting these high-risk molecular features unique to G3MB has been challenging, necessitating alternative approaches to therapy for G3-MB. One innovative approach is immunotherapy, which is largely impeded by inhibitory immune checkpoints. B7 homolog 3 (B7-H3/CD276), an immunosuppressive immune checkpoint protein and member of B7 superfamily, is significantly enriched in pediatric malignancies of CNS including G3MB. The enhanced expression of B7-H3/CD276 has been associated with aggressive and metastatic potential. B7-H3/CD276 is also a primary target of miR-1253, a novel tumor suppressor gene silenced in G3MB. Using a structure-based drug discovery pipeline, we screened the ChemBridge library of compounds to discover selective B7-H3 small-molecule inhibitors. Selective B7-H3 inhibitors Ni1 and Ni4 exhibited strong binding scores, CNS penetrance, and oral bioavailability. In vitro, both compounds had appreciably low IC50 values of 3µM (Ni1) and 0.75µM (Ni4). Further, both compounds inhibited wound healing and colony formation. Ni1 shifted the thermostability of B7-H3, suggesting in vitro biding. Ni1 has also undergone PK/PD and MTD studies in vivo, showing stability in serum, good blood-brain barrier permeability, and a half-life of 8 hours. We are now elucidating B7-H3-activated downstream signaling through JAK2/STAT3 signaling and testing the in vivo efficacy for Ni1 against G3MB tumors in a murine model.

Senkyunolide I: A Review of Its Phytochemistry, Pharmacology, Pharmacokinetics, and Drug-Likeness.

Senkyunolide I (SI) is a natural phthalide that has drawn increasing interest for its potential as a cardio-cerebral vascular drug candidate. In this paper, the botanical sources, phytochemical characteristics, chemical and biological transformations, pharmacological and pharmacokinetic properties, and drug-likeness of SI are reviewed through a comprehensive literature survey, in order to provide support for its further research and applications. In general, SI is mainly distributed in Umbelliferae plants, and it is relatively stable to heat, acid, and oxygen, with good blood-brain barrier (BBB) permeability. Substantial studies have established reliable methods for the isolation, purification, and content determination of SI. Its pharmacological effects include analgesic, anti-inflammatory, antioxidant, anti-thrombotic, anti-tumor effects, alleviating ischemia-reperfusion injury, etc. Pharmacokinetic parameters indicate that its metabolic pathway is mainly phase Ⅱ metabolism, and it is rapidly absorbed in vivo and widely distributed in the kidneys, liver, and lungs.

Development of sertraline analogues as potential anti-ischemic stroke agents

Ischemic stroke (IS) is harmful to human health and social development, and there is no medicine available at present. To find the hit compound for treating ischemic stroke, we screened 28 FDA approved nervous system drugs by using an in vitro OGD-induced stroke model. Notably, our in vitro and in vivo studies demonstrated that low-dose sertraline had good neuroprotective activities, while high-dose sertraline showed significant toxicity. Interestingly, the same high-dose sertraline in the control group did not exhibit any obvious toxic effect. Therefore, it is important to modify the structure of sertraline to improve the activity and reduce the toxicity. Stereoisomers of sertraline were first investigated to analyze the influence of stereochemistry on the neuroprotective activities, which showed no obvious difference. Then we evaluated the activity of our previously reported sertraline analogues and found that introducing amide or alkane groups to the amino moiety might be beneficial to enhance the activity and reduce the toxicity. Thus, 10 new analogues were designed, synthesized, and evaluated. Among them, compound OY-201 showed the best safety and neuroprotective activity in both in vitro and in vivo models. Moreover, it exhibited good blood-brain barrier (BBB) permeability, indicating its potential for the development of anti-ischemic stroke drugs.

Molecular docking analysis and dynamics simulation of ethanol extract of Citrus sinensis as a Keap1 and NMDA inhibitor in brain injury

Traumatic brain injury is a significant cause of mortality in young adults and disability in all age groups. This is followed by secondary injury involving various processes, such as oxidative stress which induce neuronal apoptosis. The present study aimed to analyze the active compounds of <em>Citrus sinensis</em> and predict its antioxidative activity in traumatic brain injury. Liquid chromatography/high resolution mass spectrometry (LC/HRMS) was used to identify compounds in the ethanol extract of <em>Citrus sinensis</em> peel. We analyzed pharmacokinetics, blood‑brain barrier (BBB) permeability and the toxicity of active compounds in <em>Citrus sinensis</em> peel using SwissADME and OSIRIS. The compounds with a good BBB permeability were subjected to molecular docking analysis to identify the molecular interaction with Kelch‑like ECH associated protein 1 (Keap1) and N‑methyl‑D‑aspartate (NMDA) proteins using PyRx, PyMol and Discovery Studio software. The results of the LC/HRMS analysis revealed 16 active compounds contained in the ethanol extract of the orange peel. Nootkatone, alminoprofen, linoleic acid, chanoclavine, scoparone and tangeretin were predicted to pass the BBB. The active compounds of <em>Citrus sinensis</em> strongly bound against Keap1 and NMDA, particularly scoparone and nootkatone. The strong binding affinity of scoparone‑Keap1 was ‑5.0, more than that of the control ligand, and that of nootkatone‑NMDA was ‑7.8, similar to the control ligand. The active compounds of <em>Citrus sinensis</em> peel exhibited inhibitory potential, good pharmacokinetics and toxicity profiles against Keap1 and NMDA. On the whole, these findings suggest that ethanol extract of Citrus sinensis peel has potential for use as an oxidative stress inhibitor in the treatment of brain injury.

Design of a Coumarin-Based Fluorescent Probe for Efficient In Vivo Imaging of Amyloid-β Plaques.

Amyloid-β (Aβ) is the core constituent protein of senile plaques, which is one of the key pathological hallmarks of Alzheimer's disease (AD). Here we describe the design, synthesis, and evaluation of coumarin-derived small molecule fluorophores for Aβ imaging. By embedding the aromatic coumarin framework into π bridge of a push-pull chromophore, a novel fluorescence probe XCYC-3 applicable to efficient Aβ recognition was discovered. XCYC-3 displays higher fluorescent enhancement for aggregated Aβ than monomeric Aβ, and possesses good blood-brain barrier permeability. In vitro staining and in vivo imaging studies demonstrated that XCYC-3 could efficiently recognize Aβ plaques in the brain of AD transgenic mice. These results suggest that XCYC-3 is a promising fluorescence imaging agent for Aβ, which might provide important clues for the future development of potent NIR fluorescent probes for Aβ diagnosis.

Novel 2,6-disubstituted benzofuran-3-one analogues improve cerebral ischemia/reperfusion injury via neuroprotective and antioxidative effects

There are no highly effective and safe medicines for clinical treatment of ischemic stroke, although the natural product 3-n-butylphthalide (NBP) has been approved in China for mild and moderate ischemic stroke. To discover more potent anti-cerebral ischemic agents and overcome the low stability by phthalide derivatives, benzofuran-3-one was selected as a core moiety and two types of nitric oxide (NO)-donating groups were incorporated into the structure. In this work, a series of 2,6-disubstituted benzofuran-3-one derivatives were designed and synthesised as NBP analogues, and tested as neuroprotective and antioxidative agents. Compounds 5 (without an NO donor) and 16 (with an NO donor) displayed more potent neuroprotective effects than the established clinical drugs Edaravone and NBP. More importantly, 5 and 16 also exhibited good antioxidative activity without cytotoxicity in rat primary neuronal and PC12 cells. Most active compounds showed good blood–brain barrier permeability in a parallel artificial membrane permeability assay. Furthermore, compound 5 reduced the ischemic infarct area significantly in rats subjected to ischemia/reperfusion injury, downregulated ionised calcium-binding adaptor molecule 1 and glial fibrillary acidic protein in inflammatory cells, and upregulated nerve growth factor.

Effects of long-term Ailanthus altissima extract supplementation on fear, cognition and brain antioxidant levels

IntroductionAilanthus altissima is an indigenous plant known for various remedial properties. The present study aimed to evaluate the neuroprotective potential of methanolic extract Ailanthus altissima (AA) bark as current scientific trend is searching plant for neurodegenerative diseases, worldwide. MethodologyIn in-vitro experiments, the AA was analyzed for phenols, flavonoids, antioxidative and cholinesterase inhibitory properties with subsequent detailed characterization for secondary metabolites. The in-vivo neurological effects were evaluated in rats through behavioral assessment for anxiety and memory after chronic administration (28 days) of 50–200 mg/kg of AA. At the end of behavior studies, isolated brains were biochemically tested to determine antioxidant enzyme activity. ResultsAA was found rich in phenols/flavonoids and active in radical scavenging with the presence of 13 secondary metabolites in UHPLC-MS analysis. The AA yielded anxiolytic effects dose-dependently in the open field, light/dark and elevated-plus maze tests as animals significantly (P < 0.05 vs control group) preferred open arena, illuminated zone and exposed arms of maze. Similarly, the animals treated with AA showed significant (P < 0.05 vs amnesic group) increase in spontaneous alternation, discrimination index in y-maze, novel object recognition tests. Further, AA.Cr treated rats showed noticeably shorter escape latencies in Morris water maze tests.In biochemical analysis, the dissected brains AA treated rats showed reduced levels of AChE and malondialdehyde with increased levels of first-line antioxidant enzymes i.e. glutathione peroxidase and superoxide dismutase. These observed biological effects might be attributed to phenols and flavonoids constituents owned by AA. -The in-silico studies showed thatconessine and lophirone J phytocompounds have good blood–brain barrier permeability and interaction with AChE. ConclusionThe outcomes of this study validate that bark of Ailanthus altissima might work as a source of bioactive phytochemicals of neuroprotective potential.

TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway.

Background: Cerebral ischemia-reperfusion injury (CIRI) inevitably occurs after vascular recanalization treatment for ischemic stroke. The accompanying inflammatory cascades have a major impact on outcome and regeneration after ischemic stroke. Evidences have demonstrated that TLR/MyD88/NF-κB signaling contributes to CIRI. This study aimed to investigate the druggability of MyD88 in the central nervous system (CNS) and the neuroprotective and anti-neuroinflammatory effects of the MyD88 inhibitor TJ-M2010-5 on CIRI. Methods: A middle cerebral artery occlusion (MCAO) model was used to simulate CIRI in mice. BV-2 cells were stimulated with oxygen glucose deprivation/reoxygenation (OGD/R) or lipopolysaccharide, and SH-SY5Y cells were induced by OGD/R in vitro. Neurological deficit scores and cerebral infarction volumes were evaluated. Immunofluorescence staining was performed to measure neuronal damage and apoptosis in the brain. The anti-neuroinflammatory effect of TJ-M2010-5 was evaluated by analyzing the expression of inflammatory cytokines, activation of microglia, and infiltration of peripheral myeloid cells. The expression of proteins of the MyD88/NF-κB and ERK pathway was detected by Simple Western. The concentrations of TJ-M2010-5 in the blood and brain were analyzed by liquid chromatography-mass spectrometry. Results: The cerebral infarction volume decreased in mice treated with TJ-M2010-5, with the most prominent decrease being approximately 80% of the original infarction volume. Neuronal loss and apoptosis were reduced following TJ-M2010-5 treatment. TJ-M2010-5 inhibited the infiltration of peripheral myeloid cells and the activation of microglia. TJ-M2010-5 also downregulated the expression of inflammatory cytokines and inhibited the MyD88/NF-κB and ERK pathway. Furthermore, TJ-M2010-5 showed good blood-brain barrier permeability and no neurotoxicity. Conclusion: TJ-M2010-5 has an excellent therapeutic effect on CIRI as a novel CNS drug candidate by inhibiting excessive neuroinflammatory responses.

Molecular dynamics simulations of a central nervous system-penetrant drug AZD3759 with lipid bilayer.

AZD3759 is an epidermal growth factor receptor inhibitor with good blood-brain barrier permeability, demonstrating encouraging activity against central nervous system metastases. However, the underlying mechanism was still unclear. In this study, the interaction between AZD3759 and membrane was studied with 1,2-dimyristoyl-sn-glycero-3-phosphocholine bilayer as a model lipid. Both the cationic and neutral state of AZD3759 were considered in the simulations, and the results show that cationic AZD3759 forms more hydrogen bonds with bilayer than neutral AZD3759, and Coulombic interaction has great effects in the transmembrane process of cationic AZD3759. AZD3759 prefers to reside in the interface between the hydrophilic headgroup region and hydrophobic region of bilayer, and the chloroflurobenzene moiety plays a crucial role in the insertion of AZD3759. PMF results suggest that the hydrophobic region of DMPC bilayer is permeable by AZD3759. Understanding the transmembrane mechanism of AZD3759 at molecular level may provide useful information to the design and optimization of anti-tumor drugs with improved BBB penetration. • The penetration mechanism of AZD3759 with DMPC bilayer was studied by molecular dynamics simulations. • Neutral AZD3759 could penetrate deeper into DMPC bilayer than protonated AZD3759. • The chloroflurobenzene moiety plays a significant role in the insertion of AZD3759 into DMPC bilayer. • The electrostatic interaction is the driving force for the initial binding of AZD3759 to DMPC bilayer. • Our findings may enhance the mechanism understanding of drugs with good BBB permeability.