Secretion Of Neurotrophic Factors Research Articles

Neural Stem Cell Therapy for Alzheimer’s Disease: A-State-of-the-Art Review

Alzheimer’s disease (AD) is a brain disorder that is more prevalent in developed nations and remains one of most intractable conditions so far. It is characterized by a gradual onset, a prolonged progression, and an unclear pathophysiology. At the present time, there are no effective treatments available for the disease. However, human neural stem cells (hNSCs) have the capacity to substitute lost neurons in a functional manner, strengthen synaptic networks that have been compromised, and repair the damaged brain. Due to the unavailability of restorative therapeutics, there is a significant global burden on the economy. When it comes to the treatment of neurodegenerative diseases, NSCs provide a potentially game-changing approach to treating Alzheimer’s disease. Through the delivery of trophic factors that promote the viability and regeneration of lost neurons in experimental animals suffering from neurodegenerative disorders, these treatments have the potential to facilitate beneficial recuperation. Positive restorative outcomes may be achieved in a variety of ways, including the replacement of lost cells, the combining of cells, the secretion of neurotrophic factors, the formation of endogenous stem cells, and transdifferentiation. Conversely, there are obstacles that need to be overcome before NSC-based treatments can be used in clinical settings. This review article discusses current developments in the use of neural stem cells (NSCs) for the treatment of Alzheimer’s disease (AD). In addition, we highlight the difficulties and opportunities that are involved with the use of neural stem cell transplant treatment for Alzheimer’s disease.

Neurons enhance blood–brain barrier function via upregulating claudin-5 and VE-cadherin expression due to glial cell line-derived neurotrophic factor secretion

Blood–brain barrier (BBB) prevents neurotoxins from entering central nervous system. We aimed to establish and characterize an in vitro triple co-culture BBB model consisting of brain endothelial cells hCMEC/D3, astrocytoma U251 cells, and neuroblastoma SH-SY5Y cells. Co-culture of SH-SY5Y and U251 cells markedly enhanced claudin-5 and VE-cadherin expression in hCMEC/D3 cells, accompanied by increased transendothelial electrical resistance and decreased permeability. Conditioned medium (CM) from SH-SY5Y cells (S-CM), U251 cells (U-CM), and co-culture of SH-SY5Y and U251 cells (US-CM) also promoted claudin-5 and VE-cadherin expression. Glial cell line-derived neurotrophic factor (GDNF) levels in S-CM and US-CM were significantly higher than CMs from hCMEC/D3 and U-CM. Both GDNF and US-CM upregulated claudin-5 and VE-cadherin expression, which were attenuated by anti-GDNF antibody and GDNF signaling inhibitors. GDNF increased claudin-5 expression via the PI3K/AKT/FOXO1 and MAPK/ERK pathways. Meanwhile, GDNF promoted VE-cadherin expression by activating PI3K/AKT/ETS1 and MAPK/ERK/ETS1 signaling. The roles of GDNF in BBB integrity were validated using brain-specific Gdnf silencing mice. The developed triple co-culture BBB model was successfully applied to predict BBB permeability. In conclusion, neurons enhance BBB integrity by upregulating claudin-5 and VE-cadherin expression through GDNF secretion and established triple co-culture BBB model may be used to predict drugs’ BBB permeability.

Neurons enhance blood-brain barrier function via upregulating claudin-5 and VE-cadherin expression due to glial cell line-derived neurotrophic factor secretion.

Blood-brain barrier (BBB) prevents neurotoxins from entering central nervous system. We aimed to establish and characterize an in vitro triple co-culture BBB model consisting of brain endothelial cells hCMEC/D3, astrocytoma U251 cells, and neuroblastoma SH-SY5Y cells. Co-culture of SH-SY5Y and U251 cells markedly enhanced claudin-5 and VE-cadherin expression in hCMEC/D3 cells, accompanied by increased transendothelial electrical resistance and decreased permeability. Conditioned medium (CM) from SH-SY5Y cells (S-CM), U251 cells (U-CM), and co-culture of SH-SY5Y and U251 cells (US-CM) also promoted claudin-5 and VE-cadherin expression. Glial cell line-derived neurotrophic factor (GDNF) levels in S-CM and US-CM were significantly higher than CMs from hCMEC/D3 and U-CM. Both GDNF and US-CM upregulated claudin-5 and VE-cadherin expression, which were attenuated by anti-GDNF antibody and GDNF signaling inhibitors. GDNF increased claudin-5 expression via the PI3K/AKT/FOXO1 and MAPK/ERK pathways. Meanwhile, GDNF promoted VE-cadherin expression by activating PI3K/AKT/ETS1 and MAPK/ERK/ETS1 signaling. The roles of GDNF in BBB integrity were validated using brain-specific Gdnf silencing mice. The developed triple co-culture BBB model was successfully applied to predict BBB permeability. In conclusion, neurons enhance BBB integrity by upregulating claudin-5 and VE-cadherin expression through GDNF secretion and established triple co-culture BBB model may be used to predict drugs' BBB permeability.

Glatiramer Acetate for the Treatment of Multiple Sclerosis: From First-Generation Therapy to Elucidation of Immunomodulation and Repair.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), with a putative autoimmune origin and complex pathogenesis. Modification of the natural history of MS by reducing relapses and slowing disability accumulation was first attained in the 1990 s with the development of the first-generation disease-modifying therapies. Glatiramer acetate (GA), a copolymer of L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, was discovered due to its ability to suppress the animal model of MS, experimental autoimmune encephalomyelitis. Extensive clinical trials and long-term assessments established the efficacy and the safety of GA. Furthermore, studies of the therapeutic processes induced by GA in animal models and in MS patients indicate that GA affects various levels of the innate and the adaptive immune response, generating deviation from proinflammatory to anti-inflammatory pathways. This includes competition for binding to antigen presenting cells; driving dendritic cells, monocytes, and B-cells toward anti-inflammatory responses; and stimulating T-helper 2 and T-regulatory cells. The immune cells stimulated by GA reach the CNS and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings reveal that in addition to its immunomodulatory effect, GA promotes neuroprotective repair processes such as neurotrophic factors secretion, remyelination, and neurogenesis. This review aims to provide an overview of MS pathology diagnosis and treatment as well as the diverse mechanism of action of GA. SIGNIFICANCE STATEMENT: Understanding the complex MS immune pathogenesis provided multiple targets for therapeutic intervention, resulting in a plethora of agents, with various mechanisms of action, efficacy, and safety profiles. However, promoting repair beyond the body's limited spontaneous extent is still a major challenge. GA, one of the first approved disease-modifying therapies, induces diverse immunomodulatory effects. Furthermore, GA treatment results in elevated neurotrophic factors secretion, remyelination and neurogenesis, supporting the notion that immunomodulatory treatment can support in situ a growth-promoting and repair environment.

Multi-platform analysis revealed the substance basis and mechanism of Wei-Tong-Xin in ameliorating ENS dysfunction for dyspepsia treatment

Ethnopharmacological relevanceDuodenal motility disorder is a contributing factor to dyspepsia. The traditional Chinese medicine (TCM) formula Wei-Tong-Xin (WTX), originated from the famous ancient Chinese formula “Wan Ying Yuan”, has been demonstrated efficacy in alleviating dyspepsia. Aim of the studyThe current study aims to elucidate the chemical composition of WTX to establish the pharmacodynamic material basis. On the basis of component, in depth to illuminate the mechanism by which WTX treats dyspepsia via constructing the comprehensive analysis of multi-platform. Materials and methodsThe chemical constituents of WTX were systematically analyzed by UHPLC-Q-TOF-MS/MS data processing methods. Based on this, network pharmacology was employed to predict the mechanism by which WTX improved dyspepsia. The dyspepsia mouse model was constructed, and histopathology as well as intestinal permeability were assessed using H&E staining, PAS staining and FITC-dextran assay. Protein expression was detected using Western blot, immunofluorescence, immunohistochemistry and ELISA kits. ResultsA total of 100 chemical components of WTX were preliminarily identified. Network pharmacological analysis indicated that the therapeutic mechanism of WTX in treating dyspepsia may be related to the regulation of inflammation and oxidative stress-related signaling pathways. In vivo studies showed that WTX mitigated duodenal inflammation and oxidative stress responses, repairing the intestinal mucosal barrier damaged by cisplatin (CIS). Additionally, WTX restored the number of glial cells diminished by inflammatory damage, and ameliorated the serotoninergic neuronal dysfunction caused by insufficient secretion of glia-derived neurotrophic factor (GDNF), and enhanced intestinal transit. ConclusionsIn this study, a total of 100 components of the WTX extract were identified through literature review and mass spectrometry database search. Utilizing computer technology, in conjunction with pharmacodynamic and mechanistic studies, WTX has been found to restore serotoninergic neuronal function by reducing intestinal mucosal inflammatory and oxidative damage, ultimately promoting intestinal transport and treating dyspepsia.

27 - Natriuretic peptide receptor 1 controls the secretion of brain-derived neurotrophic factor from bladder smooth muscle cells through cylic nucleotides and nitric oxide

27 - Natriuretic peptide receptor 1 controls the secretion of brain-derived neurotrophic factor from bladder smooth muscle cells through cylic nucleotides and nitric oxide

The intricate interplay between microglia and adult neurogenesis in Alzheimer's disease.

Microglia, the resident immune cells of the central nervous system, play a crucial role in regulating adult neurogenesis and contribute significantly to the pathogenesis of Alzheimer's disease (AD). Under physiological conditions, microglia support and modulate neurogenesis through the secretion of neurotrophic factors, phagocytosis of apoptotic cells, and synaptic pruning, thereby promoting the proliferation, differentiation, and survival of neural progenitor cells (NPCs). However, in AD, microglial function becomes dysregulated, leading to chronic neuroinflammation and impaired neurogenesis. This review explores the intricate interplay between microglia and adult neurogenesis in health and AD, synthesizing recent findings to provide a comprehensive overview of the current understanding of microglia-mediated regulation of adult neurogenesis. Furthermore, it highlights the potential of microglia-targeted therapies to modulate neurogenesis and offers insights into potential avenues for developing novel therapeutic interventions.

Research advances on CaMKs-mediated neurodevelopmental injury.

Calcium/calmodulin-dependent protein kinases (CaMKs) are important proteins in the calcium signaling cascade response pathway, which can broadly regulate biological functions in vivo. Multifunctional CaMKs play key roles in neural development, including neuronal circuit building, synaptic plasticity establishment, and neurotrophic factor secretion. Currently, four familial proteins, calcium/calmodulin-dependent protein kinase I (CaMKI), calcium/calmodulin-dependent protein kinase II (CaMKII), eukaryotic elongation factor 2 kinase (eEF2K, popularly known as CaMKIII) and calcium/calmodulin-dependent protein kinase IV (CaMKIV), are thought to have been the most extensively studied during neurodevelopment. Although their spatial structures are extremely similar, as well as the initial starting point of activation, both require the activation of calcium and calmodulin (CaM) complexes to be involved in the process, and the phosphorylation sites and modes of each member are different. Furthermore, due to the high structural similarity of CaMKs, their members may play synergistic roles in the regulation of neural development, but different CaMKs also have their own means of regulating neural development. In this review, we first describe the visualized protein structural forms of CaMKI, CaMKII, eEF2K and CaMKIV, and then describe the functions of each kinase in neurodevelopment. After that, we focus on four main mechanisms of neurodevelopmental damage caused by CaMKs: CaMKI/ERK/CREB pathway inhibition leading to dendritic spine structural damage; Ca2+/CaM/CaMKII through induction of mitochondrial kinetic disorders leading to neurodevelopmental damage; CaMKIII/eEF2 hyperphosphorylation affects the establishment of synaptic plasticity; and CaMKIV/JNK/NF-κB through induction of an inflammatory response leading to neurodevelopmental damage. In conclusion, we briefly discuss the pathophysiological significance of aberrant CaMK family expression in neurodevelopmental disorders, as well as the protective effects of conventional CaMKII and CaMKIII antagonists against neurodevelopmental injury.

Development of Tissue-Engineered Model of Fibrotic Scarring after Spinal Cord Injury to Study Astrocyte Activation and Neurite Outgrowth In Vitro.

Traumatic spinal cord injuries (SCI) are debilitating injuries affecting twenty-seven million people worldwide and cause functional impairments. Despite decades of research and medical advancements, current treatment options for SCI remain limited, in part due to the complex pathophysiology of spinal cord lesions including cellular transformation and extracellular matrix (ECM) remodeling. Recent studies have increased focus on fibrotic scarring after SCI, and yet much remains unclear about the impact of fibrotic scarring on SCI lesion progression. Here, using collagen and decellularized spinal cord-based composite hydrogels, a three-dimensional (3D) cell culture model mimicking the fibrous core of spinal cord lesions was implemented to investigate its influence on the surrounding astrocytes. To mimic the fibrotic milieu, collagen fibril thickness was tuned using previously established temperature-controlled casting methods. In our platforms, astrocytes in fibro-mimetic hydrogels exhibited increased levels of activation markers such as glial fibrillary acidic protein and N-cadherin. Furthermore, astrocytes in fibro-mimetic hydrogels deposited more fibronectin and laminin, further hinting that astrocytes may also contribute to fibrotic scarring. These markers were decreased when Rho-ROCK and integrin β1 were inhibited via pharmacological inhibitors. Mechanistic analysis of Yes-associated protein reveals that blocking integrin β1 prevents mechanosensing of astrocytes, contributing to altered phenotypes in variable culture conditions. In the presence of these inhibitors, astrocytes increased the secretion of brain-derived neurotrophic factor, and a greater degree of dorsal root ganglia neurite infiltration into the underlying hydrogels was observed. Altogether, this study presents a novel tissue-engineered platform to study fibrotic scarring after SCI and may be a useful platform to advance our understanding of SCI lesion aggravation.

Bone marrow mesenchymal stem cells in treatment of peripheral nerve injury.

Peripheral nerve injury (PNI) is a common neurological disorder and complete functional recovery is difficult to achieve. In recent years, bone marrow mesenchymal stem cells (BMSCs) have emerged as ideal seed cells for PNI treatment due to their strong differentiation potential and autologous transplantation ability. This review aims to summarize the molecular mechanisms by which BMSCs mediate nerve repair in PNI. The key mechanisms discussed include the differentiation of BMSCs into multiple types of nerve cells to promote repair of nerve injury. BMSCs also create a microenvironment suitable for neuronal survival and regeneration through the secretion of neurotrophic factors, extracellular matrix molecules, and adhesion molecules. Additionally, BMSCs release pro-angiogenic factors to promote the formation of new blood vessels. They modulate cytokine expression and regulate macrophage polarization, leading to immunomodulation. Furthermore, BMSCs synthesize and release proteins related to myelin sheath formation and axonal regeneration, thereby promoting neuronal repair and regeneration. Moreover, this review explores methods of applying BMSCs in PNI treatment, including direct cell transplantation into the injured neural tissue, implantation of BMSCs into nerve conduits providing support, and the application of genetically modified BMSCs, among others. These findings confirm the potential of BMSCs in treating PNI. However, with the development of this field, it is crucial to address issues related to BMSC therapy, including establishing standards for extracting, identifying, and cultivating BMSCs, as well as selecting application methods for BMSCs in PNI such as direct transplantation, tissue engineering, and genetic engineering. Addressing these issues will help translate current preclinical research results into clinical practice, providing new and effective treatment strategies for patients with PNI.

Targeting Adenylate Cyclase: A Novel Concept for Stimulation of Neurogenesis and Pharmacotherapy of Alzheimer's Disease.

The low effectiveness of existing pharmacotherapy strategies for Alzheimer's disease (AD) makes it necessary to develop a new concept for the treatment of this type of dementia. This search is promising to be carried out within the framework of the paradigm of targeting intracellular signaling pathways in Regenerative-Competent Cells (RCCs). The purpose of the research is to study the impact of adenylate cyclase (AC) inhibitor on disorders of the psychoemotional status in aged male C57BL/6 mice, as well as on the dynamics of the content and functioning of RCCs nervous tissue. We examined the effect of the AC inhibitor (2',5'-Dideoxyadenosine) on conditioned reflex activity, behavioral and emotional profile in a mouse AD model (16-month-old (aged) male C57BL/6 mice), as well as the functioning of neural stem cells (NSCs), neuronal-committed progenitors (NCPs), and neuroglial cells in the subventricular zone of the cerebral hemispheres (SVZ). In aged C57BL/6 mice, we found impairments in exploratory behavior, emotional reactivity, and memory, which are the characteristics of senile dementia. Therapy based on AC inhibition led to an increase in the number of NSCs and NPCs in the SVZ due to an increase in their proliferative activity. These changes were more pronounced in NCPs. At the same time, a decrease in the specialization intensity was recorded in NSCs. These phenomena developed against the background of increased secretion of neurotrophic growth factors by oligodendrocytes and microglial cells. The neuroregenerative effects of 2',5'-dideoxyadenosine correlated with the correction of age-related disorders of the psychoemotional status in aged mice. The results provide the basis for the development of targeted drugs based on AC inhibitors to stimulate neurogenesis as an approach for the effective treatment of AD.

Role of Piezo2 in Schwann Cell Volume Regulation and Its Impact on Neurotrophic Release Regulation.

Tactile perception relies on mechanoreceptors and nerve fibers, including c-fibers, Aβ-fibers and Aδ-fibers. Schwann cells (SCs) play a crucial role in supporting nerve fibers, with non-myelinating SCs enwrapping c-fibers and myelinating SCs ensheathing Aβ and Aδ fibers. Recent research has unveiled new functions for cutaneous sensory SCs, highlighting the involvement of nociceptive SCs in pain perception and Meissner corpuscle SCs in tactile sensation. Furthermore, Piezo2, previously associated with Merkel cell tactile sensitivity, has been identified in SCs. The goal of this study was to investigate the channels implicated in SC mechanosensitivity and the release process of neurotrophic factor secretion. Immortalized IFRS1 SCs and human primary SCs generated two distinct subtypes of SCs: undifferentiated and differentiated SCs. Quantitative PCR was employed to evaluate the expression of differentiation markers and mechanosensitive channels, including TRP channels (TRPV4, TRPM7 and TRPA1) and Piezo channels (Piezo1 and Piezo2). To validate the functionality of specific mechanosensitive channels, Ca2+ imaging and electronic cell sizing experiments were conducted under hypotonic conditions, and inhibitors and siRNAs were used. Protein expression was assessed by Western blotting and immunostaining. Additionally, secretome analysis was performed to evaluate the release of neurotrophic factors in response to hypotonic stimulation, with BDNF, a representative trophic factor, quantified using ELISA. Induction of differentiation increased Piezo2 mRNA expression levels both in IFRS1 and in human primary SCs. Both cell types were responsive to hypotonic solutions, with differentiated SCs displaying a more pronounced response. Gd3+ and FM1-43 effectively inhibited hypotonicity-induced Ca2+ transients in differentiated SCs, implicating Piezo2 channels. Conversely, inhibitors of Piezo1 and TRPM7 (Dooku1 and NS8593, respectively) had no discernible impact. Moreover, Piezo2 in differentiated SCs appeared to participate in regulatory volume decreases (RVD) after cell swelling induced by hypotonic stimulation. A Piezo2 deficiency correlated with reduced RVD and prolonged cell swelling, leading to heightened release of the neurotrophic factor BDNF by upregulating the function of endogenously expressed Ca2+-permeable TRPV4. Our study unveils the mechanosensitivity of SCs and implicates Piezo2 channels in the release of neurotrophic factors from SCs. These results suggest that Piezo2 may contribute to RVD, thereby maintaining cellular homeostasis, and may also serve as a negative regulator of neurotrophic factor release. These findings underscore the need for further investigation into the role of Piezo2 in SC function and neurotrophic regulation.

Enhancing regenerative potential: A comprehensive review of stem cell transplantation for sports-related neuronal injuries, with a focus on spinal cord injuries and peripheral nervous system damage

Neuronal injuries, as one of the consequences of sports-related incidents, exert a profound influence on the athletes' future, potentially leading to complete immobility and impeding their athletic pursuits. In cases of severe damage inflicted upon the spinal cord (SC) and peripheral nervous systems (PNS), the regenerative process is notably compromised, rendering it essentially inefficient. Among the pivotal therapeutic approaches for the enhancement and prevention of secondary SC injuries (SCI), stem cell transplantation (SCT) stands out prominently. Stem cells, whether directly involved in replacement and reconstruction or indirectly through modification and secretion of crucial bioenvironmental factors, engage in the intricate process of tissue regeneration. Stem cells, through the secretion of neurotrophic factors (NTFs) (aiming to modulate the immune system), reduction of inflammation, axonal growth stimulation, and myelin formation, endeavor to facilitate the regeneration of damaged SC tissue. The fundamental challenges of this approach encompass the proper selection of suitable stem cell candidates for transplantation and the establishment of an appropriate microenvironment conducive to SC repair. In this article, an attempt has been made to explore sports-related injuries, particularly SCI, to comprehensively review innovative methods for treating SCI, and to address the existing challenges. Additionally, some of the stem cells used in neural injuries and the process of their utilization have been discussed.

The regulation of BAI1 in astrocytes through the STAT3/EZH2 axis relieves neuronal apoptosis in rats with Alzheimer’s disease

Alzheimer’s disease (AD) is a common neurodegenerative disease. Previous studies have identified the critical role of astrocytes in the progression of AD. The focus of this study revolves around clarifying the regulatory mechanism of the STAT3/EZH2/BAI1 axis in astrocytes in AD. We successfully developed a rat model of AD, and measured the learning and cognitive ability of the rats by Morris water maze experiment. HE and Nissl’s staining were used for histomorphological identification of the rat hippocampus. Meanwhile, immunofluorescence and immunohistochemistry were used to detect astrocyte activation and brain-specific angiogenesis inhibitor-1 (BAI1) expression in rat hippocampal tissue, respectively. The role of STAT3/EZH2/BAI1 regulating axis in astrocyte activation and neuronal cell apoptosis was verified by establishing the co-culture system of astrocytes and neuronal cells in vitro. Western Blot (WB) was used to detect the expression of associated proteins, and enzyme-linked immunosorbent assay (ELISA) was used to detect astrocyte neurotrophic factor secretion. Hochest/PI staining and flow cytometry were used to observe neuronal apoptosis. Compared with the sham group, AD rats showed significantly decreased cognitive and learning abilities, noticeable hippocampal tissue damage, and significantly low levels of BAI1 expression. In in vitro models, BAI1 was found to inhibit astrocyte activation and enhance the secretion of neurotrophins, resulting in decrease of neurone apoptosis. The regulation of BAI1 by the STAT3/EZH2 axis was shown to affect astrocyte activation and neuronal cell apoptosis. In conclusion, this study represents the pioneering discovery that regulated by the STAT3/EZH2 axis, BAI1 suppresses astrocyte activation, thus reducing neuronal apoptosis.

Curcumin Improves Neurogenesis in Alzheimer's Disease Mice via the Upregulation of Wnt/β-Catenin and BDNF.

Adult neurogenesis in the dentate gyrus (DG) is impaired during Alzheimer's disease (AD) progression. Curcumin has been reported to reduce cell apoptosis and stimulate neurogenesis. This study aimed to investigate the influence of curcumin on adult neurogenesis in AD mice and its potential mechanism. Two-month-old male C57BL/6J mice were injected with soluble β-amyloid (Aβ1-42) using lateral ventricle stereolocalization to establish AD models. An immunofluorescence assay, including bromodeoxyuridine (BrdU), doublecortin (DCX), and neuron-specific nuclear antigen (NeuN), was used to detect hippocampal neurogenesis. Western blot and an enzyme-linked immunosorbent assay (ELISA) were used to test the expression of related proteins and the secretion of brain-derived neurotrophic factor (BDNF). A Morris water maze was used to detect the cognitive function of the mice. Our results showed that curcumin administration (100 mg/kg) rescued the impaired neurogenesis of Aβ1-42 mice, shown as enhanced BrdU+/DCX+ and BrdU+/NeuN+ cells in DG. In addition, curcumin regulated the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) -mediated glycogen synthase kinase-3β (GSK3β) /Wingless/Integrated (Wnt)/β-catenin pathway and cyclic adenosine monophosphate response element-binding protein (CREB)/BDNF in Aβ1-42 mice. Inhibiting Wnt/β-catenin and depriving BDNF could reverse both the upregulated neurogenesis and cognitive function of curcumin-treated Aβ1-42 mice. In conclusion, our study indicates that curcumin, through targeting PI3K/Akt, regulates GSK3β/Wnt/β-catenin and CREB/BDNF pathways, improving the adult neurogenesis of AD mice.

KYNA Ameliorates Glutamate Toxicity of HAND by Enhancing Glutamate Uptake in A2 Astrocytes.

Reactive astrocytes are key players in HIV-associated neurocognitive disorders (HAND), and different types of reactive astrocytes play opposing roles in the neuropathologic progression of HAND. A recent study by our group found that gp120 mediates A1 astrocytes (neurotoxicity), which secrete proinflammatory factors and promote HAND disease progression. Here, by comparing the expression of A2 astrocyte (neuroprotective) markers in the brains of gp120 tgm mice and gp120+/α7nAChR-/- mice, we found that inhibition of alpha 7 nicotinic acetylcholine receptor (α7nAChR) promotes A2 astrocyte generation. Notably, kynurenine acid (KYNA) is an antagonist of α7nAChR, and is able to promote the formation of A2 astrocytes, the secretion of neurotrophic factors, and the enhancement of glutamate uptake through blocking the activation of α7nAChR/NF-κB signaling. In addition, learning, memory and mood disorders were significantly improved in gp120 tgm mice by intraperitoneal injection of kynurenine (KYN) and probenecid (PROB). Meanwhile, the number of A2 astrocytes in the mouse brain was significantly increased and glutamate toxicity was reduced. Taken together, KYNA was able to promote A2 astrocyte production and neurotrophic factor secretion, reduce glutamate toxicity, and ameliorate gp120-induced neuropathological deficits. These findings contribute to our understanding of the role that reactive astrocytes play in the development of HAND pathology and provide new evidence for the treatment of HAND via the tryptophan pathway.

Dental Pulp Stem Cell-Derived Exosomes Promote Sciatic Nerve Regeneration via Optimizing Schwann Cell Function.

Repair strategies for injured peripheral nerve have achieved great progresses in recent years. However, the clinical outcomes remain unsatisfactory. Recent studies have found that exosomes secreted by dental pulp stem cells (DPSC-exos) have great potential for applications in nerve repair. In this study, we evaluated the effects of human DPSC-exos on improving peripheral nerve regeneration. Initially, we established a coculture system between DPSCs and Schwann cells (SCs) in vitro to assess the effect of DPSC-exos on the activity of embryonic dorsal root ganglion neurons (DRGs) growth in SCs. We extracted and labeled human DPSC-exos, which were subsequently utilized in uptake experiments in DRGs and SCs. Subsequently, we established a rat sciatic nerve injury model to evaluate the therapeutic potential of DPSC-exos in repairing sciatic nerve damage. Our findings revealed that DPSC-exos significantly promoted neurite elongation by enhancing the proliferation, migration, and secretion of neurotrophic factors by SCs. In vivo, DPSC-exos administration significantly improved the walking behavior, axon regeneration, and myelination in rats with sciatic nerve injuries. Our study underscores the vast potential of DPSC-exos as a therapeutic tool for tissue-engineered nerve construction.

Complex antidepressant therapy with the inclusion of various neuroprotectors in inpatient gerontopsychiatric practice

IntroductionDepressions are the most common mental disorders in elderly and senile patients. In these patients, there is a decrease in neurotrophic potential. Treatment of such patients with antidepressants alone does not always allow to achieve complete normalization of the secretion of neurotrophic factors and complete restoration of neurogenesis processes. In this regard, it is important to expand therapeutic opportunities to develop new therapeutic strategies for pharmacotherapy of late-age depression.ObjectivesComparative evaluation of the effectiveness of two types of complex antidepressant therapy with the inclusion of different neuroprotectors (actovegin or cerebrolysin) in the treatment of late-life depression in the therapeutic regimen.MethodsThe study included 2 groups of patients with mild and moderate depressive episode (DE), comparable in basic demographic and clinical parameters.The 1st group included 21 people, including 7 men (33.3%) and 14 women (66.7%), median age were 69 years [66; 76]. In 10 patients (47.6%), DE was diagnosed as part of recurrent depressive disorder (DDR), in 9 patients (42.9%) - as part of bipolar affective disorder (BAR), and in 2 patients (9.5%) is a single DE. Group 2 included 20 patients, 5 of them men (25%) and 15 women (75%), median age were 64 years [62; 70]. In 11 patients (55%), DE was diagnosed as part of DDR, in 6 patients (30%) - as part of BAR, and in 3 patients (15%) – single DE.The 1st group of patients received complex antidepressant therapy with the inclusion of actovegin for one month, the 2nd group - with the inclusion of cerebrolysin. The effectiveness of the therapy was assessed on the HAMD-17 and HARS scales.ResultsA comparative study demonstrated the effectiveness of both types of complex antidepressant therapy used.A comparative assessment of the effectiveness of the therapeutic response in two groups of patients showed no statistically significant differences in the reduction of depressive disorders after 2 weeks of therapy. Only by the end of the therapeutic course there was a more pronounced reduction of depressive disorders in the 1st therapeutic group (73.6% vs 63.6% (p < 0.05)).Reduction of anxiety disorders, assessed on the HARS scale, was noted both by the 14th and 28th day of therapy in both therapeutic groups. However, it turned out to be more pronounced in the 1st therapeutic group: by the 14th day of therapy, the reduction of anxiety in the 1st and 2nd groups of patients was 36.4% and 30.0%, respectively (p < 0.05), and by the end of therapy - 77.7% and 60.0%, respectively (p < 0.01).ConclusionsThe augmentation of antidepressant therapy with drugs with multimodal activity, actovegin and cerebrolysin, should be considered as effective and it can be recommended for inclusion in the therapeutic regimen for the treatment of late-age depression in a psychiatric hospital.Disclosure of InterestNone Declared

Transplantation of dorsal root ganglia overexpressing the NaChBac sodium channel improves locomotion after complete SCI

Spinal cord injury (SCI) is a debilitating condition currently lacking treatment. Severe SCI causes the loss of most supraspinal inputs and neuronal activity caudal to the injury, which, coupled with the limited endogenous capacity for spontaneous regeneration, can lead to complete functional loss even in anatomically incomplete lesions. We hypothesized that transplantation of mature dorsal root ganglia (DRG), genetically modified to express the NaChBac sodium channel, could serve as a therapeutic option for functionally complete SCI. We found that NaChBac expression increased the intrinsic excitability of DRG neurons, promoted cell survival and neurotrophic factor secretion in vitro. Transplantation of NaChBac-expressing dissociated DRGs improved voluntary locomotion seven weeks after injury compared to control groups. Animals transplanted with NaChBac-expressing DRGs also possessed higher tubulin-positive neuronal fiber and myelin preservation, although serotonergic descending fibers remained unaffected. We observed early preservation of the corticospinal tract fourteen days after injury and transplantation which was lost seven weeks after injury. Nevertheless, transplantation of NaChBac-expressing DRGs increased the neuronal excitatory input, by increased number of VGlut2 contacts, immediately caudal to the injuries. Our work suggests that the transplantation of NaChBac-expressing dissociated DRGs can rescue significant motor function retaining an excitatory neuronal relay activity immediately caudal to injury.

Neuroprotective effects of the salidroside derivative SHPL-49 via the BDNF/TrkB/Gap43 pathway in rats with cerebral ischemia

Ischemic stroke is a common intravascular disease and one of the leading causes of death and disability. The salidroside derivative SHPL-49, which we previously synthesized, significantly attenuates cerebral ischemic injury in a rat model of permanent middle cerebral artery occlusion. To explore the neuroprotective mechanism of SHPL-49, the effects of SHPL-49 on the expression levels of neurotrophic factors in neurons and microglia and the polarization of microglia were investigated in the present study. SHPL-49 activated the brain-derived neurotrophic factor (BDNF) pathway, decreased the number of degenerated neurons, and accelerated neurogenesis in rats with cerebral ischemia. In addition, SHPL-49 promoted the polarization of microglia toward the M2 phenotype to alleviate neuroinflammation. In BV2 cells, SHPL-49 upregulated CD206 mRNA and protein levels and inhibited CD86 mRNA and protein levels. SHPL-49 also increased neurotrophic factor secretion in BV2 cells, which indirectly promoted the survival of primary neurons after oxygen-glucose deprivation (OGD). Proteomics analysis revealed that SHPL-49 promoted growth-associated protein 43 (Gap43) expression. SHPL-49 enhanced synaptic plasticity and increased Gap43 protein levels via activation of the BDNF pathway in the OGD primary neuron model. These results indicate that SHPL-49 prevents cerebral ischemic injury by activating neurotrophic factor pathways and altering microglial polarization. Thus, SHPL-49 is a potential neuroprotective agent.