Treatment Of CNS Diseases Research Articles

Homology modeling and molecular docking study of metabotropic glutamate receptor 5 variant F: an attempt to develop drugs for treating CNS diseases

Abstract G protein-coupled receptors (GPCRs) constitute the largest protein family involved in signal transduction and are the main targets for drug delivery. The metabotropic glutamate receptors (mGluRs) are class C of GPCRs that contribute to the modulation of glutamatergic neurotransmission which regulates vital physiological processes and is recognized as a potential therapeutic target throughout the central nervous system. Intracellular C-terminal domains of mGluR are the main targets for proteins regulating these receptors and are also involved in alternative splicing, regulation by phosphorylation, and modulatory protein-protein interactions. Class C of GPCRs exist as dimers and is mediated by interactions between the venus tryflap domain and the transmembrane domain. The mGluR5 variant F can be regulated by both positive and negative allosteric modulators that can potentiate or inhibit the endogenous ligand and glutamate, respectively. Moreover, mGluR5 is involved in many disorders including fragile X syndrome/autism spectrum disorder, schizophrenia, anxiety, addiction, chronic pain and epilepsy, etc. The main purpose of current computational work is to determine the 3D structures of the target protein and their active sites to design new drug molecules as potential biochemical agents. The 3D model of the mGluR5 variant F was constructed through homology modeling techniques using MOE and I-TESSER programs. RAMPAGE and ERRATE online servers were used for the 3D structure evaluation and validation. Furthermore, the mGluR5 variant F was docked with 20 mavoglurant derivatives that act as antagonists. Mavoglurant derivatives 3, 4, 6, 10, 13, 18, and 19 showed a maximum of four interactions with the mGluR5 variant F, whereas derivatives 7, 8, 9, 11, 12, 15, 16, 17 and 20 showed a maximum of three interactions with the mGluR5 variant F. The remaining four mavoglurant derivatives expressed two interactions each with mGluR5 variant F. The docking score for these derivatives ranged between −15.55 and −08.210 kcal mol−1 suggesting their strong interactions with the mGluR5 variant F. Their 3D structure and docking study provides a potential base for the synthesis of new drug candidates to treat brain disorders.

BBB opening by low pulsed electric fields, depicted by delayed-contrast MRI, enables efficient delivery of therapeutic doxorubicin doses into mice brains

BackgroundPharmacological treatment of CNS diseases is limited due to the presence of the blood-brain barrier (BBB). Recent years showed significant advancement in the field of CNS drug delivery enablers, with technologies such as MR-guided focused ultrasound reaching clinical trials. This have inspired researchers in the field to invent novel brain barriers opening (BBo) technologies that are required to be simple, fast, safe and efficient. One such technology, recently developed by us, is BDF (Barrier Disrupting Fields), based on low pulsed electric fields (L-PEFs) for opening the BBB in a controlled, safe, reversible and non-invasive manner. Here, we conducted an in vivo study to show that BDF is a feasible technology for delivering Doxorubicin (Doxo) into mice brain. Means for depicting BBBo levels were developed and applied for monitoring the treatment and predicting response. Overall, the goals of the presented study were to demonstrate the feasibility for delivering therapeutic Doxo doses into naïve and tumor-bearing mice brains and applying delayed–contrast MRI (DCM) for monitoring the levels of BBBo.MethodsL-PEFs were applied using plate electrodes placed on the intact skull of naïve mice. L-PEFs/Sham mice were scanned immediately after the procedure by DCM (“MRI experiment”), or injected with Doxo and Trypan blue followed by delayed (4 h) perfusion and brain extraction (“Doxo experiment”). Doxo concentrations were measured in brain samples using confocal microscopy and compared to IC50 of Doxo in glioma cell lines in vitro. In order to map BBBo extent throughout the brain, pixel by pixel MR image analysis was performed using the DCM data. Finally, the efficacy of L-PEFs in combination with Doxo was tested in nude mice bearing intracranial human glioma tumors.ResultsSignificant amount of Doxo was found in cortical regions of all L-PEFs-treated mice brains (0.50 ± 0.06 µg Doxo/gr brain) while in Sham brains, Doxo concentrations were below or on the verge of detection limit (0.03 ± 0.02 µg Doxo/gr brain). This concentration was x97 higher than IC50 of Doxo calculated in gl261 mouse glioma cells and x8 higher than IC50 of Doxo calculated in U87 human glioma cells. DCM analysis revealed significant BBBo levels in the cortical regions of L-PEFs-treated mice; the average volume of BBBo in the L-PEFs-treated mice was x29 higher than in the Sham group. The calculated BBBo levels dropped exponentially as a function of BBBo threshold, similarly to the electric fields distribution in the brain. Finally, combining non-invasive L-PEFs with Doxo significantly decreased brain tumors growth rates in nude mice.ConclusionsOur results demonstrate significant BBBo levels induced by extra-cranial L-PEFs, enabling efficient delivery of therapeutic Doxo doses into the brain and reducing tumor growth. As BBBo was undetectable by standard contrast-enhanced MRI, DCM was applied to generate maps depicting the BBBo levels throughout the brain. These findings suggest that BDF is a promising technology for efficient drug delivery into the brain with important implications for future treatment of brain cancer and additional CNS diseases.

Design of prodrug for stereoisomers of omapatrilat to cross the blood-brain barrier using docking, homology modeling, MD, and QM/MM methods

In this study, we designed a suitable ester prodrug for omapatrilat to penetrate the blood-brain barrier and treat CNS diseases. Based on the ADMET properties, the methyl carboxylate ester of omapatrilat was chosen from among several prodrug structures. Sixteen methyl carboxylate esters were constructed for omapatrilat. The structure of brain carboxylesterase was derived via homology modeling, and molecular docking was used to determine the most potent stereoisomers against brain carboxylesterase. The top three stereoisomer complexes, and the apo form of the protein, were then considered using molecular dynamics simulation and MM/GBSA analysis. Following the simulation, structural analysis was performed using RMSD, RMSF, Rg , and hydrogen bond analysis tools. Our data demonstrated that the prodrug of RSSR is a suitable structure for crossing the blood-brain barrier and binding to brain carboxylesterase. In addition, we found via QM/MM calculation that the catalytic reaction of the prodrug of RSSR against brain carboxylesterase occurs via two steps, including acylation and diacylation steps. Based on our findings, we propose a clinical trial of a methyl carboxylate ester prodrug of omapatrilat’s RSSR for the treatment of brain diseases. Communicated by Ramaswamy H. Sarma

BRAIN CHOLECYSTOKININ SYSTEM IN NEUROTIC PATHOLOGY

Violation and discoordination of mental processes leads to changes in the ratio of the main neurotransmitters content and further to mental disorders. A significant role in such processes is played by neuropeptides, in particular anti-anxiety ones, which include cholecystokinin (CCK) and its receptors. It has been established that stimulation of CCK receptors modulates the mesolimbic system of reward, anxiety and satiety. CCK-1 (the intestine) and CCK-2 type receptors (the CNS and stomach) are isolated. In the central nervous system, the short O-sulfated form of CCK-8 and the non-sulfated form of CCK-5 predominate. It was shown that the effect of CCK on the corresponding receptors inhibits GABA-ergic receptors in the subcortical nuclei, which mediates the transmission of nerve signals from the endocannabinoid system. A significant number of CCK receptors, their agonists and antagonists were found in the body. Potentially, blockers of these receptors can be combined with other agents for the treatment of CNS diseases. In CCK, it was shown an anxiogenic effect, which was realized through the influence of a selective CCK-2 receptors agonist. There is information that CCK-4 causes anxiogenic effects due to its influence on other neurotransmitters, in particular, due to neuromodulation of the dopaminergic system, and can interact with other neurotransmission systems. In behavioral tests, the anxiolytic effect of CCK-2 receptor blockers is shown. The participation of this system in the pathogenesis of anxiety is confirmed by the influence of non-selective agonists of CCK receptors and agonists of CCK-2 receptors in the "elevated cross-shaped maze" test. At the same time, CCK-2 receptor blockers reduced anxiety in this test. In clinical studies, they suppressed panic when administered as a bolus. However, the problem of bioavailability of compounds remains unsolved. The significant diversity of CCK receptors and their expression in all parts of the brain also complicates their application greatly. So, the CCK system of the brain is involved in the development of the main manifestations of anxiety pathology, but there are prospects for the medical use of substances that regulate the functional activity of CCK receptors.

Enhanced delivery of antibodies across the blood-brain barrier via TEMs with inherent receptor-mediated phagocytosis

The near impermeability of the blood-brain barrier (BBB) and the unique neuroimmune environment of the CNS prevents the effective use of antibodies in neurological diseases. Delivery of biotherapeutics to the brain can be enabled through receptor-mediated transcytosis via proteins such as the transferrin receptor, although limitations such as the ability to use Fc-mediated effector function to clear pathogenic targets can introduce safety liabilities. Hence, novel delivery approaches with alternative clearance mechanisms are warranted. Binders that optimized transport across the BBB, known as transcytosis-enabling modules (TEMs), were identified using a combination of antibody discovery techniques and pharmacokinetic analyses. Functional activity of TEMs were subsequently evaluated by imaging for the ability of myeloid cells to phagocytose target proteins and cells. We demonstrated significantly enhanced brain exposure of therapeutic antibodies using optimal transferrin receptor or CD98 TEMs. We found that these modules also mediated efficient clearance of tau aggregates and HER2+ tumor cells via a non-classical phagocytosis mechanism through direct engagement of myeloid cells. This mode of clearance potentially avoids the known drawbacks of FcγR-mediated antibody mechanisms in the brain such as the neurotoxic release of proinflammatory cytokines and immune cell exhaustion. Our study reports a new brain delivery platform that harnesses receptor-mediated transcytosis to maximize brain uptake and uses a non-classical phagocytosis mechanism to efficiently clear pathologic proteins and cells. We believe these findings will transform therapeutic approaches to treat CNS diseases. This research was funded by Janssen, Pharmaceutical Companies of Johnson & Johnson.

Horticultural Therapy Course as an Educational-Therapeutic Tool of Rehabilitation for Individuals with MSDs

The article presents the authors’ course “Horticultural Therapy”, which includes various activities related to the interaction with flora and its images. Evidence suggests that Ukrainian discourse lacks methodical materials on horticultural therapy and, thus, requires methods that can contribute to developing the skills of conscious psychological separation from constant parental care, taking responsibility for their lives, setting real-life goals and destroying the position of helplessness in individuals with MSDs. The article aims to theoretically justify, methodically develop and present the results from implementing the authors’ course “Horticultural Therapy” in rehabilitation centres. The authors’ methodical complex is based on the use of the following methods: analysis of theoretical and methodical sources; modelling of educational conditions and programmes; methods of implementing the didactic content in the educational-rehabilitational process; expert evaluation; statistical methods. The verification quasi-experiment of the modelled conditions for corrective learning has shown a significant increase in social skills in individuals with MSDs. Besides, findings confirm the increased levels of their independence, social and personal incentives, household and self-care skills. The international relevance of the article lies in the further development of nature-centric methods of corrective pedagogy, conductive pedagogy and non-medical treatment of CNS diseases, which is an important area of neurorehabilitation today.

A REVIEW ON GREEN-SYNTHESIS OF CERIUM OXIDE NANOPARTICLES: FOCUS ON CENTRAL NERVOUS SYSTEM DISORDERS

Green Synthesized Cerium oxide nanoparticles (CeO2NPs) have sparked a lot of interest in numerous disciplines of science and Technology during the past decade. A wide range of biological resources has been employed in synthesizing CeO2NPs, including plants, microorganisms, and other biological products. Biosynthesis procedures, current knowledge, and prospects in the synthesis of Green synthesis of CeO2NPs are also discussed. Neurodegenerative diseases, such as aging, trauma, Alzheimer's and Parkinson's, and other neurological problems, are linked to higher oxidative stress and superoxide radicals generation. Cerium oxide nanoparticles' antioxidant properties suggest that they may be useful in the treatment of CNS diseases. The biological antioxidant benefits of cerium oxide nanoparticles on extending cell and organism lifespan, preventing a free radical attack, and preventing trauma-induced neurological damage are discussed in this section. CeO2NPs, an aspect of nanotechnology, would emerge as a novel drug delivery carrier through therapeutic strategies. In several diseases oxidative stress and inflammation. CeO2NPs exhibited a remarkable ability to switch between+3 and+4 oxidation states making this an efficient therapeutic option and an effective drug delivery agent. Further Reactive oxygen and nitrogen species. The overall goal of this study is to provide reasonable insight into CeO2NPs as new therapeutic agents and to solve the challenges, of safely and effectively employing these CeO2NPs for efficient management of Central Nervous System diseases.

Mechanochemical Synthesis Method for Drugs Used in the Treatment of CNS Diseases under PTC Conditions

Phase transfer catalysis (PTC) is an excellent possibility in the synthesis of organic compounds as it allows the reactions to be carried out under the conditions of green chemistry, while maintaining high yields and selectivity. The great advantage of these reactions is also the possibility of carrying out the reactions not only under conventional conditions, but also mechanochemically in solvent-free processes. Bearing this in mind, we decided to develop a new method for the synthesis of known biologically active compounds from the group of long-chain arylpiperazines (LCAPs). The first mortar trials were very promising and prompted us to carry out a series of ball mill reactions. One of the technological problems that we encountered while conducting reactions in the ball mill was the difficulty in extracting the post-reaction mixture. We tested the effects of additives improving the insulation of the product, such as, e.g., starch, zeolites, and silica. Research has proven that with appropriate process conditions using TBAB as a catalyst and in the presence of potassium carbonate and a small amount of Zeolite ZSM5 or silica, aripiprazole can be obtained with a yield of 90% in just five minutes. The obtained results are very promising and it is worth considering them as an alternative to the synthesis of other compounds from the LCAPS group.

Ultrasound-enhanced drug delivery to spinal cord tumors

The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) are major obstacles to the treatment of CNS diseases and disorders as they prevent the passage of most therapeutic agents from the blood pool to the CNS tissue. Transient, reversible opening of the BBB using ultrasound and microbubbles (MBs) has been extensively studied and has reached clinical investigations. Ultrasound and MBs can similarly modify the BSCB, although applications in the spinal cord have received less attention. We have previously demonstrated ultrasound and MB-mediated opening of the BSCB in rodents, as well as in large animals through the intact spine, using a spine-specific pulse scheme called short-burst phase keying (SBPK). In this talk, we will discuss our work evaluating treatment control approaches for controlling SBPK exposures and will present recent results from drug delivery studies in rodent models of primary and metastatic spinal cord tumors.

New N-aryl-N′-aryl-/(thio)ureido-/sulfamoylamino-derivatives of alkyl/alkylcarbamoyl piperazines: Effect of structural modifications on selectivity over 5-HT1A receptor

The 5-HT1A receptors are an important biological target in the treatment of CNS diseases. Recently, their importance in the context of non-CNS disease entities has also been postulated. In the light of these reports, we designed a new group of urea derivatives of N-aryl-N′-aryl-/(thio)ureido-/sulfamoylamino-derivatives of alkyl/alkylcarbamoyl piperazines as 5-HT1AR ligands, focusing on increasing receptor selectivity. We made structural modifications in three areas of the molecule. In the course of our research, we obtained a ligand with reduced basicity (6f), which, despite the loss of the protonable nitrogen atom, did not lose its affinity for the 5-HT1AR (Ki = 35 nM) with a simultaneous increase in selectivity. In particular, a decrease in affinity for D2R (Ki = 1940 nM) was observed, which was analyzed using molecular modeling methods, including FMO and molecular dynamics. Basic ADME-Tox parameters were characterized for 6f, confirming its potential applicability in pharmacotherapy.

Viral Vectors in Transgenic Research: Prospects for the Treatment of CNS Diseases and Gene Therapy

Viral vectors are of great clinical interest due to their high efficiency, which allows them to find practical applications in gene therapy. The review presents current research data on various fish species as potential models for the use of viral vectors. During the study of high-performance adenoviral vectors data on the stable expression of transgenes in the body of Danio rerio and other fish species was obtained. The features of the use of adeno-associated vectors in the study of transneuronal transfer of the glucuronidase protein in the projection neurons of the ventral tegmental area and striatum to treat metabolic insufficiency in case of mucopolysaccharidosis VII are considered. Taking into consideration the wide set of genetically modified Danio rerio strains, ethical aspects, and the acceptability of applying this model in neurogenic studies, it is clear that Danio rerio, as well as other fish species, can be used as an alternative for early preclinical evaluation of the efficiency of viral vectors.

Lipid Nanocarriers Overlaid with Chitosan for Brain Delivery of Berberine via the Nasal Route.

This research aimed to design, optimize, and evaluate berberine-laden nanostructured lipid carriers overlaid with chitosan (BER-CTS-NLCs) for efficient brain delivery via the intranasal route. The nanostructured lipid carriers containing berberine (BER-NLCs) were formulated via hot homogenization and ultrasonication strategy and optimized for the influence of a variety of causal variables, including the amount of glycerol monostearate (solid lipid), poloxamer 407 (surfactant) concentration, and oleic acid (liquid lipid) amount, on size of the particles, entrapment, and the total drug release after 24 h. The optimal BER-NLCs formulation was then coated with chitosan. Their diameter, in vitro release, surface charge, morphology, ex vivo permeability, pH, histological, and in vivo (pharmacokinetics and brain uptake) parameters were estimated. BER-CTS-NLCs had a size of 180.9 ± 4.3 nm, sustained-release properties, positive surface charge of 36.8 mV, and augmented ex-vivo permeation via nasal mucosa. The histopathological assessment revealed that the BER-CTS-NLCs system is safe for nasal delivery. Pharmacokinetic and brain accumulation experiments showed that animals treated intranasally with BER-CTS-NLCs had substantially greater drug levels in the brain. The ratios of BER brain/blood levels at 30 min, AUCbrain/AUCblood, drug transport percentage, and drug targeting efficiency for BER-CTS-NLCs (IN) were higher compared to BER solution (IN), suggesting enhanced brain targeting. The optimized nanoparticulate system is speculated to be a successful approach for boosting the effect of BER in treating CNS diseases, such as Alzheimer’s disease, through intranasal therapy.

Transcriptomic and Gene Therapy Successes in Treating CNS Diseases

Transcriptomic and Gene Therapy Successes in Treating CNS Diseases

Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia-Relevance for Mental Diseases.

The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1–15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.

A new class of 5-HT1A receptor antagonists with procognitive and antidepressant properties.

Aims: 5-HT1A receptor antagonists constitute a potential group of drugs in the treatment of CNS diseases. The aim of this study was to search for new procognitive and antidepressant drugs among amide derivatives of aminoalkanoic acids with 5-HT1A receptor antagonistic properties. Materials & methods: Thirty-three amides were designed and evaluated in silico for their drug-likeness. The synthesized compounds were tested in vitro for their 5-HT1A receptor affinity and functional profile. Moreover, their selectivity over 5-HT7, 5-HT2Aand D2 receptors and ability to inhibit phosphodiesterases were evaluated. Results:A selected 5-HT1A receptor antagonist 20 (Ki=35nM, Kb=4.9nM) showed procognitive and antidepressant activity in vivo. Conclusion: Novel 5-HT1A receptor antagonists were discovered and shown as potential psychotropic drugs.

Deciphering the Influence of Cigarette Smoke Carcinogens on CNS Associated Biomolecules: A Computational Synergistic Approach.

Human health issues caused by Cigarette Smoke Carcinogens (CSC) are increasing rapidly every day and challenging the scientific community to provide a better understanding in order to avoid its impact on communities. Cigarette smoke also contains tobacco-based chemical compounds harmful to human beings, either smokers or non-smokers. We have tested 7H-Dibenzo[c,g]carbazole (7H-DBC) and Dibenz[a,h]acridine (DBAD) derivatives of Asz-arenes along with N'-Nitrosoanabasine (NAB) and N-Nitrosoanatabine (NAT) derivatives of N-Nitrosamines molecular interaction with CNS biomolecules. Computational synergistic approaches like system biology and molecular interaction techniques were implemented to conduct the analysis. CSC efficiently interacted with NRAS, KRAS, CDH1, and RAC1 molecular targets in CNS. We have also performed the interactome analysis followed by system biology approaches and found that HSPA8 is the most important hub protein for the network generated for CSC-hampered genes of CNS. We have also identified 6 connector proteins, namely TP53, HSP90AA1, PPP2CA, CDH1, CTNNB1, and ARRB1. Further analysis revealed that NRAS and CDH1 have maximum interactions with all the selected CSC. The obtained structural analysis data could be utilized to assess the carcinogenic effect of CSC and could be useful in the treatment of CNS diseases and disorders induced, especially by tobacco-specific carcinogens, or it could also be used in vivo/ in vitro experimentation model designing.

Protective effects of Lavandula stoechas L. methanol extract against 6-OHDA-induced apoptosis in PC12 cells

Ethnopharmacological relevanceParkinson's disease (PD) is a neurodegenerative disorder associated with oxidative stress-induced neuronal damage and death. In European and Persian Traditional Medicine, aerial parts (leaves, stems, and flowers) of Lavandula stoechas L. have been widely used for treating neurodegenerative disorders including PD.Aim of the study: Herein, the protective effects of L. stoechas methanol extract were investigated on 6-hydroxydopamine (6-OHDA)-induced cytotoxicity and oxidative damage in PC12 cells. Materials and methodsThe cells were pretreated with a standardized L. stoechas methanol extract (2.5–20 μg/mL) for 24 h and exposed to 6-OHDA (200 μM) thereafter. The cell viability percentage was determined by AlamarBlue test. Intracellular reactive oxygen species (ROS) production was determined by a fluorimetric method using 2′,7′-dichlorodihydrofluorescein diacetate and cellular apoptosis was assessed by the fluorescent probe propidium iodide test. Finally, the expression of proteins involved in apoptosis pathway (Phospho SAPK/JNK, SAPK/JNK, p44/42 MAPK (ERK1/2) and Poly ADP ribose polymerase (PARP)) was measured via Western blot analysis. ResultsTreatment of PC12 cells with 6-OHDA could significantly increase cytotoxicity, ROS level, and cell apoptosis. Pretreatment of PC12 cells with the extract could significantly decrease 6-OHDA cytotoxicity, ROS production, (2.5 and 5 μg/mL) and cell apoptosis (5 μg/mL). Western blot analysis showed that 6-OHDA exposure could increase the expression of proteins involved in apoptosis signaling, while pretreatment with L. stoechas (5 μg/mL) reduced apoptotic proteins. ConclusionsThe present study demonstrated that L. stoechas, which has been traditionally used in Persian Medicine for treating CNS diseases, is a valuable source of active compounds with neuroprotective, anti-oxidant, and anti-apoptotic activity.

Transcriptomic and Gene Therapy Successes in Treating CNS Diseases

Transcriptomic and Gene Therapy Successes in Treating CNS Diseases

Therapeutic Plasticity of Neural Stem Cells.

Neural stem cells (NSCs) have garnered significant scientific and commercial interest in the last 15 years. Given their plasticity, defined as the ability to develop into different phenotypes inside and outside of the nervous system, with a capacity of almost unlimited self-renewal, of releasing trophic and immunomodulatory factors, and of exploiting temporal and spatial dynamics, NSCs have been proposed for (i) neurotoxicity testing; (ii) cellular therapies to treat CNS diseases; (iii) neural tissue engineering and repair; (iv) drug target validation and testing; (v) personalized medicine. Moreover, given the growing interest in developing cell-based therapies to target neurodegenerative diseases, recent progress in developing NSCs from human-induced pluripotent stem cells has produced an analog of endogenous NSCs. Herein, we will review the current understanding on emerging conceptual and technological topics in the neural stem cell field, such as deep characterization of the human compartment, single-cell spatial-temporal dynamics, reprogramming from somatic cells, and NSC manipulation and monitoring. Together, these aspects contribute to further disentangling NSC plasticity to better exploit the potential of those cells, which, in the future, might offer new strategies for brain therapies.

Critical Role of Nrf2 in Experimental Ischemic Stroke.

Ischemic stroke is one of the leading causes of death and long-term disability worldwide; however, effective clinical approaches are still limited. The transcriptional factor Nrf2 is a master regulator in cellular and organismal defense against endogenous and exogenous stressors by coordinating basal and stress-inducible activation of multiple cytoprotective genes. The Nrf2 network not only tightly controls redox homeostasis but also regulates multiple intermediary metabolic processes. Therefore, targeting Nrf2 has emerged as an attractive therapeutic strategy for the prevention and treatment of CNS diseases including stroke. Here, the current understanding of the Nrf2 regulatory network is critically examined to present evidence for the contribution of Nrf2 pathway in rodent ischemic stroke models. This review outlines the literature for Nrf2 studies in preclinical stroke and focuses on the in vivo evidence for the role of Nrf2 in primary and secondary brain injuries. The dynamic change and functional importance of Nrf2 signaling, as well as Nrf2 targeted intervention, are revealed in permanent, transient, and global cerebral ischemia models. In addition, key considerations, pitfalls, and future potentials for Nrf2 studies in preclinical stroke investigation are discussed.