Therapy Of Brain Diseases Research Articles

Photodynamic opening of the blood-brain barrier affects meningeal lymphatics and the brain's drainage in healthy male mice.

Here, we present the new vascular effects of photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA). PDT with 5-ALA induces a leakage of both the meningeal and cerebral blood vessels. The extravasation of photo-excited 5-ALA from the leaky blood vessels into the meninges causes photo-damage of the meningeal lymphatics (MLVs) leading to a dramatic reducing the MLV network and brain's drainage. The PDT-induced impairment of lymphatic regulation of brain's drainage can lead to excessive accumulation of fluids in brain tissues, which is important to consider in the PDT therapy for brain diseases as s possible side effect of PDT with 5-ALA.

Beyond wrecking a wall: revisiting the concept of blood-brain barrier breakdown in ischemic stroke.

The blood-brain barrier constitutes a dynamic and interactive boundary separating the central nervous system and the peripheral circulation. It tightly modulates the ion transport and nutrient influx, while restricting the entry of harmful factors, and selectively limiting the migration of immune cells, thereby maintaining brain homeostasis. Despite the well-established association between blood-brain barrier disruption and most neurodegenerative/neuroinflammatory diseases, much remains unknown about the factors influencing its physiology and the mechanisms underlying its breakdown. Moreover, the role of blood-brain barrier breakdown in the translational failure underlying therapies for brain disorders is just starting to be understood. This review aims to revisit this concept of "blood-brain barrier breakdown," delving into the most controversial aspects, prevalent challenges, and knowledge gaps concerning the lack of blood-brain barrier integrity. By moving beyond the oversimplistic dichotomy of an "open"/"bad" or a "closed"/"good" barrier, our objective is to provide a more comprehensive insight into blood-brain barrier dynamics, to identify novel targets and/or therapeutic approaches aimed at mitigating blood-brain barrier dysfunction. Furthermore, in this review, we advocate for considering the diverse time- and location-dependent alterations in the blood-brain barrier, which go beyond tight-junction disruption or brain endothelial cell breakdown, illustrated through the dynamics of ischemic stroke as a case study. Through this exploration, we seek to underscore the complexity of blood-brain barrier dysfunction and its implications for the pathogenesis and therapy of brain diseases.

Co-transplantation of autologous treg cells: A groundbreaking cell therapy for brain diseases

Cell therapy and regenerative medicine have made remarkable progress in treating neurodegenerative disorders. Induced pluripotent stem cells (iPSCs) offer a promising source for cell replacement therapies, but their practical application faces challenges due to poor survival and integration after transplantation. Park et al. propose a novel therapeutic strategy involving the co-transplantation of regulatory T cells (Tregs) and iPSC-derived dopamine neurons. This combined approach enhances the survival of transplanted cells and protects against neuroinflammation-induced damage. In PD animal models, the co-transplantation approach significantly suppressed the host immune response, resulting in improved behavioral recovery. Additionally, Tregs demonstrate acute neuroprotection and contribute to delayed neuro-restoration in ischemic stroke. This combined approach of cell therapy with immunomodulation offers a promising avenue for advancing our understanding of neurological diseases and promoting the development of novel treatments.

Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases.

Cerebrovascular diseases and their sequalae, such as ischemic stroke, chronic cerebral hypoperfusion, and vascular dementia are significant contributors to adult disability and cognitive impairment in the modern world. Astrocytes are an integral part of the neurovascular unit in the CNS and play a pivotal role in CNS homeostasis, including ionic and pH balance, neurotransmission, cerebral blood flow, and metabolism. Astrocytes respond to cerebral insults, inflammation, and diseases through unique molecular, morphological, and functional changes, collectively known as reactive astrogliosis. The function of reactive astrocytes has been a subject of debate. Initially, astrocytes were thought to primarily play a supportive role in maintaining the structure and function of the nervous system. However, recent studies suggest that reactive astrocytes may have both beneficial and detrimental effects. For example, in chronic cerebral hypoperfusion, reactive astrocytes can cause oligodendrocyte death and demyelination. In this review, we will summarize the (1) roles of ion transporter cascade in reactive astrogliosis, (2) role of reactive astrocytes in vascular dementia and related dementias, and (3) potential therapeutic approaches for dementing disorders targeting reactive astrocytes. Understanding the relationship between ion transporter cascade, reactive astrogliosis, and cerebrovascular diseases may reveal mechanisms and targets for the development of therapies for brain diseases associated with reactive astrogliosis.

Recent advances in photobiomodulation therapy for brain diseases

AbstractLight therapy techniques, such as photobiomodulation therapy (PBMT), photodynamic therapy (PDT), and laser photoablation, have gained widespread attention and become indispensable physiotherapy methods in clinical practice. PBMT involves the application of low‐level laser/LED to modulate the function of nerve cells, relieve neuroinflammation, promote neurogenesis and vascular growth. Recent studies have shown that PBMT holds promise as a complementary or alternative treatment of Alzheimer's disease (AD), traumatic brain injury (TBI), major depressive disorder (MDD), etc. However, the therapeutic effect of PBMT is influenced by various factors, such as the patients' condition, brain structure and function, illumination parameters, etc. Therefore, the optimized parameters, personalized therapeutic schedules, and precise evaluation of the therapeutic effect are crucial to the treatment success. In this review, we identified the recent experimental and clinical successes, existing obstacles, and future opportunities for PBMT in the treatment of the brain diseases. As a non‐invasive, side‐effect‐free, and highly accessible technique, PBMT brings a glimmer of light for the treatment of neuropsychiatric disorders and the neuro‐rejuvenation of human brains.

Application of quantum dots in brain diseases and their neurotoxic mechanism.

The early-stage diagnosis and therapy of brain diseases pose a persistent challenge in the field of biomedicine. Quantum dots (QDs), nano-luminescent materials known for their small size and fluorescence imaging capabilities, present promising capabilities for diagnosing, monitoring, and treating brain diseases. Although some investigations about QDs have been conducted in clinical trials, the concerns about the toxicity of QDs have continued. In addition, the lack of effective toxicity evaluation methods and systems and the difference between in vivo and in vitro toxicity evaluation hinder QDs application. The primary objective of this paper is to introduce the neurotoxic effects and mechanisms attributable to QDs. First, we elucidate the utilization of QDs in brain disorders. Second, we sketch out three pathways through which QDs traverse into brain tissue. Ultimately, expound upon the adverse consequences of QDs on the brain and the mechanism of neurotoxicity in depth. Finally, we provide a comprehensive summary and outlook on the potential development of quantum dots in neurotoxicity and the difficulties to be overcome.

Neuropsychiatric Behavioral Assessments in Mice After Acute and Long-Term Treatments of Low-Intensity Pulsed Ultrasound.

Introduction: To evaluate whether both acute and chronic low-intensity pulsed ultrasound (LIPUS) affect brain functions of healthy male and female mice. Methods: Ultrasound (frequency: 1.5MHz; pulse: 1.0kHz; spatial average temporal average (SATA) intensity: 25mW/cm2; and pulse duty cycle: 20%) was applied at mouse head in acute test for 20minutes, and in chronic experiment for consecutive 10days, respectively. Behaviors were then evaluated. Results: Both acute and chronic LIPUS at 25mW/cm2 exposure did not affect the abilities of movements, mating, social interaction, and anxiety-like behaviors in the male and female mice. However, physical restraint caused struggle-like behaviors and short-time memory deficits in chronic LIPUS groups in the male mice. Conclusion: LIPUS at 25mW/cm2 itself does not affect brain functions, while physical restraint for LIPUS therapy elicits struggle-like behaviors in the male mice. An unbound helmet targeted with ultrasound intensity at 25-50mW/cm2 is proposed for clinical brain disease therapy.

Potential of Zinc Oxide-Graphene Quantum Dots and Zinc Oxide-Nitrogen-Doped Graphene Quantum Dot Nanocomposites as Neurotrophic Agents.

Over the past few decades, zinc oxide nanoparticles have also proven to be essential to a variety of scientific research sectors, including antimicrobial therapy, tissue engineering, bioimaging, biosensors, drug delivery, gene delivery, and bioimaging. There is an urgent need to establish and develop unique alternative treatment modalities to treat neurodegenerative disorders due to the shortcomings of the existing drugs. As a possible therapy for brain diseases and disorders, the ability of the nanoparticles to cross the blood-brain barrier (BBB) as well as their reduced toxicity, solubility, and biodegradability has lately attracted attention. Scientists are quietly turning their attention to develop green synthesis of nanoparticles as an alternative to the physical and chemical techniques of producing the same. Existing literature has emphasized the use of ZnO for the potential treatment of cerebral ischemia and its neuroprotective properties. This work discusses the potential of ZnO prepared using Gynura cusimba extract and its nanocomposites with graphene quantum dots (GQDs) and its nitrogen doped variant, N-GQDs as neurotrophic agents, in accordance with our previous report on the use of GQDs and N-GQDs as neurotrophic agents. Pristine ZnO nanoparticles as well as composites were duly characterized by using several techniques to confirm the formation of the nanocomposites. Biological evaluation using the neurite outgrowth assay following the cell viability assay revealed that incorporation of GQDs and N-GQDs enhanced the neurite length in comparison to that of pristine ZnO with the nanocomposites of N-GQDs showing comparatively better results, corroborated by the real-time PCR studies as well.

Key Features in the Design and Function of Nanocarriers for Intranasal Administration of Gene Therapy in Huntington Disease.

A major obstacle to fulfilling the therapeutic promise of gene therapies for hereditary brain diseases, such as Huntington' Disease (HD), is the requirement for viral vectors and/or an invasive delivery system (stereotaxic injection into brain or infusion into the intrathecal space). HD is an autosomal dominant neurodegenerative disease for which several clinical trials have demonstrated gene-lowering effects following intrathecal administration. These technical limitations have given impetus to the development of alternative non-invasive delivery systems for gene therapy of brain diseases. The overall objective of this review is to discuss the key features in the design of nanocarriers for intranasal administration of gene-therapy for HD, focusing primarily on our series of published work on the use of nanocarriers for gene therapy. Design and development of nanocarriers packaged with gene-lowering agents represents a significant advance towards non-invasive nose-to-brain delivery of gene therapy for HD and other hereditary brain disorders.

Autophagy in neural stem cells and glia for brain health and diseases.

Autophagy is a multifaceted cellular process that not only maintains the homeostatic and adaptive responses of the brain but is also dynamically involved in the regulation of neural cell generation, maturation, and survival. Autophagy facilities the utilization of energy and the microenvironment for developing neural stem cells. Autophagy arbitrates structural and functional remodeling during the cell differentiation process. Autophagy also plays an indispensable role in the maintenance of stemness and homeostasis in neural stem cells during essential brain physiology and also in the instigation and progression of diseases. Only recently, studies have begun to shed light on autophagy regulation in glia (microglia, astrocyte, and oligodendrocyte) in the brain. Glial cells have attained relatively less consideration despite their unquestioned influence on various aspects of neural development, synaptic function, brain metabolism, cellular debris clearing, and restoration of damaged or injured tissues. Thus, this review composes pertinent information regarding the involvement of autophagy in neural stem cells and glial regulation and the role of this connexion in normal brain functions, neurodevelopmental disorders, and neurodegenerative diseases. This review will provide insight into establishing a concrete strategic approach for investigating pathological mechanisms and developing therapies for brain diseases.

The Use of Photodynamic Therapy for Head, Neck, and Brain Diseases.

Head-neck cancers as a group have the 7th highest rate of incidence worldwide. The most often diagnosed disease of the head and neck is squamous cell carcinoma (90% of cases). Another specific group of tumors is brain tumors. These can be divided into primary tumors and secondary tumors associated with metastasis. Research shows that treating head and neck cancers continues to be problematic and challenging, and researchers are actively seeking new treatments that would improve survival rates and reduce side effects. Irradiation of tumor tissue with the optimal wavelength of light in photodynamic therapy (PDT) generates predominantly singlet oxygen in tissue-based photosensitizers (PSs) or reactive oxygen radicals in the case of vascular PSs leading to cellular apoptosis and necrosis. A very important feature of PDT is that cells cannot become immune to the effects of singlet oxygen or reactive oxygen radicals. However, photosensitizer (PS) transport is influenced by the specific structures of cancer tumors and the concentration of PS decreases in cells far from the vessel lumen. Therefore, PSs may not reach tumor interiors, which decreases therapy effectiveness. The use of drug carriers and 3rd generation PSs that contain biocompatible functional groups makes it possible to control transport. This review of the current literature on PDT was conducted through databases such as PubMed and Scopus. The types of publications considered included clinical studies and most of the articles included were published in English. Based on the publications collected, we conclude that researchers have demonstrated the potential of PDT as a therapeutic platform for head, neck, and brain diseases.

3D printing-based frugal manufacturing of glass pipettes for minimally invasive delivery of therapeutics to the brain.

Intracerebral delivery of agents in liquid form is usually achieved through commercially available and durable metal needles. However, their size and texture may contribute to mechanical brain damage. Glass pipettes with a thin tip may significantly reduce injection-associated brain damage but require access to prohibitively expensive programmable pipette pullers. This study is to remove the economic barrier to the application of minimally invasive delivery of therapeutics to the brain, such as chemical compounds, viral vectors, and cells. We took advantage of the rapid development of free educational online resources and emerging low-cost 3D printers by designing an affordable pipette puller (APP) to remove the cost obstacle. We showed that our APP could produce glass pipettes with a sharp tip opening down to 20 μm or less, which is sufficiently thin for the delivery of therapeutics into the brain. A pipeline from pipette pulling to brain injection using low-cost and open-source equipment was established to facilitate the application of the APP. In the spirit of frugal science, our device may democratize glass pipette-puling and substantially promote the application of minimally invasive and precisely controlled delivery of therapeutics to the brain for finding more effective therapies of brain diseases.

Tat-RAN attenuates brain ischemic injury in hippocampal HT-22 cells and ischemia animal model

Oxidative stress plays a key role in the pathogenesis of neuronal injury, including ischemia. Ras-related nuclear protein (RAN), a member of the Ras superfamily, involves in a variety of biological roles, such as cell division, proliferation, and signal transduction. Although RAN reveals antioxidant effect, its precise neuroprotective mechanisms are still unclear. Therefore, we investigated the effects of RAN on HT-22 cell which were exposed to H2O2-induced oxidative stress and ischemia animal model by using the cell permeable Tat-RAN fusion protein. We showed that Tat-RAN transduced into HT-22 cells, and markedly inhibited cell death, DNA fragmentation, and reactive oxygen species (ROS) generation under oxidative stress. This fusion protein also controlled cellular signaling pathways, including mitogen-activated protein kinases (MAPKs), NF-κB, and apoptosis (Caspase-3, p53, Bax and Bcl-2). In the cerebral forebrain ischemia animal model, Tat-RAN significantly inhibited both neuronal cell death, and astrocyte and microglia activation. These results indicate that RAN significantly protects against hippocampal neuronal cell death, suggesting Tat-RAN will help to develop the therapies for neuronal brain diseases including ischemic injury.

Living Cells and Cell-Derived Vesicles: A Trojan Horse Technique for Brain Delivery.

Brain diseases remain a significant global healthcare burden. Conventional pharmacological therapy for brain diseases encounters huge challenges because of the blood-brain barrier (BBB) limiting the delivery of therapeutics into the brain parenchyma. To address this issue, researchers have explored various types of drug delivery systems. Cells and cell derivatives have attracted increasing interest as "Trojan horse" delivery systems for brain diseases, owing to their superior biocompatibility, low immunogenicity, and BBB penetration properties. This review provided an overview of recent advancements in cell- and cell-derivative-based delivery systems for the diagnosis and treatment of brain diseases. Additionally, it discussed the challenges and potential solutions for clinical translation.

Advances of NIR Light Responsive Materials for Diagnosis and Treatment of Brain Diseases

AbstractBrain diseases pose a great threat to human health worldwide, thus it is of great importance to explore new materials for their diagnosis and therapy. Compared with the ultraviolet (UV) and visible light, near infrared (NIR) light has better biosafety, lower tissue auto‐fluorescence, and stronger penetration into skull. Hence, NIR light responsive materials have attracted great attention recently which can not only realize the high spatial resolution and signal‐to‐noise ratio imaging for diagnosis, but also achieve effective NIR light triggered treatment noninvasively. Besides, the brain lesions can be visualized clearly by NIR imaging, which can provide more accurate information for guiding treatments. Therefore, this work systematically summarizes the recent advances of NIR light responsive materials for diagnosis and treatment of brain diseases. Firstly, this work briefly reviews the pathological features of blood brain barrier (BBB) and the rational design of materials to target brain disease. Then, the emerging approaches for diagnosis and treatment of various brain diseases with NIR light responsive materials are introduced. Subsequently, the imaging‐guided therapies are elaborated, such as the fluorescence imaging guided surgery and sonodynamic therapy. Finally, some challenges and prospects on the design of NIR light responsive materials for precise diagnosis and therapy of brain diseases are put forward.

Non-invasive PTEN mRNA brain delivery effectively mitigates growth of orthotopic glioblastoma

Messenger RNA (mRNA) based gene therapy holds great promise for treating various brain-related disorders including brain cancer. However, mRNA instability, inability to pass the blood-brain barrier (BBB) and lack of tumour targeting, hindering the further application of mRNA in brain disease therapy. Here we designed a new mRNA nanomedicine (ABNPs@mRNA) and demonstrated that it could effectively address the above challenges by combining three distinct design strategies: ApoE peptide based “two birds, one stone” targeting, cell membrane based biomimetic cloaking and tumour microenvironment responsive controlled drug release. To effectively target to glioblastoma (GBM), we loaded ABNPs@mRNA with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) mRNA, a tumour suppressor that is mutated or inactive in 20–40% of GBM. Loss of PTEN activity in GBM patients correlates with therapeutic resistance, oncogenesis and poor prognosis. Together, our three design elements enabled ABNPs@mRNA to deliver a maximum PTEN mRNA concentration of 7.22% injection dose (ID)/g in brain tumour tissue. In the orthotopic GBM mouse models (U87MG and patient-derived CSC2 GSCs xenograft), treatment with ABNPs@mRNA resulted in a remarkable extension of median survival time relative to mice receiving PBS (49 d versus 23 d in U87MG and 40 d versus 23 d in CSC2 model). Importantly, ABNPs@mRNA nanomedicine caused negligible side effects in major organs including liver and kidney. Considering the stability, safety, non-invasive brain delivery and GBM inhibition efficacy, our new mRNA nanomedicine may unlock a new avenue for mRNA application in GBM inhibition and beyond.

Reactive Oxygen Species-Responsive Transformable and Triple-Targeting Butylphthalide Nanotherapy for Precision Treatment of Ischemic Stroke by Normalizing the Pathological Microenvironment.

High potency and safe therapies are still required for ischemic stroke, which is a leading cause of global death and disability. Herein, a reactive oxygen species (ROS)-responsive, transformable, and triple-targeting dl-3-n-butylphthalide (NBP) nanotherapy was developed for ischemic stroke. To this end, a ROS-responsive nanovehicle (OCN) was first constructed using a cyclodextrin-derived material, which showed considerably enhanced cellular uptake in brain endothelial cells due to notably reduced particle size, morphological transformation, and surface chemistry switching upon triggering via pathological signals. Compared to a nonresponsive nanovehicle, this ROS-responsive and transformable nanoplatform OCN exhibited a significantly higher brain accumulation in a mouse model of ischemic stroke, thereby affording notably potentiated therapeutic effects for the nanotherapy derived from NBP-containing OCN. For OCN decorated with a stroke-homing peptide (SHp), we found significantly increased transferrin receptor-mediated endocytosis, in addition to the previously recognized targeting capability to activated neurons. Consistently, the engineered transformable and triple-targeting nanoplatform, i.e., SHp-decorated OCN (SON), displayed a more efficient distribution in the injured brain in mice with ischemic stroke, showing considerable localization in endothelial cells and neurons. Furthermore, the finally formulated ROS-responsive transformable and triple-targeting nanotherapy (NBP-loaded SON) demonstrated highly potent neuroprotective activity in mice, which outperformed the SHp-deficient nanotherapy at a 5-fold higher dose. Mechanistically, our bioresponsive, transformable, and triple-targeting nanotherapy attenuated the ischemia/reperfusion-induced endothelial permeability and improved dendritic remodeling and synaptic plasticity of neurons in the injured brain tissue, thereby promoting much better functional recovery, which were achieved by efficiently enhancing NBP delivery to the ischemic brain tissue, targeting injured endothelial cells and activated neurons/microglial cells, and normalizing the pathological microenvironment. Moreover, preliminary studies indicated that the ROS-responsive NBP nanotherapy displayed a good safety profile. Consequently, the developed triple-targeting NBP nanotherapy with desirable targeting efficiency, spatiotemporally controlled drug release performance, and high translational potential holds great promise for precision therapy of ischemic stroke and other brain diseases.

Brain Waste Removal System and Sleep: Photobiomodulation as an Innovative Strategy for Night Therapy of Brain Diseases.

Emerging evidence suggests that an important function of the sleeping brain is the removal of wastes and toxins from the central nervous system (CNS) due to the activation of the brain waste removal system (BWRS). The meningeal lymphatic vessels (MLVs) are an important part of the BWRS. A decrease in MLV function is associated with Alzheimer's and Parkinson's diseases, intracranial hemorrhages, brain tumors and trauma. Since the BWRS is activated during sleep, a new idea is now being actively discussed in the scientific community: night stimulation of the BWRS might be an innovative and promising strategy for neurorehabilitation medicine. This review highlights new trends in photobiomodulation of the BWRS/MLVs during deep sleep as a breakthrough technology for the effective removal of wastes and unnecessary compounds from the brain in order to increase the neuroprotection of the CNS as well as to prevent or delay various brain diseases.

The Role of CD4+ T Cells in the Immunotherapy of Brain Disease by Secreting Different Cytokines.

Upon different stimulation, naïve CD4+ T cells differentiate into various subsets of T helper (Th) cells, including Th1, Th2, Th17, and Tregs. They play both protective and pathogenic roles in the central nervous system (CNS) by secreting different cytokines. Failure of the homeostasis of the subgroups in the CNS can result in different brain diseases. Recently, immunotherapy has drawn more and more attention in the therapy of various brain diseases. Here, we describe the role of different CD4+ T cell subsets and their secreted cytokines in various brain diseases, as well as the ways in which by affecting CD4+ T cells in therapy of the CNS diseases. Understanding the role of CD4+ T cells and their secreted cytokines in the immunotherapy of brain disease will provide new targets and therapeutics for the treatment of brain disease. The role of CD4 + T cell subtypes in different diseases and their associated regulatory genes, proteins, and enzymes. CD4 + T cell subtypes play both protective (green) and pathogenic (red) roles in different brain diseases. The immune regulatory effects of CD4 + T cells and their subtypes are promoted or inhibited by different genes, proteins, and enzymes.

Routes of administration for adeno-associated viruses carrying gene therapies for brain diseases.

Gene therapy is a powerful tool to treat various central nervous system (CNS) diseases ranging from monogenetic diseases to neurodegenerative disorders. Adeno-associated viruses (AAVs) have been widely used as the delivery vehicles for CNS gene therapies due to their safety, CNS tropism, and long-term therapeutic effect. However, several factors, including their ability to cross the blood-brain barrier, the efficiency of transduction, their immunotoxicity, loading capacity, the choice of serotype, and peripheral off-target effects should be carefully considered when designing an optimal AAV delivery strategy for a specific disease. In addition, distinct routes of administration may affect the efficiency and safety of AAV-delivered gene therapies. In this review, we summarize different administration routes of gene therapies delivered by AAVs to the brain in mice and rats. Updated knowledge regarding AAV-delivered gene therapies may facilitate the selection from various administration routes for specific disease models in future research.