CNS Diseases Research Articles

The influnce of oxytocin on the central nervous system by different routes of administration

Background. One of the unresolved problems on the way to improving the pharmacotherapy of CNS diseases is the development and creation of technologies that allow drugs to cross the blood-brain barrier (BBB). One way to bypass the blood-brain barrier is to use the intranasal route of administration. Delivery of the drug is carried out due to the peculiarities of the mechanism of transport of substances.
 Aim. To study the effect of intranasal administration of oxytocin on the behavior of mice and its content in various brain structures.
 Materials and methods. The study used 60 outbred mice divided into 6 groups. The first group of mice were intact and did not present with oxytocin or physiological solution. The second and third groups of mice found a single injection of 20 and 300 l of oxytocin 5 IU intraperitoneally, respectively. The fourth group of mice was injected intranasally with oxytocin 5 IU in an amount of 20 l. The fifth group of mice received 20 l of saline intranasally and the sixth group of mice received 300 l of saline intraperitoneally. Behavioral effects were recorded in the elevated plus maze for 5 min, the duration of stay in the open arm, the number of transitions between the arms, and the number of hangings from the arms were assessed. Then measured the concentration of oxytocin in the following structures: olfactory bulb, striatum, hypothalamus and hippocampus using enzyme immunoassay.
 Results. Intranasal administration of oxytocin causes changes in behavior in mice, in particular, a decrease in the degree of anxiety (anxiolytic effect). When timing the open arms in the plus maze test, it was found that mice administered intranasal oxytocin required more time spent in the arms (32.444.28 s versus the control group with a value of 5.661.96 s). ), the number of transitions between the sleeves increased (1.900.10 s versus 1.100.10 s in the control group) and the number of hangings from the sleeves (8.441.37 versus 3.770.98 in the control group). There was an increase in one of the indicators - the number of hanging from the sleeve after intraperitoneal injection of 300 l of oxytocin, which may indicate the manifestation of an anxiolytic effect of oxytocin. The remaining groups: intranasal saline injection, intraperitoneal saline injection, intraperitoneal injection of 20 l of oxytocin did not show significant changes in behavior compared with the control group. In addition, it was found that after intranasal administration of oxytocin, its content increased in certain brain structures the hypothalamus and hippocampus.
 Conclusion. The results of this study indicate the potential efficacy of intranasal administration of oxytocin in the treatment of diseases affecting the central nervous system.

Clinical and etiological features of hydrocephalus in infants

Aim. To analyze the causes and clinical course of hydrocephalus in infants and its association with various etiological factors.Materials and Methods. The study involved a retrospective analysis of data from 47 infants who were hospitalized in the Pediatric Neurosurgery Department of the Republican Scientific Center of Neurosurgery named after Shifobakhsh between the years 2020 and 2022. The patients were evaluated using a comprehensive range of diagnostic techniques, including CT, MRI, neuro-ophthalmoscopy, and neurosonography.Results. Among the infants with hydrocephalus, infectious-inflammatory CNS diseases were identified as the primary cause in 23 cases (48.9%), cranial-brain trauma in 12 cases (25.6%), brain tumor processes in 7 cases (14.9%), and congenital factors in 5 cases (10.6%). All 47 (100%) patients presented with generalized cerebral symptoms and exhibited signs of hypertensive-hydrocephalic syndrome.Conclusion. Our findings demonstrate that hydrocephalus in infants most commonly develops following the occurrence of infectious-inflammatory CNS diseases, while congenital causes are relatively less prevalent. The investigation of the clinical features and etiology of hydrocephalus enables the selection of appropriate diagnostic strategies and optimal surgical treatment methods.

Aquaporin 4 and its Relationship with Brain Astrocytomas – Literature Review

Abstract Background Aquaporins (AQPs) are a family of membrane proteins that regulate the osmotic permeability of the plasma membrane. There are described in the literature a total of 13 types of Aquaporins in mammals, each with different places of expression. In addition to water, some AQPs allow the passage of glycerol and ammonia, being called Aquaglyceroproteins. In the central nervous system, AQPs 1 and 4 are expressed, being responsible for the water regulation in the blood-brain barrier. These two AQPs are believed to participate in the pathophysiological process that governs the behavior of various CNS diseases, such as trauma and primary tumors. More particularly, there are quite controversial data in the literature on the expression of AQP4 in tumors and its relationship with disease progression and treatment possibility. Objective This paper aims to perform a literature review on the function and expression of AQP4 in the CNS and primary tumors of this system, to compile what is in the literature on the subject and raise new possible research hypotheses. Methods The PUBMED platform was used for bibliographic survey using “Aquaporin 4,” “expression” and “astrocytomas” as keywords. Articles older than 2008 and articles that did not address AQP4 expression in astrocytomas were excluded. In the selected articles, the following topics were investigated: AQP4 structure, brain and tumor localization, and relationship with peritumoral edema. Results Regarding the structure and location of AQP4, the literature presents two isoforms of AQP4: M1 and M23. Both form clusters of AQP4 called “orthogonal arrays of proteins - OAPs.” In the tumor tissue, the literature shows a decrease in the formation of OAPs and an increase in the expression of both AQP4 isoforms, besides losing their polarity, diffusing through the cytoplasmic membrane. As for the function of AQP4 in tumors, AQP4 assists in cell migration and invasion, in addition to participating in cell proliferation and apoptosis. Regarding the relationship with cerebral edema, there are controversial knowledge. Studies have shown that increased AQP4 aggravates cytotoxic edema of tumor cells and, by assisting in cell migration and angiogenesis, indirectly assist in the formation of vasogenic edema by breaking the blood-brain barrier. Other studies, however, point to the increase in AQP4 as a protective mechanism to combat vasogenic edema that occurs in tumor formation. Furthermore, the literature presents a therapeutic proposal in which, by inhibiting AQP4 expression, tumor migration and cerebral edema decrease in rats with glioblastoma. Discussion As shown in the literature, there is a difference in histopathological structure between high and low grade gliomas. However, there are common changes between them. These common changes could then be used as a factor of severity or evolution of low-grade to high-grade tumors. Moreover, it is not yet possible to perceive the true relationship of AQP4 expression and increased VEGF evolution of peritumoral edema. Finally, it can be hypothesized that since the expression ratio between AQP4 isoforms in normal tissue is greater than in some tumors, the decrease in this ratio is due either to decreased M23 expression or increased of the isoform M1. Conclusion Further studies are needed to understand the physiology and pathophysiology involving AQP4 in astrocytomas to create effective therapeutic proposals to combat this disease.

Prospects of pharmacological regulation of aquaporin function in CNS diseases

The review analyzes the results of scientific research on the role of aquaporins in the pathogenesis of CNS diseases and the possibility of their pharmacological regulation.
 Aquaporins (AQP) are proteins involved in the transmembrane transport of water and other substances. They form the water channels of cell membranes and are widely represented in various mammalian cells, including the membranes of human brain and spinal cord cells. To date, about 300 types of proteins of the aquaporin family have been discovered, of which 13 (AQP0AQP12) have been identified in human cells. Localization of different types of AQP in CNS structures, their functional activity and involvement in the development of CNS diseases differ. There are mainly three types of AQPs in the central nervous system: AQP1, AQP4 and AQP9. The results of scientific research indicate the most important role of AQP in maintaining water-salt homeostasis and ensuring physiological processes in the central nervous system, and also confirm the role of AQP in the pathogenesis of a number of diseases of the central nervous system (cerebral edema of various genesis, invasion of tumor cells and the formation of peritumorous edema, in the development of autoimmune diseases opticomyelitis, Alzheimers disease). Pharmacological regulation of the functional activity of aquaporins can influence the course of these diseases. Therefore, there is a natural interest in drugs that can change the expression of AQP.
 Proteins of the aquaporin family provide transmembrane transport of water and play an essential role in the development of pathological conditions of the central nervous system. They can be potential targets for pharmacological effects in a number of diseases of the central nervous system. The search and study of drugs affecting the expression and functional activity of AQP is pathogenetically justified and is a promising direction in the development of pharmacotherapy strategies for cerebral edema, malignant brain tumors and other CNS diseases.

GM-CSF Promotes the Survival of Peripheral-Derived Myeloid Cells in the Central Nervous System for Pain-Induced Relapse of Neuroinflammation.

We recently discovered a (to our knowledge) new neuroimmune interaction named the gateway reflex, in which the activation of specific neural circuits establishes immune cell gateways at specific vessel sites in organs, leading to the development of tissue-specific autoimmune diseases, including a multiple sclerosis (MS) mouse model, experimental autoimmune encephalomyelitis (EAE). We have reported that peripheral-derived myeloid cells, which are CD11b+MHC class II+ and accumulate in the fifth lumbar (L5) cord during the onset of a transfer model of EAE (tEAE), play a role in the pain-mediated relapse via the pain-gateway reflex. In this study, we investigated how these cells survive during the remission phase to cause the relapse. We show that peripheral-derived myeloid cells accumulated in the L5 cord after tEAE induction and survive more than other immune cells. These myeloid cells, which highly expressed GM-CSFRα with common β chain molecules, grew in number and expressed more Bcl-xL after GM-CSF treatment but decreased in number by blockade of the GM-CSF pathway, which suppressed pain-mediated relapse of neuroinflammation. Therefore, GM-CSF is a survival factor for these cells. Moreover, these cells were colocalized with blood endothelial cells (BECs) around the L5 cord, and BECs expressed a high level of GM-CSF. Thus, GM-CSF from BECs may have an important role in the pain-mediated tEAE relapse caused by peripheral-derived myeloid cells in the CNS. Finally, we found that blockade of the GM-CSF pathway after pain induction suppressed EAE development. Therefore, GM-CSF suppression is a possible therapeutic approach in inflammatory CNS diseases with relapse, such as MS.

HIF prolyl hydroxylase 2/3 deletion disrupts astrocytic integrity and exacerbates neuroinflammation.

Astrocytes constitute the parenchymal border of the blood-brain barrier (BBB), modulate the exchange of soluble and cellular elements, and are essential for neuronal metabolic support. Thus, astrocytes critically influence neuronal network integrity. In hypoxia, astrocytes upregulate a transcriptional program that has been shown to boost neuroprotection in several models of neurological diseases. We investigated transgenic mice with astrocyte-specific activation of the hypoxia-response program by deleting the oxygen sensors, HIF prolyl-hydroxylase domains 2 and 3 (Phd2/3). We induced astrocytic Phd2/3 deletion after onset of clinical signs in experimental autoimmune encephalomyelitis (EAE) that led to an exacerbation of the disease mediated by massive immune cell infiltration. We found that Phd2/3-ko astrocytes, though expressing a neuroprotective signature, exhibited a gradual loss of gap-junctional Connexin-43 (Cx43), which was induced by vascular endothelial growth factor-alpha (Vegf-a) expression. These results provide mechanistic insights into astrocyte biology, their critical role in hypoxic states, and in chronic inflammatory CNS diseases.

Brain‐Targeted Exosomes‐Based Drug Delivery System to Overcome the Treatment Bottleneck of Brainstem Glioma

AbstractBrain health is the humans’ primary goal in achieving health and longevity. Brainstem glioma (BSG) has a high disability and mortality rate, posing a serious threat to children's brain health. Delivery of drugs to the brainstem is limited by poor tumor targeting and low blood‐brain barrier (BBB) permeability. Thus, it is a great challenge to construct intracranial drug delivery systems with strong biocompatibility, low immunogenicity, and high BBB permeability for the delivery of drugs targeting BSG. Exosomes, as the next generation of novel delivery systems, have been widely used to across the BBB due to their advantages of good biocompatibility, stability, and permeability of the BBB and have made corresponding breakthroughs in targeted drug delivery for CNS diseases. This review summarizes natural, polypeptide functionalized, and physical methods‐assisted brain‐targeted exosomes‐based drug delivery systems, the drug treatment bottleneck of BSG, and highlights the potential of using a brain‐targeted exosomes‐based drug delivery system to overcome the drug treatment bottleneck of BSG. It provides new insights into using exosomes‐based drug delivery for BSG treatment.

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.

Prospects of pharmacological regulation of aquaporin function in CNS diseases

The review analyzes the results of scientific research on the role of aquaporins in the pathogenesis of CNS diseases and the possibility of their pharmacological regulation.
 Aquaporins (AQP) are proteins involved in the transmembrane transport of water and other substances. They form the water channels of cell membranes and are widely represented in various mammalian cells, including the membranes of human brain and spinal cord cells. To date, about 300 types of proteins of the aquaporin family have been discovered, of which 13 (AQP0AQP12) have been identified in human cells. Localization of different types of AQP in CNS structures, their functional activity and involvement in the development of CNS diseases differ. There are mainly three types of AQPs in the central nervous system: AQP1, AQP4 and AQP9. The results of scientific research indicate the most important role of AQP in maintaining water-salt homeostasis and ensuring physiological processes in the central nervous system, and also confirm the role of AQP in the pathogenesis of a number of diseases of the central nervous system (cerebral edema of various genesis, invasion of tumor cells and the formation of peritumorous edema, in the development of autoimmune diseases opticomyelitis, Alzheimers disease). Pharmacological regulation of the functional activity of aquaporins can influence the course of these diseases. Therefore, there is a natural interest in drugs that can change the expression of AQP.
 Proteins of the aquaporin family provide transmembrane transport of water and play an essential role in the development of pathological conditions of the central nervous system. They can be potential targets for pharmacological effects in a number of diseases of the central nervous system. The search and study of drugs affecting the expression and functional activity of AQP is pathogenetically justified and is a promising direction in the development of pharmacotherapy strategies for cerebral edema, malignant brain tumors and other CNS diseases.

Molecular mechanisms of transport of substances across the blood-brain barrie as targets for pharmacological action. Part 2. Modern methods of delivery of pharmacological agents to the central nervous system

One of the unresolved problems on the way to improving the pharmacotherapy of CNS diseases is the development and creation of technologies that allow drugs to cross the blood-brain barrier (BBB). The review discusses modern methods of drug delivery to the CNS. The advantages and disadvantages of the main pharmacological strategies for directly overcoming the BBB and an alternative to this are shown. New methods of drug delivery to the brain with damage (physical, chemical, etc.) and without disruption of the blood-brain barrier structure (small molecules, cell-mediated transport, stem cells) are considered. The prospects for the use of artificial nanosized drug transporters are discussed. An alternative strategy of pharmacological action on the CNS structures (intranasal route) is shown to be promising. Possible mechanisms of action of pharmacological agents on CNS structures bypassing the BBB are considered.

Selective antagonists of calcium-permeable GluA1 AMPA-receptors as potential antiaddictive agents

An increase in synaptic dopamine levels, particularly in the nucleus accumbens sheath, is a critical initial response for encoding a drugs positive effect and the development of associative learning, which is crucial for finding drugs in response to their rewarding effects.
 This study aims to review current data describing the role of AMPA glutamate receptors in the pathological drug search that occurs during the transition from drug use to drug abuse.
 Publications reviewed and analyzed the journal publications in international databases (PubMed, Web of Science, Scopus, RSCI) on the mechanisms of interaction between dopamine and AMPA glutamate receptors in drug addiction pathogenesis are reviewed and analyzed.
 After repeated exposure to psychostimulant drugs, the dopamine response to narcogen administration becomes sensitized, which is responsible for drugs of abuse over other natural reinforcers. The nucleus accumbens contains convergent inputs of dopamine and glutamate, which modulate the response to psychostimulant drugs. Simultaneously, a constant increase in AMPA-receptors lacking the GluA2 subunit was observed, which leads to an increase in conductivity and initiates a cascade of calcium-dependent signaling. With the development of compulsive drug seeking, the expression of AMPA-receptors in the nucleus accumbens increases.
 Based on this hypothesis, it is reasonable to propose drugs for the treatment of drug dependence that counteract the neuroplastic changes in AMPA-receptors caused by repeated drug exposure and leading to addiction. IEM-1460 and IEM-2131, which are two GluA1 AMPA blockers, have been proposed as potential therapeutic agents against addiction and other CNS diseases.

Antiviral activity of glucosylceramide synthase inhibitors in alphavirus infection of the central nervous system.

Virus-induced CNS diseases impose a considerable human health burden worldwide. For many viral CNS infections, neither antiviral drugs nor vaccines are available. In this study, we examined whether the synthesis of glycosphingolipids, major membrane lipid constituents, could be used to establish an antiviral therapeutic target. We found that neuroinvasive Sindbis virus altered the sphingolipid levels early after infection in vitro and increased the levels of gangliosides GA1 and GM1 in the sera of infected mice. The alteration in the sphingolipid levels appears to play a role in neuroinvasive Sindbis virus replication, as treating infected cells with UDP-glucose ceramide glucosyltransferase (UGCG) inhibitors reduced the replication rate. Moreover, the UGCG inhibitor GZ-161 increased the survival rates of Sindbis-infected mice, most likely by reducing the detrimental immune response activated by sphingolipids in the brains of Sindbis virus-infected mice. These findings suggest a role for glycosphingolipids in the host immune response against neuroinvasive Sindbis virus and suggest that UGCG inhibitors should be further examined as antiviral therapeutics for viral infections of the CNS.

Th17/IL-17 Axis in HTLV-1-Associated Myelopathy Tropical Spastic Paraparesis and Multiple Sclerosis: Novel Insights into the Immunity During HAMTSP.

Human T lymphotropic virus-associated myelopathy/tropical spastic paraparesis (HTLV/TSP), also known as HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and multiple sclerosis (MS) are chronic debilitating diseases of the central nervous system; although the etiology of which is different, similarities have been observed between these two demyelinating diseases, especially in clinical manifestation and immunopathogenesis. Exorbitant response of the immune system to the virus and neurons in CNS is the causative agent of HAM/TSP and MS, respectively. Helper T lymphocyte-17 cells (Th17s), a component of the immune system, which have a proven role in immunity and autoimmunity, mediate protection against bacterial/fungal infections. The role of these cells has been reviewed in several CNS diseases. A pivotal role for Th17s is presented in demyelination, even more axial than Th1s, during MS. The effect of Th17s is not well determined in HTLV-1-associated infections; however, the evidence that we have supplied in this review illustrates the attendance, also the role of Th17 cells during HAM/TSP. Furthermore, for better conception concerning the trace of these cells in HAM/TSP, a comparative characterization with MS, the resembling disease, has been applied here.

Immune Regulatory Functions of Macrophages and Microglia in Central Nervous System Diseases.

Macrophages can be characterized as a very multifunctional cell type with a spectrum of phenotypes and functions being observed spatially and temporally in various disease states. Ample studies have now demonstrated a possible causal link between macrophage activation and the development of autoimmune disorders. How these cells may be contributing to the adaptive immune response and potentially perpetuating the progression of neurodegenerative diseases and neural injuries is not fully understood. Within this review, we hope to illustrate the role that macrophages and microglia play as initiators of adaptive immune response in various CNS diseases by offering evidence of: (1) the types of immune responses and the processes of antigen presentation in each disease, (2) receptors involved in macrophage/microglial phagocytosis of disease-related cell debris or molecules, and, finally, (3) the implications of macrophages/microglia on the pathogenesis of the diseases.

Alterations in the properties of the glutamatergic system of the rat hippocampus in a lithium-pilocarpine model of temporal lobe epilepsy

Status epilepticus (SE) triggers many pathological changes in the nervous system that are not yet fully understood and may lead to the development of epilepsy. In this work, we studied the effects of SE on the properties of excitatory glutamatergic transmission in the hippocampus in a rat model of lithium-pilocarpine temporal lobe epilepsy. Studies were performed 1 day (acute phase of the model), 3 and 7 days (latent phase), and 30 to 80 days (chronic phase) after SE. Using real-time PCR, we found that in the latent phase there is a decrease in gene expression of GluA1 and GluA2 AMPA receptor subunits, which may also be accompanied by an increased proportion of calcium-permeable AMPA receptors, which play an essential role in the pathogenesis of many CNS diseases. In acute brain slices we found a decrease in the efficiency of excitatory synaptic neurotransmission in all phases of the model when recording field responses in the CA1 region of the hippocampus in response to stimulation of Schaffer collaterals by electric currents of different intensities. However, in the chronic phase we found an increase in the frequency of spontaneous excitatory postsynaptic potentials, indicating an increased background activity of the glutamatergic system in epilepsy. This is also supported by a decrease in the threshold of hind limb extension in the test of maximal electroshock seizure in rats with temporal lobe epilepsy compared to control animals. The results obtained indicate the presence of a number of functional alterations in the glutamatergic system related to epilepsy. These findings can be used to develop antiepileptogenic therapy.

Evaluation of acute oral toxicity of Ipomoea turpethum extract loaded polymeric nanoparticles in Wistar rats.

Introduction: The amalgamation of novel drug delivery techniques and potential drugs is considered the most promising tool for the treatment of diseases. In our study, we have employed N-isopropyl acrylamide, N-vinyl pyrrolidone, and acrylic acid (NIPAAM-VP-AA) copolymeric nanoparticles for delivering Ipomoea turpethum root extract. I. turpethum is a perennial herb (Convolvulaceae family) and has been used as medicine for ages. The present study was conducted to evaluate the safety of I. turpethum root extract-loaded NIPAAM-VP-AA polymeric nanoparticles (NVA-IT) in Wistar rats. Methods: An acute oral toxicity study was conducted in accordance with OECD guidelines 423 for the testing of chemicals. Different doses of NVA-IT i.e., 5mg/kg, 50mg/kg, 300mg/kg, and 2000mg/kg were administered to female Wistar rats in a stepwise manner using oral gavage. The toxicity signs were thoroughly observed for the next 14days. At the end of the study, the blood and vital organs were harvested for hematological, biochemical, and histopathological studies. Result: No mortality or pathological anomalies were observed even at the highest dose which exemplifies that the lethal dose would be more than 2000mg/kg body weight (GSH category 5). Behavioral changes, biochemical parameters, and histopathology of vital organs were normal after NVA-IT administration. Conclusion: This study demonstrated that NVA-IT nanoparticles are non-toxic and can be considered for therapeutic use in different diseases, such as inflammation, CNS diseases, Cancer, etc.

B cell targeted therapies in inflammatory autoimmune disease of the central nervous system.

Cumulative evidence along several lines indicates that B cells play an important role in the pathological course of multiple sclerosis (MS), neuromyelitisoptica spectrum disorders (NMOSD) and related CNS diseases. This has prompted extensive research in exploring the utility of targeting B cells to contain disease activity in these disorders. In this review, we first recapitulate the development of B cells from their origin in the bone marrow to their migration to the periphery, including the expression of therapy-relevant surface immunoglobulin isotypes. Not only the ability of B cells to produce cytokines and immunoglobulins seems to be essential in driving neuroinflammation, but also their regulatory functions strongly impact pathobiology. We then critically assess studies of B cell depleting therapies, including CD20 and CD19 targeting monoclonal antibodies, as well as the new class of B cell modulating substances, Bruton´s tyrosinekinase (BTK) inhibitors, in MS, NMOSD and MOGAD.

Regulatory T cell expansion promotes white matter repair after stroke

Recent research highlights the function of regulatory T cells (Tregs) in white matter integrity in CNS diseases. Approaches that expand the number of Tregs have been utilized to improve stroke recovery. However, it remains unclear if Treg augmentation preserves white matter integrity early after stroke or promotes white matter repair. This study evaluates the effect of Treg augmentation on white matter injury and repair after stroke. Adult male C57/BL6 mice randomly received Treg or splenocyte (2 million, iv) transfer 2 h after transient (60 min) middle cerebral artery occlusion (tMCAO). Immunostaining showed improved white matter recovery after tMCAO in Treg-treated mice compared to mice received splenocytes. In another group of mice, IL-2/IL-2 antibody complexes (IL-2/IL-2Ab) or isotype IgG were administered (i.p) for 3 consecutive days starting 6 h after tMCAO, and repeated on day 10, 20 and 30. The IL-2/IL-2Ab treatment boosted the number of Tregs in blood and spleen and increased Treg infiltration into the ischemic brain. Longitudinal in vivo and ex vivo diffusion tensor imaging analysis revealed an increase in fractional anisotropy 28d and 35d, but not 14d, after stroke in IL-2/IL-2Ab-treated mice compared to isotype-treated mice, suggesting a delayed improvement in white matter integrity. IL-2/IL-2Ab also improved sensorimotor functions (rotarod test and adhesive removal test) 35d after stroke. There were correlations between white matter integrity and behavior performance. Immunostaining confirmed the beneficial effects of IL-2/IL-2Ab on white matter structures 35d after tMCAO. IL-2/IL-2Ab treatment starting as late as 5d after stroke still improved white matter integrity 21d after tMCAO, suggesting long-term salutary effects of Tregs on the late-stage tissue repair. We also found that IL-2/IL-2Ab treatment reduced the number of dead/dying OPCs and oligodendrocytes in the brain 3d after tMCAO. To confirm the direct effect of Tregs on remyelination, Tregs were cocultured with lysophosphatidyl choline (LPC)-treated organotypic cerebella. LPC exposure for 17 h induced demyelination in organotypic cultures, followed by gradual spontaneous remyelination upon removal of LPC. Co-culture with Tregs accelerated remyelination in organotypic cultures 7d after LPC. In conclusion, Boosting the number of Tregs protects oligodendrocyte lineage cells early after stroke and promotes long-term white matter repair and functional recovery. IL-2/IL-2Ab represents a feasible approach of Treg expansion for stroke treatment.

Multitargeting Histamine H3 Receptor Ligands among Acetyl- and Propionyl-Phenoxyalkyl Derivatives

Alzheimer's disease (AD) is a neurodegenerative disorder, for which there is no effective cure. Current drugs only slow down the course of the disease, and, therefore, there is an urgent need to find effective therapies that not only treat, but also prevent it. Acetylcholinesterase inhibitors (AChEIs), among others, have been used for years to treat AD. Histamine H3 receptors (H3Rs) antagonists/inverse agonists are indicated for CNS diseases. Combining AChEIs with H3R antagonism in one structure could bring a beneficial therapeutic effect. The aim of this study was to find new multitargetting ligands. Thus, continuing our previous research, acetyl- and propionyl-phenoxy-pentyl(-hexyl) derivatives were designed. These compounds were tested for their affinity to human H3Rs, as well as their ability to inhibit cholinesterases (acetyl- and butyrylcholinesterases) and, additionally, human monoamine oxidase B (MAO B). Furthermore, for the selected active compounds, their toxicity towards HepG2 or SH-SY5Y cells was evaluated. The results showed that compounds 16 (1-(4-((5-(azepan-1-yl)pentyl)oxy)phenyl)propan-1-one) and 17 (1-(4-((6-(azepan-1-yl)hexyl)oxy)phenyl)propan-1-one) are the most promising, with a high affinity for human H3Rs (Ki: 30 nM and 42 nM, respectively), a good ability to inhibit cholinesterases (16: AChE IC50 = 3.60 µM, BuChE IC50 = 0.55 µM; 17: AChE IC50 = 1.06 µM, BuChE IC50 = 2.86 µM), and lack of cell toxicity up to 50 µM.

Negishi Cross‐Coupling in the Preparation of Benzyl Substituted Pyrrolo[2,3‐d]pyrimidine Based CSF1R Inhibitors

AbstractThe colony‐stimulating factor 1 receptor (CSF1R) is a protein kinase emerging as an attractive target with clinical relevance in cancer, CNS and inflammatory diseases. Molecular docking experiments followed by synthesis and structure–activity relationship have been used to identify low molecular weight structures as promising hits for lead optimization. These molecules are synthesized from a 4‐chloro‐6‐iodo‐pyrrolo[2,3‐d]pyrimidine building block using Negishi and Suzuki–Miyaura cross‐coupling reactions in high yields. Several inhibitors possessed excellent enzymatic potency, and the parent compound preferably binds to the autoinhibited form of CSF1R. Cellular and in vivo profiling indicate that further tuning of drug structure is needed prior to efficacy studies.