Therapy Of Brain Diseases Research Articles

Low-intensity exercise combined with sodium valproate attenuates kainic acid-induced seizures and associated co-morbidities by inhibiting NF-κB signaling in mice.

Sodium valproate (VPA) is a broad-spectrum anticonvulsant that is effective both in adults and children suffering from epilepsy, but it causes psychiatric and behavioral side effects in patients with epilepsy. In addition, 30% of patients with epilepsy develop resistance to VPA. At present, regular physical exercise has shown many benefits and has become an effective complementary therapy for various brain diseases, including epilepsy. Therefore, we wondered whether VPA combined with exercise would be more effective in the treatment of seizures and associated co-morbidities. Here, we used a mouse model with kainic acid (KA)-induced epilepsy to compare the seizure status and the levels of related co-morbidities, such as cognition, depression, anxiety, and movement disorders, in each group using animal behavioral experiment and local field potential recordings. Subsequently, we investigated the mechanism behind this phenomenon by immunological means. Our results showed that low-intensity exercise combined with VPA reduced seizures and associated co-morbidities. This phenomenon seems to be related to the Toll-like receptor 4, activation of the nuclear factor kappa B (NF-κB), and release of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), and IL-6. In brief, low-intensity exercise combined with VPA enhanced the downregulation of NF-κB-related inflammatory response, thereby alleviating the seizures, and associated co-morbidities.

The Phytochemical Potential for Brain Disease Therapy and the Possible Nanodelivery Solutions for Brain Access.

Plant-derived phytochemicals have gifted humans with vast therapeutic potentials. Yet, the unique features of the blood–brain barrier significantly limit their accession to the target tissue and thus clinical translation in brain disease treatment. Herein, we explore the medicinal outcomes of both the rare examples of phytochemicals that can easily translocate across the blood–brain barrier and most of the phytochemicals that were reported with brain therapeutic effects, but a bizarre amount of dosage is required due to their chemical nature. Lastly, we offer the nanodelivery platform that is capable of optimizing the targeted delivery and application of the non-permeable phytochemicals as well as utilizing the permeable phytochemicals for boosting novel applications of nanodelivery toward brain therapies.

Discovery of new chemotypes of dual 5-HT2A/D2 receptor antagonists with a strategy of drug design methodologies.

Aim: Through the application of structure- and ligand-based methods, the authors aimed to create an integrative approach to developing a computational protocol for the rational drug design of potent dual 5-HT2A/D2 receptor antagonists without off-target activities on H1 receptors. Materials & methods: Molecular dynamics and virtual docking methods were used to identify key interactions of the structurally diverse antagonists in the binding sites of the studied targets, and to generate their bioactive conformations for further 3D-quantitative structure-activity relationship modeling. Results & conclusion: Toward the goal of finding multi-potent drugs with a more effective and safer profile, the obtained results led to the design of a new set of dual antagonists and opened a new perspective on the therapy for complex brain diseases.

Challenges in the Development of Drug Delivery Systems Based on Small Extracellular Vesicles for Therapy of Brain Diseases.

Small extracellular vesicles (sEVs) have ∼30–200 nm diameter size and may act as carriers of different cargoes, depending on the cell of origin or on the physiological/pathological condition. As endogenous nanovesicles, sEVs are important in intercellular communication and have many of the desirable features of an ideal drug delivery system. sEVs are naturally biocompatible, with superior targeting capability, safety profile, nanometric size, and can be loaded with both lipophilic and hydrophilic agents. Because of their biochemical and physical properties, sEVs are considered a promising strategy over other delivery vehicles in the central nervous system (CNS) since they freely cross the blood-brain barrier and they can be directed to specific nerve cells, potentiating a more precise targeting of their cargo. In addition, sEVs remain stable in the peripheral circulation, making them attractive nanocarrier systems to promote neuroregeneration. This review focuses on the recent progress in methods for manufacturing, isolating, and engineering sEVs that can be used as a therapeutic strategy to overcome neurodegeneration associated with pathologies of the CNS, with particular emphasis on Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis diseases, as well as on brain tumors.

Automated measurement of fluorescence signals reveals a significant increase of the graft-derived neurite extension in neonates compared to aged rats.

Background– Neural tissue grafting is an acceptable form of cell therapy for brain injury and diseases. However, methods that can evaluate the graft integration and measure axonal extensions in a 3D environment are limited in scale, inconvenient, and operator intensive.Method– We stained grafts with a fluorescent antibody and then quantified the amount of fluorescence through the entire brain. To achieve this, we created an automated computer program designed to sort out authentic staining from background noise without any user input, enabling the analysis of thousands of images.Results– Our program could compensate for variations in the background brightness between images in all animals. Using this program, we show that human induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) progenitor cells integrate better into the striatum of neonates than older rats.Conclusion– Our program can quantify quickly and conveniently the integration of neural grafts in a 3D environment without depending on a blinded human operator. We expect this method to be a useful tool to assess the efficiency of graft-enhancing treatments for neurodegenerative diseases or other neural reconstruction attempts.

Extracellular Vesicles Taken up by Astrocytes.

Extracellular vesicles (EVs) are composed of lipid bilayer membranes and contain various molecules, such as mRNA and microRNA (miRNA), that regulate the functions of the recipient cell. Recent studies have reported the importance of EV-mediated intercellular communication in the brain. The brain contains several types of cells, including neurons and glial cells. Among them, astrocytes are the most abundant glial cells in the mammalian brain and play a wide range of roles, from structural maintenance of the brain to regulation of neurotransmission. Furthermore, since astrocytes can take up EVs, it is possible that EVs originating from inside and outside the brain affect astrocyte function, which in turn affects brain function. However, it has not been fully clarified whether the specific targeting mechanism of EVs to astrocytes as recipient cells exists. In recent years, EVs have attracted attention as a cell-targeted therapeutic approach in various organs, and elucidation of the targeting mechanism of EVs to astrocytes may pave the way for new therapies for brain diseases. In this review, we focus on EVs in the brain that affect astrocyte function and discuss the targeting mechanism of EVs to astrocytes.

Electroacupuncture improves repeated social defeat stress-elicited social avoidance and anxiety-like behaviors by reducing Lipocalin-2 in the hippocampus

BackgroundPost-traumatic stress disorder (PTSD) is a trauma-related disorder that is associated with pro-inflammatory activation and neurobiological impairments in the brain and leads to a series of affective-like behaviors. Electroacupuncture (EA) has been proposed as a clinically useful therapy for several brain diseases. However, the potential role of EA treatment in PTSD and its molecular and cellular mechanisms has rarely been investigated.MethodsWe used an established preclinical social defeat stress mouse model to study whether EA treatment modulates PTSD-like symptoms and understand its underlying mechanisms. To this end, male C57BL/6 mice were subjected to repeated social defeat stress (RSDS) for 6 consecutive days to induce symptoms of PTSD and treated with EA at Baihui (GV 20) and Dazhui (GV 14) acupoints.ResultsThe stimulation of EA, but not needle insertion at Baihui (GV 20) and Dazhui (GV 14) acupoints effectively improved PTSD-like behaviors such as, social avoidance and anxiety-like behaviors. However, EA stimulation at the bilateral Tianzong (SI11) acupoints did not affect the PTSD-like behaviors obtained by RSDS. EA stimulation also markedly inhibited astrocyte activation in both the dorsal and ventral hippocampi of RSDS-treated mice. Using next-generation sequencing analysis, our results showed that EA stimulation attenuated RSDS-enhanced lipocalin 2 expression in the hippocampus. Importantly, using double-staining immunofluorescence, we observed that the increased lipocalin 2 expression in astrocytes by RSDS was also reduced by EA stimulation. In addition, intracerebroventricular injection of mouse recombinant lipocalin 2 protein in the lateral ventricles provoked social avoidance, anxiety-like behaviors, and the activation of astrocytes in the hippocampus. Interestingly, the overexpression of lipocalin 2 in the brain also altered the expression of stress-related genes, including monoamine oxidase A, monoamine oxidase B, mineralocorticoid receptor, and glucocorticoid receptor in the hippocampus.ConclusionsThis study suggests that the treatment of EA at Baihui (GV 20) and Dazhui (GV 14) acupoints improves RSDS-induced social avoidance, anxiety-like behaviors, astrocyte activation, and lipocalin 2 expression. Furthermore, our findings also indicate that lipocalin 2 expression in the brain may be an important biomarker for the development of PTSD-related symptoms.

Advances in Stem Cell Therapy for Brain Diseases via the Intranasal Route.

Stem cell therapy efficiently targets the brain for most neurological disorders like migraine, Parkinsonism, schizophrenia, Alzheimer's disease, and brain injury. The major obstacles in potential brain targeting are the physiological barriers like blood-brain-barrier and bloodcerebrospinal fluid barrier. The conventional injectable route or direct transplantation of stem cells results in brain injury and is less feasible clinically. The alternative to these invasive routes is the intranasal route that is non-invasive, easily repeatable technique and highly effective in brain targeting without crossing the blood-brain barrier. Extensive research has been undertaken for the delivery of stem cells to the brain via the intranasal route that holds great potential in overcoming the existing barriers. Nanotechnology is emerging as a novel interdisciplinary field in the arena of stem cell research. The combination of nanotechnology coupled with stem cell therapy has led to synergistic outcomes in diagnostic and therapeutic applications of neurological diseases. This review provides insights into stem cell-based nanotherapy for brain targeting via the intranasal route.

Diffusion magnetic resonance imaging data: development of methods and tools for diagnosis and treatment of brain diseases

The use of quantitative mapping of diffusion characteristics carries great potential for diagnosis and therapy of brain diseases, since it potentially allows to classify tumors, determine the degree of their malignancy, differentiate various morphological structures of tumor and non-tumor pathologies (such as tumor stroma, necrotic zones, cysts, various types of edema, etc.), and predict the course and outcome of diseases, in particular, a clinical response to treatment. Based on diffusion weighted magnetic resonance imaging (MRI), it is possible to perform 3D modeling of the white matter pathways of the brain, which is called tractography. In addition to a unique ability to visualize the location of tracts in relation to intracranial pathologies, this technology allows to build and analyze complex maps of communication networks in the brain (connectomics). The review is devoted to the discussion of the physical and technical concept of diffusion weighted MRI, the key ways of its application in tumor and non-tumor processes, and problems that complicate correct interpretation of results. Since the problem of developing software for diffusion MRI data remains relevant, this review presents our own experience in developing an application as part of a project on creating effective methods for processing diffusion MRI data and modeling white matter tracts.

Mechanisms of Sound-Induced Opening of the Blood-Brain Barrier.

The blood-brain barrier (BBB) poses a significant challenge for drug delivery to the brain. The limitations of our knowledge about the nature of BBB explain the slow progress in the therapy of brain diseases and absence of methods for drug delivery to the brain in clinical practice. Here, we show that the BBB opens for high-molecular-weight compounds after exposure to loud sound (100dB 370Hz) in rats. The role of stress induced by loud sound and the systemic and molecular mechanisms behind it are discussed in the framework of the BBB. This opens an informative platform for novel fundamental knowledge about the nature of BBB and for the development of a noninvasive brain drug delivery technology.

Ultrasound for the Brain: A Review of Physical and Engineering Principles, and Clinical Applications.

The emergence of new ultrasound technologies has improved our understanding of the brain functions and offered new opportunities for the treatment of brain diseases. Ultrasound has become a valuable tool in preclinical animal and clinical studies as it not only provides information about the structure and function of brain tissues but can also be used as a therapy alternative for brain diseases. High-resolution cerebral flow images with high sensitivity can be acquired using novel functional ultrasound and super-resolution ultrasound imaging techniques. The noninvasive treatment of essential tremors has been clinically approved and it has been demonstrated that the ultrasound technology can revolutionize the currently existing treatment methods. Microbubble-mediated ultrasound can remotely open the blood-brain barrier enabling targeted drug delivery in the brain. More recently, ultrasound neuromodulation received a great amount of attention due to its noninvasive and deep penetration features and potential therapeutic benefits. This review provides a thorough introduction to the current state-of-the-art research on brain ultrasound and also introduces basic knowledge of brain ultrasound including the acoustic properties of the brain/skull and engineering techniques for ultrasound. Ultrasound is expected to play an increasingly important role in the diagnosis and therapy of brain diseases.

Mapping the Human Brain: What Is the Next Frontier?

Abstract The structure and function of the human brain have long been the topic of exploration by scientists. To understand how the brain works, researchers have created various brain navigation maps, i.e. brain atlases, which are still being developed and improved. To clarify the trend of human brain mapping and to achieve better applications in brain science and diseases, this commentary briefly traces the history of human brain mapping and describes insights into the next stage of building brain atlases.

Medial prefrontal cortex and the temporal control of action.

Across species, the medial prefrontal cortex guides actions in time. This process can be studied using behavioral paradigms such as simple reaction-time and interval-timing tasks. Temporal control of action can be influenced by prefrontal neurotransmitters such as dopamine and acetylcholine and is highly relevant to human diseases such as Parkinson's disease, schizophrenia, and attention-deficit hyperactivity disorder (ADHD). We review evidence that across species, medial prefrontal lesions impair the temporal control of action. We then consider neurophysiological correlates in humans, primates, and rodents that might encode temporal processing and relate to cognitive-control mechanisms. These data have informed brain-stimulation studies in rodents and humans that can compensate for timing deficits. This line of work illuminates basic mechanisms of temporal control of action in the medial prefrontal cortex, which underlies a range of high-level cognitive processing and could contribute to new biomarkers and therapies for human brain diseases.

Spectrally resolved passive acoustic imaging

Ultrasound in combination with circulating microbubble contrast agents has emerged as a promising modality for therapy and imaging of brain diseases. Despite progress, the need for spatio-temporal mapping and control of the cerebrovascular microbubble dynamics necessitates the development of fast and spectrally resolved trans-skull imaging methods. In this talk, we will present our recent efforts towards establishing such methods. First, we will introduce a general methodology using the angular spectrum (AS) approach in a heterogeneous medium, which is based on a numerical marching scheme to approximate the full implicit solution, and reveal its functionality for trans-skull passive acoustic imaging (70% source localization error reduction from 2.89 ± 1.76 mm to 0.68 ± 52 mm). Then, we will demonstrate the ability of AS in combination with a nonlinear state controller that uses specific frequency bands of the microbubble acoustic emissions (harmonic, ultra-harmonic, etc.) to attain stable cavitation activity for tens of seconds. Finally, we will present our progress towards adapting the AS method for rapid visualization of vessel structures with diameters of a few hundreds of microns. The superior image quality and computation efficiency (>100-fold faster from time-domain delay-and-sum methods) of AS offers unique opportunities for spectrally resolved passive acoustic imaging and image guided therapy of human disease.

Corrigendum to: Gene therapy for global brain diseases: one small step for mice, one giant leap for humans

Corrigendum to: Gene therapy for global brain diseases: one small step for mice, one giant leap for humans

Gene therapy for global brain diseases: one small step for mice, one giant leap for humans.

This scientific commentary refers to ‘Global CNS correction in a large brain model of human alpha-mannosidosis by intravascular gene therapy’, by Yoon et al. (doi:10.1093/brain/awaa161).

Novel in vitro assay to investigate radiation induced changes in the functionality of human embryonic stem cell-derived neurospheres

Ionizing radiation (IR) is increasingly used for diagnostics and therapy of severe brain diseases. However, IR also has adverse effects on the healthy brain tissue, particularly on the neuronal network. This is true for adults but even more pronounced in the developing brain of unborn and pediatric patients. Epidemiological studies on children receiving radiotherapy showed an increased risk for cognitive decline ranging from mild deficits in academic functioning to severe late effects in intellectual ability and language as a consequence of altered neuronal development and connectivity.To provide a comprehensive approach for the analysis of radiation-induced alterations in human neuronal functionality, we developed an in vitro assay by combining microelectrode array (MEA) analyses and human embryonic stem cell (hESC) derived three-dimensional neurospheres (NS). In our proof of principle study, we irradiated hESC with 1 Gy X-rays and let them spontaneously differentiate into neurons within NS. After the onset of neuronal activity, we recorded and analyzed the activity pattern of the developing neuronal networks. The network activity in NS derived from irradiated hESC was significantly reduced, whereas no differences in molecular endpoints such as cell proliferation and transcript or protein expression analyses were found. Thus, the combination of MEA analysis with a 3D model for neuronal functionality revealed radiation sequela that otherwise would not have been detected. We therefore strongly suggest combining traditional biomolecular methods with the new functional assay presented in this work to improve the risk assessment for IR-induced effects on the developing brain.

Photostimulation of cerebral and peripheral lymphatic functions

AbstractThe recently rediscovered meningeal lymphatic system (MLS) opens new insight into pathways of brain clearing and drainage functions that play an important role in neurorehabilitation. The development of breakthrough strategies for augmentation of MLS might be a promising therapeutic target for preventing of neurological diseases. Here we demonstrate photostimulation (PS, 1268 nm) of clearing and drainage function of MLS in healthy male mice. We uncover PS‐mediated increase of the mesenteric lymphatic permeability to fluorescent macrophages via a decrease of expression of tight junction and transendothelial resistance. In sum, our results clearly show PS stimulation of meningeal clearing and drainage functions as well as effects of PS on permeability of the lymphatic endothelium to macrophages. These findings open new strategies for alternative nonpharmacological therapy of brain diseases via PS modulation of lymphatic mechanisms of the homeostasis of central nervous system.

Potential Therapeutic Approaches Against Brain Diseases Associated with Cytomegalovirus Infections.

Cytomegalovirus (CMV) is one of the major human health threats worldwide, especially for immunologically comprised patients. CMV may cause opportunistic infections, congenital infections, and brain diseases (e.g., mental retardation and glioblastoma). The etiology of brain diseases associated with human CMV (HCMV) infections is usually complex and it is particularly difficult to treat because HCMV has a life-long infection in its hosts, high mutation rate, and latent infections. Moreover, it is almost impossible to eradicate latent viruses in humans. Although there has been progress in drug discovery recently, current drugs used for treating active CMV infections are still limited in efficacy due to side effects, toxicity, and viral resistance. Fortunately, letermovir which targets the HCMV terminase complex rather than DNA polymerase with fewer adverse reactions has been approved to treat CMV infections in humans. The researchers are focusing on developing approaches against both productive and latent infections of CMV. The gene or RNA targeting approaches including the external guide sequences (EGSs)-RNase, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and transcription activator-like effector nucleases (TALENs) are being investigated to remove acute and/or latent CMV infections. For the treatment of glioblastoma, vaccine therapy through targeting specific CMV antigens has improved patients’ survival outcomes significantly and immunotherapy has also emerged as an alternative modality. The advanced research for developing anti-CMV agents and approaches is promising to obtain significant outcomes and expecting to have a great impact on the therapy of brain diseases associated with CMV infections.

Photobiomodulation of lymphatic drainage and clearance: perspective strategy for augmentation of meningeal lymphatic functions.

There is a hypothesis that augmentation of the drainage and clearing function of the meningeal lymphatic vessels (MLVs) might be a promising therapeutic target for preventing neurological diseases. Here we investigate mechanisms of photobiomodulation (PBM, 1267 nm) of lymphatic drainage and clearance. Our results obtained at optical coherence tomography (OCT) give strong evidence that low PBM doses (5 and 10 J/cm2) stimulate drainage function of the lymphatic vessels via vasodilation (OCT data on the mesenteric lymphatics) and stimulation of lymphatic clearance (OCT data on clearance of gold nanorods from the brain) that was supported by confocal imaging of clearance of FITC-dextran from the cortex via MLVs. We assume that PBM-mediated relaxation of the lymphatic vessels can be possible mechanisms underlying increasing the permeability of the lymphatic endothelium that allows molecules transported by the lymphatic vessels and explain PBM stimulation of lymphatic drainage and clearance. These findings open new strategies for the stimulation of MLVs functions and non-pharmacological therapy of brain diseases.