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The central nervous system, one of the most delicate microenvironments of the body, is protected by the blood-brain barrier regulating its homeostasis. Blood-brain barrier is a highly complex structure that tightly regulates the movement of ions of a limited number of small molecules and of an even more restricted number of macromolecules from the...
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Central nervous system diseases negatively affect patients and society. Providing successful noninvasive treatments for these diseases is challenging because of the presence of the blood–brain barrier. While protecting the brain’s homeostasis, the barrier limits the passage of almost all large-molecule drugs and most small-molecule drugs. A noninva...
Citations
... Phenylalanine in food undergoes microbial action to transform into phenylacetate, which then combines with glycine to synthesize phenylacetylglutamine, also known as PAGly. PAGly has a molecular weight of < 200, which allows it to cross the blood-brain barrier (BBB) and perform direct action (Nair et al., 2018). Here, it was observed that PAGly administration reduced the infarct size and improved the neurological behavioral scores in I/R rats. ...
Phenylacetylglycine (PAGly) is a small molecule derived from phenylalanine in the gut via glycine degradation and conjugation. It has been associated with both the progression of atherosclerosis and protective effects on the myocardium. This study evaluated the function and the underlying mechanisms of PAGly in a rat cerebral ischemia/reperfusion (I/R) injury model. The results indicated that PAGly markedly alleviated cerebral infarct volume (P = 0.0024) and improved the neurobehavioral outcomes (P = 0.0149) after I/R injury. PAGly is structurally analogous to catecholamines and binds to β2-adrenergic receptors (β2AR) on microglia without altering the expression of these receptors (P = 0.9137), but instead inhibiting their activity. It was also observed that when β2AR was engaged in microglia, PAGly suppressed the release of TNF-α (P = 0.0018), IL-1β (P = 0.0310), and IL-6 (P = 0.0017), thereby reducing neuronal apoptosis (P = 0.000003). Furthermore, the protective effect of PAGly diminished after the administration of β2AR-specific agonist fenoterol (P = 0.0055). These data indicate that PAGly mitigates cerebral I/R injury by inhibiting microglial inflammation via β2AR, highlighting its potential as a therapeutic agent. These findings position PAGly as a promising candidate for therapeutic intervention in cerebrovascular injuries, warranting further exploration in clinical settings.
... The traversal of the blood-brain barrier to deliver drugs to the brain represents a significant obstacle in the treatment of brain tumors. 114 EVs derived from grapefruit have been shown to deliver functional siRNA to both GL26-luc and A549-luc cells, inhibiting the expression of the luciferase gene within these cells. Subsequently, grapefruit-derived EVs carrying JSI-124 were delivered intranasally to the brain, inhibiting GL-26 tumor growth and thereby prolonging the survival of mice. ...
Inflammation involves complex immune responses where cytokines such as TNF-α, IL-1, and IL-6 promote vasodilation and increased vascular permeability to facilitate immune cell migration to inflammation sites. Persistent inflammation is linked to diseases like cancer, arthritis, and neurodegenerative disorders. Although oral anti-inflammatory drugs are favored for their non-invasiveness and cost-effectiveness, their efficacy is often compromised due to gastrointestinal degradation and limited bioavailability. Recent advancements highlight the potential of extracellular vesicles (EVs) as nanocarriers that enhance drug delivery by encapsulating therapeutic agents, ensuring targeted release and reduced toxicity. These EVs, derived from dietary sources and cell cultures, exhibit excellent biocompatibility and stability, presenting a novel approach in anti-inflammatory therapies. This review discusses the classification and advantages of orally administered EVs (O-EVs), their mechanism of action, and their emerging role in treating inflammatory conditions, positioning them as promising vectors in the development of innovative anti-inflammatory drug delivery systems.
... Dopamine also cannot penetrate the BBB, so it may be inferred that its analogue SK608 cannot either ( Figure 2). Utilizing nano-dimensional vehicles with vast surface areas can help overcome the difficulties in penetration across the complicated physiology of the BBB [109,110]. Alternatively, intranasal administration is a non-invasive method that bypasses the BBB to allow the direct access of drugs to the central nervous system, which has been showing promising results recently [111][112][113]. ...
The relapse rate of substance abusers is high, and addiction rehabilitation adjunct drugs need to be developed urgently. There have been numerous reports on blocking the formation of substance addiction, but studies on drugs that can alleviate withdrawal symptoms are very limited. Both the dopamine transporter (DAT) hypothesis and D3 dopamine receptor (D3R) hypothesis are proposed. DAT activators reduce the extracellular dopamine level, and D3R antagonists reduce the neuron’s sensitivity to dopamine, both of which may exacerbate the withdrawal symptoms subsequently. The D3R partial agonist SK608 has biased signaling properties via the G-protein-dependent pathway but did not induce D3R desensitization and, thus, may be a promising drug for the withdrawal symptoms. Drugs for serotoninergic neurons or GABAergic neurons and anti-inflammatory drugs may have auxiliary effects to addiction treatments. Drugs that promote structural synaptic plasticity are also discussed.
... The blood-brain barrier (BBB) prevents medications to treat brain diseases from entering the brain; in fact, even the very smallest molecules cannot penetrate the BBB (Nair et al., 2018). Nano-drug delivery systems have become a promising method given their abilities to protect drugs from degradation, to transport drugs to action targets, to prolong the blood circulation time, and reduce toxicity to the human body. ...
... The BBB maintains a relatively stable internal environment for the brain tissue and ensures normal physiological functions in the CNS and the transmission of nutrients into the brain. However, the BBB also hinders the delivery of diagnostic and therapeutic medicines into the brain; approximately 98% of small-molecule drugs, and almost all macromolecular drugs, cannot be delivered into the brain (Nair et al., 2018). ...
... Many researchers have recognized the hindrance created by the BBB with regards to drug delivery; thus, many researchers have attempted to develop new technologies to allow the penetration of the BBB and formulate new drug delivery strategies (Nair et al., 2018). There are three commonly used approaches to administer molecules through the BBB, including systemic absorption, nasal, and intracerebroventricular methods (Figure 2 and Table 3; Wan et al., 2020). ...
Remyelination failure is one of the main characteristics of multiple sclerosis and is potentially correlated with disease progression. Previous research has shown that the extracellular matrix is associated with remyelination failure because remodeling of the matrix often fails in both chronic and progressive multiple sclerosis. Fibronectin aggregates are assembled and persistently exist in chronic multiple sclerosis, thus inhibiting remyelination. Although many advances have been made in the mechanisms and treatment of multiple sclerosis, it remains very difficult for drugs to reach pathological brain tissues; this is due to the complexity of brain structure and function, especially the existence of the blood-brain barrier. Therefore, herein, we review the effects of fibronectin aggregates on multiple sclerosis and the efficacy of different forms of drug delivery across the blood-brain barrier in the treatment of this disease.
... 5 The use of nanoparticles for drug delivery to the brain is a promising alternative due to the possibility of surface multifunctionalization that can promote the targeting or/and crossing enhancement to the BBB. 42 Among functionalization options is the use of surfactants, with polysorbates being the most efficient for targeting to the brain when compared with poloxamers, poloxamine 908, Cremophor ® EZ, Cremophor ® RH 40, polyoxyethylene-(23)-lauryl ether (Brij ® 35). 43 Consistent with previous reports, MFS-AN nanoparticles, which were prepared with poloxamer 407, 29 did not reach the brain in adequate amounts to control the cerebral infection. ...
Objectives:
To develop alginate nanoparticles functionalized with polysorbate 80 (P80) as miltefosine carriers for brain targeting in the oral treatment of cryptococcal meningitis.
Methods:
Miltefosine-loaded alginate nanoparticles functionalized or not with P80 were produced by an emulsification/external gelation method and the physicochemical characteristics were determined. The haemolytic activity and cytotoxic and antifungal effects of nanoparticles were assessed in an in vitro model of the blood-brain barrier (BBB). A murine model of disseminated cryptococcosis was used for testing the efficacy of oral treatment with the nanoparticles. In addition, serum biomarkers were measured for toxicity evaluation and the nanoparticle biodistribution was analysed.
Results:
P80-functionalized nanoparticles had a mean size of ∼300 nm, a polydispersity index of ∼0.4 and zeta potential around -50 mV, and they promoted a sustained drug release. Both nanoparticles were effective in decreasing the infection process across the BBB model and reduced drug cytotoxicity and haemolysis. In in vivo cryptococcosis, the oral treatment with two doses of P80 nanoparticles reduced the fungal burden in the brain and lungs, while the non-functionalized nanoparticles reduced fungal amount only in the lungs, and the free miltefosine was not effective. In addition, the P80-functionalization improved the nanoparticle distribution in several organs, especially in the brain. Finally, treatment with nanoparticles did not cause any toxicity in animals.
Conclusions:
These results support the potential use of P80-functionalized alginate nanoparticles as miltefosine carriers for non-toxic and effective alternative oral treatment, enabling BBB translocation and reduction of fungal infection in the brain.
... BBB is a highly effective barrier that protects the most delicate and complex organ in the human body, the brain (Nair et al., 2018). This complex system consists of endothelial cells, pericytes, astroglia, perivascular mast cells and basal lamina and controls the flow of ions, chemicals, and macromolecules from the blood to the brain. ...
Worldwide, populations face significant burdens from neurodegenerative disorders (NDDs), especially Alzheimer's and Parkinson's diseases. Although there are many proposed etiologies for neurodegenerative disorders, including genetic and environmental factors, the exact pathogenesis for these disorders is not fully understood. Most patients with NDDs are given lifelong treatment to improve their quality of life. There are myriad treatments for NDDs; however, these agents are limited by their side effects and difficulty in passing the blood–brain barrier (BBB). Furthermore, the central nervous system (CNS) active pharmaceuticals could offer symptomatic relief for the patient's condition without providing a complete cure or prevention by targeting the disease's cause. Recently, Mesoporous silica nanoparticles (MSNs) have gained interest in treating NDDs since their physicochemical properties and inherent ability to pass BBB make them possible drug carriers for several drugs for NDDs treatment. This paper provides insight into the pathogenesis and treatment of NDDs, along with the recent advances in applying MSNs as fibril scavengers. Moreover, the application of MSNs-based formulations in enhancing or sustaining drug release rate, and brain targeting via their responsive release properties, besides the neurotoxicity of MSNs, have been reviewed.
... The chemical structure of the therapeutics will not hinder the permeation when it is encapsulated in nanomedicines. Biomimetic and physicochemical properties of the nanomedicine guided the permeation of impermeable therapeutics to the BBB [212]. ...
It is well known that the presence of a blood–brain barrier (BBB) makes drug delivery to the brain more challenging. There are various mechanistic routes through which therapeutic molecules travel and deliver the drug across the BBB. Among all the routes, the transcellular route is widely explored to deliver therapeutics. Advances in nanotechnology have encouraged scientists to develop novel formulations for brain drug delivery. In this article, we have broadly discussed the BBB as a limitation for brain drug delivery and ways to solve it using novel techniques such as nanomedicine, nose-to-brain drug delivery, and peptide as a drug delivery carrier. In addition, the article will help to understand the different factors governing the permeability of the BBB, as well as various formulation-related factors and the body clearance of the drug delivered into the brain.
... Certain nanoparticles can lead to a cytotoxic effects by generating reactive oxygen species (ROS) (Kwon et al., 2019). Recent studies reported that NPs can pass through all cell walls and even blood-brain barrier (Nair et al., 2018). There are various metal NPs that can be used as antimicrobial agents, e.g., Ag, CuO, ZnO, TiO 2 , and Fe 3 O 4 . ...
Nano iron oxide has shown great potential to function as a universal and low-cost antimicrobial agent. In this work, we fabricated a new class of mesoporous hexagon magnetic iron oxide nanosheets (HMI-NS) modified by 3-aminopropyltriethoxysilane (APTES) through a simple synthesis route as a novel vehicle tracking building (VTB) antimicrobial agent. The VTB-MHI-NSs had a uniform platform-like structure with an average size of 45 nm and well-scattered active sites in the inner core and saline shell with microbicidal effect. Tests revealed that the modification of iron oxide nanosheets caused an improvement in antimicrobial activity against bacteria and fungi. The developed bioactive behavior of The VTB-MHI-NSs can be due to the system architectures, arrangement of crystal atomic-scale, and mesopore windows. This organically functionalized tailoring of The VTB-MHI-NSs can influence the particle size, shape, and surface properties, thereby creating significant extracellular interactions and exerting intracellular effects that cause antimicrobial activity. The appropriate functionalization of the hexagonal outer surface of the mesopore windows enabled the modulation of loading and microbial cell interaction and played a key role in offering sustained platform-like nanosheets that attached to the microbe, causing cell death. Therefore, the mesoporous organic functionalized hexagon iron oxide nanosheets can be considered in water future clean-up processes.
... Therefore, the downregulation of this gene might not only trigger the metastasis and invasion of cancerous cells but could also impact chemotherapy resistance in cancer cells [157]. The BBB protects the brain but makes treating neurological illnesses, such as gliomas, more challenging [180]. Many dosage forms aimed at crossing the BBB have been developed and are under investigation; however, few drug delivery systems can successfully cross the BBB. ...
Despite the multiple ongoing and novel initiatives for developing brain-targeted drug delivery systems, insurmountable obstacles remain. A perfect drug delivery device that can bypass the brain–blood barrier and boost therapeutic efficacy is urgently needed for clinical applications. Exosomes hold unrivaled benefits as a drug delivery vehicle for treating brain diseases due to their endogenous and innate attributes. Unique properties, such as the ability to penetrate physical barriers, biocompatibility, innate targeting features, ability to leverage natural intracellular trafficking pathways, favored tumor homing, and stability, make exosomes suitable for brain-targeted drug delivery. Herein, we provide an overview of recent exosome-based drug delivery nanoplatforms and discuss how these inherent vesicles can be used to deliver therapeutic agents to the brain to cure neurodegenerative diseases, brain tumors, and other brain disorders. Moreover, we review the current roadblocks associated with exosomes and other brain-targeted drug delivery systems and discuss future directions for achieving successful therapy outcomes.
... The methods adopted for CSF collection can also be used for drug or tracer administration into the intrathecal space [12]. The penetration of most drugs is restricted by the blood-brain barrier; therefore, many small drug compounds and proteins cannot enter the CNS [16]. Moreover, the blood-CSF barrier, formed by choroid plexus epithelial cells, limits drug entry into the CNS [1,2]. ...
Background
Cerebrospinal fluid (CSF) provides a close representation of pathophysiological changes occurring in the central nervous system (CNS); therefore, it has been employed in pathogenesis research and biomarker development for CNS disorders. CSF obtained from valid mouse models relevant to CNS disorders can be an important resource for successful biomarker and drug development. However, the limited volume of CSF that can be collected from tiny intrathecal spaces and the technical difficulties involved in CSF sampling has been a bottleneck that has hindered the detailed analysis of CSF in mouse models.
Methods
We developed a novel chronic dural port (CDP) method without cannulation for CSF collection of mice. This method enables easy and repeated access to the intrathecal space in a free-moving, unanesthetized mouse, thereby enabling continuous long-term CSF collection with minimal tissue damage and providing a large volume of high-quality CSF from a single mouse. When combined with chemical biosensors, the CDP method allows for real-time monitoring of the dynamic changes in neurochemicals in the CSF at a one-second temporal resolution in free-moving mice. Moreover, the CDP can serve as a direct access point for the intrathecal injection of CSF tracers and drugs.
Results
We established a CDP implantation and continuous CSF collection protocol. The CSF collected using CDP was not contaminated with blood and maintained physiological concentrations of basic electrolytes and proteins. The CDP method did not affect mouse’s physiological behavior or induce tissue damage, thereby enabling a stable CSF collection for up to four weeks. The spatio-temporal distribution of CSF tracers delivered using CDP revealed that CSF metabolism in different brain areas is dynamic. The direct intrathecal delivery of centrally acting drugs using CDP enabled real-time behavioral assessments in free-moving mice.
Conclusions
The CDP method enables the collection of a large volume of high-quality CSF and direct intrathecal drug administration with real-time behavioral assessment in free-moving mice. Combined with animal models relevant to CNS disorders, this method provides a unique and valuable platform for biomarker and therapeutic drug research.
