Search Results (79)

Oxidative stress due to increased reactive oxygen species (ROS) formation and/or inflammation is considered to play an important role in ischemic stroke injury. Leukemia inhibitory factor (LIF) has been shown to protect both oligodendrocytes and neurons from ischemia by upregulating endogenous anti-oxidants, though the effect of ischemia and the protective role of LIF treatment in mitochondrial function have not been studied. The goal of this study was to determine whether LIF protects ischemia-induced altered mitochondrial bioenergetics in reproductively senescent aged rats of both sexes (≥18 months old), approximately equivalent to the average age of human stroke patients. Animals were euthanized at 3 days after permanent middle cerebral artery occlusion (MCAO) surgery. We found that MCAO surgery significantly reduced mitochondrial oxidative phosphorylation in both the ipsilateral striatum and prefrontal cortex in male aged rats compared to their respective contralateral regions of the brain. MCAO injury showed mitochondrial bioenergetic dysfunction only in the striatum in female rats; however, the prefrontal cortex remained unaffected to the injury. LIF-treated rats significantly prevented mitochondrial dysfunction in the striatum in male rats compared to their vehicle-treated counterparts. Collectively, MCAO-induced mitochondrial dysfunction and LIF’s potential as a therapeutic biomolecule exhibited sex- and tissue-specific effects, varying between the striatum and prefrontal cortex in male and female rats. Full article

Chitinase-3-like protein 1 (CHI3L1) has been implicated in multiple sclerosis (MS) pathology, yet its precise role remains unclear. To elucidate its involvement, we performed proteomic analysis of cerebrospinal fluid (CSF) from relapsing-remitting MS (RRMS) patients using two-dimensional difference gel electrophoresis (2D-DIGE). CHI3L1 emerged as the most upregulated protein in recurrent RRMS. ELISA confirmed significantly elevated CHI3L1 levels in recurrent RRMS and secondary progressive MS (SPMS) patients, with levels decreasing in steroid responders but increasing in non-responders. Immunohistochemistry of MS brain autopsies revealed CHI3L1 expression predominantly in mature oligodendrocytes. In an experimental autoimmune encephalomyelitis (EAE) model, CHI3L1 was highly expressed in the spinal cord, particularly in oligodendrocytes and microglia/macrophages. Functional studies demonstrated that recombinant CHI3L1 (rCHI3L1) protected oligodendrocytes from LPC-induced cell death by attenuating ER stress (GRP78, ORP150). Moreover, rCHI3L1 counteracted IFN-β- and PSL-mediated inhibition of oligodendrocyte differentiation. In microglia, rCHI3L1 suppressed LPS-induced proinflammatory markers (IL-1β, iNOS). In vivo, rCHI3L1 administration significantly mitigated EAE severity by reducing gliosis, demyelination, and axonal degeneration. These findings highlight CHI3L1 as a critical modulator of neuroinflammation and oligodendrocyte survival, positioning it as a promising therapeutic target for MS. Full article

Mesenchymal progenitor cells (MPC) are effective in reducing tissue loss, preserving white matter, and improving forelimb function after a spinal cord injury (SCI). We proposed that by preconditioning the mouse by the intravenous delivery (IV) of MPCs for 24 h following SCI, this would provide a more favorable tissue milieu for an NSC intraspinal bridging transplantation at day three and day seven. In combination, these transplants will provide better anatomical and functional outcomes. The intravenous MSCs would provide cell protection and reduce inflammation. NSCs would provide a tissue bridge for axonal regeneration and myelination and reconnect long tract spinal pathways. Results showed that initial protection of the injury site by IV MPCs transplantation resulted in no increased survival of the NSCs transplanted at day seven. However, integration of transplanted NSCs was increased at the day three timepoint, indicating MPCs influence very early immune signaling. We show, in this study, that MPC transplantation resulted in a co-operative NSC cell survival improvement on day three post-SCI. In addition to increased NSC survival on day three, there was an increase in NSC-derived mature oligodendrocytes at this early timepoint. An in vitro analysis confirmed MPC-driven oligodendrocyte differentiation, which was statistically increased when compared to control NSC-only cultures. These observations provide important information about the combination, delivery, and timing of two cellular therapies in treating SCI. This study provides important new data on understanding the MPC inflammatory signaling within the host tissue and timepoints for cellular transplantation survival and oligodendroglia differentiation. These results demonstrate that MPC transplantation can alter the therapeutic window for intraspinal transplantation by controlling both the circulating inflammatory response and local tissue milieu. Full article

Hypothermia (HT) is used clinically for neonatal hypoxic–ischemic encephalopathy (HIE); however, the brain protection is incomplete and selective regional vulnerability and lifelong consequences remain. Refractory damage and impairment with HT cooling/rewarming could result from unchecked or altered persisting cell death and proteinopathy. We tested two hypotheses: (1) HT modifies neurodegeneration type, and (2) intrinsically disordered proteins (IDPs) and encephalopathy cause toxic conformer protein (TCP) proteinopathy neonatally. We studied postmortem human neonatal HIE cases with or without therapeutic HT, neonatal piglets subjected to global hypoxia-ischemia (HI) with and without HT or combinations of HI and quinolinic acid (QA) excitotoxicity surviving for 29–96 h to 14 days, and human oligodendrocytes and neurons exposed to QA for cell models. In human and piglet encephalopathies with normothermia, the neuropathology by hematoxylin and eosin staining was similar; necrotic cell degeneration predominated. With HT, neurodegeneration morphology shifted to apoptosis-necrosis hybrid and apoptotic forms in human HIE, while neurons in HI piglets were unshifting and protected robustly. Oligomers and putative TCPs of α-synuclein (αSyn), nitrated-Syn and aggregated αSyn, misfolded/oxidized superoxide dismutase-1 (SOD1), and prion protein (PrP) were detected with highly specific antibodies by immunohistochemistry, immunofluorescence, and immunoblotting. αSyn and SOD1 TCPs were seen in human HIE brains regardless of HT treatment. αSyn and SOD1 TCPs were detected as early as 29 h after injury in piglets and QA-injured human oligodendrocytes and neurons in culture. Cell immunophenotyping by immunofluorescence showed αSyn detected with antibodies to aggregated/oligomerized protein; nitrated-Syn accumulated in neurons, sometimes appearing as focal dendritic aggregations. Co-localization also showed aberrant αSyn accumulating in presynaptic terminals. Proteinase K-resistant PrP accumulated in ischemic Purkinje cells, and their target regions had PrP-positive neuritic plaque-like pathology. Immunofluorescence revealed misfolded/oxidized SOD1 in neurons, axons, astrocytes, and oligodendrocytes. HT attenuated TCP formation in piglets. We conclude that HT differentially affects brain damage in humans and piglets. HT shifts neuronal cell death to other forms in human while blocking ischemic necrosis in piglet for sustained protection. HI and excitotoxicity also acutely induce formation of TCPs and prion-like proteins from IDPs globally throughout the brain in gray matter and white matter. HT attenuates proteinopathy in piglets but seemingly not in humans. Shifting of cell death type and aberrant toxic protein formation could explain the selective system vulnerability, connectome spreading, and persistent damage seen in neonatal HIE leading to lifelong consequences even after HT treatment. Full article

Multiple sclerosis (MS) is an autoimmune disease that damages the myelin sheath around the central nervous system axons, leading to neurological dysfunction. Although the initial damage is driven by inflammation, hypoxia has been reported in several brain regions of MS patients, but the significance of this for prognosis and treatment remains unclear. Neuroinflammation can induce hypoxia, and hypoxia can induce and exacerbate neuroinflammation, forming a vicious cycle. Within MS lesions, demyelination is often followed by remyelination, which may restore neurological function. However, demyelinated axons are vulnerable to damage, which leads to the accumulation of the permanent neurological dysfunction typical in MS, with this vulnerability heightened during hypoxia. Clinically approved therapies for MS are immunomodulatory, which can reduce relapse frequency/severity, but there is a lack of pro-regenerative therapies for MS, for example promoting remyelination. All tissues have protective responses to hypoxia, which may be relevant to MS lesions, especially during remyelinating episodes. When oxygen levels are reduced in the brain, constitutively expressed hypoxia-inducible factors (HIF) are stabilised, upregulating hundreds of genes, including neuroprotective factors. Furthermore, astrocytes upregulate heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) in the early stage of MS. HB-EGF promotes protective mechanisms and induces oligodendrocyte and neuron differentiation and survival. This review article outlines the neuroinflammation and hypoxia cycle in MS pathology and identifies potential therapeutic targets to limit neurodegeneration and/or promote regeneration. Both HIF and HB-EGF signalling pathways induce endogenous protection mechanisms in the CNS, promoting neuroprotection and remyelination directly, but also indirectly by modulating the immune response in MS. Promoting such endogenous protective signalling pathways could be an effective therapy for MS patients. Full article

Under conditions of amino acid deficiency, mammalian cells activate a nutrient-sensing kinase known as general control nonderepressible 2 (GCN2). The activation of GCN2 results in the phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 (eIF2α), which can be phosphorylated by three other three integrated stress response (ISR) kinases, reducing overall protein synthesis. GCN2 activation also promotes the translation of specific mRNAs, some of which encode transcription factors that enhance the transcription of genes involved in the synthesis, transport, and metabolism of amino acids to restore cellular homeostasis. The phosphorylation of eIF2α has been shown to protect oligodendrocytes, the cells responsible for producing myelin in the central nervous system during remyelination. Here, we explore the potential role of the kinase GCN2 in the myelination process. We challenged mice deficient in the GCN2-encoding gene with a pharmacological demyelinating stimulus (cuprizone) and evaluated the recovery of myelin as well as ISR activation through the levels of eIF2α phosphorylation. Our findings indicate that GCN2 controls the establishment of myelin by fine-tuning its abundance and morphology in the central nervous system. We also found that GCN2 is essential for remyelination. Surprisingly, we discovered that GCN2 is necessary to maintain eIF2α levels during remyelination. Full article

Epilepsy is a chronic neurological disorder marked by recurrent seizures, significantly impacting individuals worldwide. Current treatments are often ineffective for a third of patients and can cause severe side effects, necessitating new therapeutic approaches. Glial cells, particularly astrocytes, microglia, and oligodendrocytes, are emerging as crucial targets in epilepsy management. Astrocytes regulate neuronal homeostasis, excitability, and synaptic plasticity, playing key roles in maintaining the blood–brain barrier (BBB) and mediating neuroinflammatory responses. Dysregulated astrocyte functions, such as reactive astrogliosis, can lead to abnormal neuronal activity and seizure generation. They release gliotransmitters, cytokines, and chemokines that may exacerbate or mitigate seizures. Microglia, the innate immune cells of the CNS, contribute to neuroinflammation, glutamate excitotoxicity, and the balance between excitatory and inhibitory neurotransmission, underscoring their dual role in seizure promotion and protection. Meanwhile, oligodendrocytes, primarily involved in myelination, also modulate axonal excitability and contribute to the neuron–glia network underlying seizure pathogenesis. Understanding the dynamic interactions of glial cells with neurons provides promising avenues for novel epilepsy therapies. Targeting these cells may lead to improved seizure control and better clinical outcomes, offering hope for patients with refractory epilepsy. Full article

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulator of cellular defence mechanisms, essential for maintaining the brain’s health. Nrf2 supports mitochondrial function and protects against oxidative damage, which is vital for meeting the brain’s substantial energy and antioxidant demands. Furthermore, Nrf2 modulates glial inflammatory responses, playing a pivotal role in preventing neuroinflammation. This review explores these multifaceted functions of Nrf2 within the central nervous system, focusing on its activity across various brain cell types, including neurons, astrocytes, microglia, and oligodendrocytes. Due to the brain’s vulnerability to oxidative stress and metabolic challenges, Nrf2 is emerging as a key therapeutic target to enhance resilience against oxidative stress, inflammation, mitochondrial dysfunction, and demyelination, which are central to many neurodegenerative diseases. Full article

GABAergic signaling and GABA_B receptors play crucial roles in regulating the physiology of oligodendrocyte-lineage cells, including their proliferation, differentiation, and myelination. Therefore, they are promising targets for studying how spinal oligodendrocyte precursor cells (OPCs) respond to injuries and neurodegenerative diseases like multiple sclerosis. Taking advantage of the temporally controlled and cell-specific genetic downregulation of GABA_B receptors from OPCs, our investigation addresses their specific influence on OPC behavior in the gray and white matter of the mouse spinal cord. Our results show that, while GABA_B receptors do not significantly alter spinal cord myelination under physiological conditions, they distinctly regulate the OPC differentiation and Ca²⁺ signaling. In addition, we investigate the impact of OPC-GABA_B receptors in two models of toxic demyelination, namely, the cuprizone and the lysolecithin models. The genetic downregulation of OPC-GABA_B receptors protects against demyelination and oligodendrocyte loss. Additionally, we observe the enhanced resilience to cuprizone-induced pathological alterations in OPC Ca²⁺ signaling. Our results provide valuable insights into the potential therapeutic implications of manipulating GABA_B receptors in spinal cord OPCs and deepen our understanding of the interplay between GABAergic signaling and spinal cord OPCs, providing a basis for future research. Full article

Neurodegenerative diseases represent a significant global health burden, characterized by progressive loss of neuronal function and structure. While traditionally viewed as primarily neuronal disorders, recent research has highlighted the crucial roles of neuroglia-astrocytes, microglia, and oligodendrocytes in the pathogenesis and progression of these diseases. This review explores the dual nature of glial cells in neurodegenerative processes, focusing on their protective and potentially harmful functions in Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and other neurodegenerative disorders. We examine the complex interactions between different glial cell types and neurons, highlighting recent discoveries in glial-neuronal metabolic coupling, neuroinflammation, and protein aggregation. Advanced technologies, such as single-cell RNA sequencing and spatial transcriptomics, have revealed unprecedented glial heterogeneity and disease-specific glial states, reshaping our understanding of these cells’ roles in health and disease. The review also discusses emerging concepts in neuroglial research, including the role of extracellular vesicles in disease propagation, epigenetic regulation of glial function, and the application of artificial intelligence in glial biology. Finally, we explore the therapeutic implications of targeting glia in neurodegenerative diseases, addressing both the promising avenues and challenges in developing glial-focused interventions. By integrating recent advances in neuroglial research, this review provides a comprehensive overview of the field and highlights future directions for research and therapeutic development. Understanding the complex roles of neuroglia in neurodegenerative diseases is crucial for developing more effective treatments and ultimately improving patient outcomes. Full article

Neuroinflammation, characterised by the activation of immune cells in the central nervous system (CNS), plays a dual role in both protecting against and contributing to the progression of neurodegenerative diseases, such as Alzheimer’s disease (AD) and multiple sclerosis (MS). This review explores the role of phosphoinositide 3-kinase (PI3K), a key enzyme involved in cellular survival, proliferation, and inflammatory responses, within the context of neuroinflammation. Two PI3K isoforms of interest, PI3Kγ and PI3Kδ, are specific to the regulation of CNS cells, such as microglia, astrocytes, neurons, and oligodendrocytes, influencing pathways, such as Akt, mTOR, and NF-κB, that control cytokine production, immune cell activation, and neuroprotection. The dysregulation of PI3K signalling is implicated in chronic neuroinflammation, contributing to the exacerbation of neurodegenerative diseases. Preclinical studies show promise in targeting neuronal disorders using PI3K inhibitors, such as AS605240 (PI3Kγ) and idelalisib (PI3Kδ), which have reduced inflammation, microglial activation, and neuronal death in in vivo models of AD. However, the clinical translation of these inhibitors faces challenges, including blood–brain barrier (BBB) permeability, isoform specificity, and long-term safety concerns. This review highlights the therapeutic potential of PI3K modulation in neuroinflammatory diseases, identifying key gaps in the current research, particularly in the need for brain-penetrating and isoform-specific inhibitors. These findings underscore the importance of future research to develop targeted therapies that can effectively modulate PI3K activity and provide neuroprotection in chronic neurodegenerative disorders. Full article

Background: Neurodegenerative diseases can cause vision loss by damaging retinal ganglion cells in the optic nerve. Novel phosphine-borane compounds (PBs) can protect these cells from oxidative stress via the reduction of disulfide bonds. However, the specific targets of these compounds are unknown. Proteomic evidence suggests that myelin oligodendrocyte glycoprotein (MOG) is a potential target. MOG is of significant interest due to its role in anti-MOG optic neuritis syndrome. Methods: We used in silico modeling to explore the structural consequences of cleaving the extracellular domain MOG disulfide bond, both in isolation and in complex with anti-MOG antibodies. The potential binding of PBs to this bond was examined using molecular docking. Results: Cleaving the disulfide bond of MOG altered the structure of MOG dimers and reduced their energetic favorability by 46.13 kcal/mol. The energy profiles of anti-MOG antibody complexes were less favorable when the disulfide bond of MOG was reduced in the monomeric state by 55.21 kcal/mol, but the reverse was true in the dimeric state. PBs exhibited reducing capabilities with the MOG extracellular disulfide bond, with this best-scoring compound binding with an energy of −28.54 kcal/mol to the MOG monomer and −24.97 kcal/mol to the MOG dimer. Conclusions: These findings suggest that PBs can affect the structure of MOG dimers and the formation of antibody complexes by reducing the MOG disulfide bond. Structural changes in MOG could have implications for neurodegenerative diseases and anti-MOG syndrome. Full article

Agathisflavone is a flavonoid that exhibits anti-inflammatory and anti-oxidative properties. Here, we investigated the neuroprotective effects of agathisflavone on central nervous system (CNS) neurons and glia in the cerebellar slice ex vivo model of neonatal ischemia. Cerebellar slices from neonatal mice, in which glial fibrillary acidic protein (GFAP) and SOX10 drive expression of enhanced green fluorescent protein (EGFP), were used to identify astrocytes and oligodendrocytes, respectively. Agathisflavone (10 μM) was administered preventively for 60 min before inducing ischemia by oxygen and glucose deprivation (OGD) for 60 min and compared to controls maintained in normal oxygen and glucose (OGN). The density of SOX-10⁺ oligodendrocyte lineage cells and NG2 immunopositive oligodendrocyte progenitor cells (OPCs) were not altered in OGD, but it resulted in significant oligodendroglial cell atrophy marked by the retraction of their processes, and this was prevented by agathisflavone. OGD caused marked axonal demyelination, determined by myelin basic protein (MBP) and neurofilament (NF70) immunofluorescence, and this was blocked by agathisflavone preventative treatment. OGD also resulted in astrocyte reactivity, exhibited by increased GFAP-EGFP fluorescence and decreased expression of glutamate synthetase (GS), and this was prevented by agathisflavone pretreatment. In addition, agathisflavone protected Purkinje neurons from ischemic damage, assessed by calbindin (CB) immunofluorescence. The results demonstrate that agathisflavone protects neuronal and myelin integrity in ischemia, which is associated with the modulation of glial responses in the face of ischemic damage. Full article

Primary demyelinating disorders of the central nervous system (CNS) include multiple sclerosis and the orphan conditions neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein IgG-associated disease (MOGAD). Curative technologies under development aim to selectively block autoimmune reactions against specific autoantigens while preserving the responsiveness of the immune system to other antigens. Our analysis focused on target patient selection for such developments, carefully considering the relevant clinical, regulatory, and market-related aspects. We found that the selection of patients with orphan conditions as target populations offers several advantages. Treatments for orphan conditions are associated with limited production capacity, qualify for regulatory incentives, and may require significantly shorter and lower-scale clinical programs. Furthermore, they may meet a higher acceptable cost-effectiveness threshold in order to compensate for the low numbers of patients to be treated. Finally, curative technologies targeting orphan indications could enter less competitive markets with lower risk of generic price erosion and would benefit from additional market protection measures available only for orphan products. These advantages position orphan conditions and subgroups as the most attractive target indications among primary demyelinating disorders of the CNS. The authors believe that after successful proof-of-principle demonstrations in orphan conditions, broader autoimmune patient populations may also benefit from the success of these pioneering developments. Full article

Infections may affect the course of autoimmune inflammatory diseases of the central nervous system (CNS), such as multiple sclerosis (MS). Infections with lactate dehydrogenase-elevating virus (LDV) protected mice from developing experimental autoimmune encephalomyelitis (EAE), a mouse counterpart of MS. Uninfected C57BL/6 mice immunized with the myelin oligodendrocyte glycoprotein peptide (MOG35–55) experienced paralysis and lost weight at a greater rate than mice who had previously been infected with LDV. LDV infection decreased the presentation of the MOG peptide by CD11b+CD11c+ dendritic cells (DC) to pathogenic T lymphocytes. When comparing non-infected mice to infected mice, the histopathological examination of the CNS showed more areas of demyelination and CD45+ and CD3+, but not Iba1+ cell infiltration. These results suggest that the protective effect of LDV infection against EAE development is mediated by a suppression of myelin antigen presentation by a specific DC subset to autoreactive T lymphocytes. Such a mechanism might contribute to the general suppressive effect of infections on autoimmune diseases known as the hygiene hypothesis. Full article