Experimental Periodontitis Worsens Dopaminergic Neuronal Degeneration.

AIM: To investigate the hypothesis supporting the link between periodontitis and dopaminergic neuron degeneration. MATERIALS AND METHODS: Adult male Wistar rats were used to induce dopaminergic neuronal injury with 6-hydroxydopamine (6-OHDA) neurotoxin and experimental periodontitis via ligature placement. Motor function assessments were conducted before and after periodontitis induction in controls and 6-OHDA-injury-induced rats. Tissue samples from the striatum, jaw and blood were collected for molecular analyses, encompassing immunohistochemistry of tyrosine hydroxylase, microglia and astrocyte, as well as micro-computed tomography, to assess alveolar bone loss and for the analysis of striatal oxidative stress and plasma inflammatory markers. RESULTS: The results indicated motor impairment in 6-OHDA-injury-induced rats exacerbated by periodontitis, worsening dopaminergic striatal degeneration. Periodontitis alone or in combination with 6-OHDA-induced lesion was able to increase striatal microglia, while astrocytes were increased by the combination only. Periodontitis increased striatal reactive oxygen species levels and plasma tumour necrosis factor-alpha levels in rats with 6-OHDA-induced lesions and decreased the anti-inflammatory interleukin-10. CONCLUSIONS: This study provides original insights into the association between periodontitis and a neurodegenerative condition. The increased inflammatory pathway associated with both 6-OHDA-induced dopaminergic neuron lesion and periodontal inflammatory processes corroborates that the periodontitis-induced systemic inflammation may aggravate neuroinflammation in Parkinson's-like disease, potentially hastening disease progression.

Mechanisms of mitochondrial resilience in teleostean radial glia under hypoxic stress.

Radial glial cells (RGCs) are remarkable cells, essential for normal development of the vertebrate central nervous system. In teleost fishes, RGCs play a pivotal role in neurogenesis and regeneration of injured neurons and glia. RGCs also exhibit resilience to environmental stressors like hypoxia via metabolic adaptations. In this study, we assessed the physiology of RGCs following varying degrees of hypoxia, with an emphasis on reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), mitophagy, and energy metabolism. Our findings demonstrated that hypoxia significantly elevated ROS production and induced MMP depolarization in RGCs. The mitochondrial disturbances were closely associated with increased mitophagy, based on the co-localization of mitochondria and lysosomes. Key mitophagy-related genes were also up-regulated, including those of the BNIP3/NIX mediated pathway as well as the FUNDC1 mediated pathway. Such responses suggest robust cellular mechanisms are initiated to counteract mitochondrial damage due to increasing hypoxia. A significant metabolic shift from oxidative phosphorylation to glycolysis was also observed in RGCs, which may underlie an adaptive response to sustain cellular function and viability following a reduction in oxygen availability. Furthermore, hypoxia inhibited the synthesis of mitochondrial complexes subunits in RGCs, potentially related to elevated HIF-2α expression with 3 % O2. Taken together, RGCs appear to exhibit complex adaptive responses to hypoxic stress, characterized by metabolic reprogramming and the activation of mitophagy pathways to mitigate mitochondrial dysfunction.

Solanesol alleviates CFA-induced chronic inflammatory pain via inhibition of proinflammatory cytokines in spinal glial cells.

Solanesol, an aliphatic terpene alcohol predominantly found in solanaceous plants, has gained recognition for its anti-inflammatory, antibacterial, and neuroprotective properties. This study investigates the potential efficacy of solanesol in alleviating chronic inflammatory pain induced by injection of complete Freund's adjuvant (CFA) into the left hind paw. Behavioral assessments revealed a significant reduction in mechanical and thermal hypersensitivity following solanesol administration, accompanied by a partial alleviation of concomitant anxiety-like behaviors. Mechanistically, Western blot analysis demonstrated a substantial decrease in the levels of TNF-α and IL-1ß after solanesol administration. Immunohistochemical staining further revealed a notable suppression of microglial and astrocytic activation induced by CFA injection. These findings collectively suggest that solanesol holds promise as a latent therapeutic agent for the treatment of chronic inflammatory pain.

Toxicity of zinc oxide nanoparticles: Cellular and behavioural effects.

Due to their extensive use, the release of zinc oxide nanoparticles (ZnO NP) into the environment is increasing and may lead to unintended risk to both human health and ecosystems. Access of ZnO NP to the brain has been demonstrated, so their potential toxicity on the nervous system is a matter of particular concern. Although evaluation of ZnO NP toxicity has been reported in several previous studies, the specific effects on the nervous system are not completely understood and, particularly, effects on genetic material and on organism behaviour are poorly addressed. We evaluated the potential toxic effects of ZnO NP in vitro and in vivo, and the role of zinc ions (Zn2+) in these effects. In vitro, the ability of ZnO NP to be internalized by A172 glial cells was verified, and the cytotoxic and genotoxic effects of ZnO NP or the released Zn2+ ions were addressed by means of vital dye exclusion and comet assay, respectively. In vivo, behavioural alterations were evaluated in zebrafish embryos using a total locomotion assay. ZnO NP induced decreases in viability of A172 cells after 24 h of exposure and genetic damage after 3 and 24 h. The involvement of the Zn2+ ions released from the NP in genotoxicity was confirmed. ZnO NP exposure also resulted in decreased locomotor activity of zebrafish embryos, with a clear role of released Zn2+ ions in this effect. These findings support the toxic potential of ZnO NP showing, for the first time, genetic effects on glial cells and proving the intervention of Zn2+ ions.

Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8-800 murine model of Friedreich ataxia.

Friedreich ataxia is a hereditary neurodegenerative disorder resulting from reduced levels of the protein frataxin due to an expanded GAA repeat in the FXN gene. This deficiency causes progressive degeneration of specific neuronal populations in the cerebellum and the consequent loss of movement coordination and equilibrium, which are some of the main symptoms observed in affected individuals. Like in other neurodegenerative diseases, previous studies suggest that glial cells could be involved in the neurodegenerative process and disease progression in patients with Friedreich ataxia. In this work, we followed and characterized the progression of changes in the cerebellar cortex in the latest version of Friedreich ataxia humanized mouse model, YG8-800 (Fxnnull:YG8s(GAA)>800), which carries a human FXN transgene containing >800 GAA repeats. Comparative analyses of behavioral, histopathological, and biochemical parameters were conducted between the control strain Y47R and YG8-800 mice at different time points. Our findings revealed that YG8-800 mice exhibit an ataxic phenotype characterized by poor motor coordination, decreased body weight, cerebellar atrophy, neuronal loss, and changes in synaptic proteins. Additionally, early activation of glial cells, predominantly astrocytes and microglia, was observed preceding neuronal degeneration, as was increased expression of key proinflammatory cytokines and downregulation of neurotrophic factors. Together, our results show that the YG8-800 mouse model exhibits a stronger phenotype than previous experimental murine models, reliably recapitulating some of the features observed in humans. Accordingly, this humanized model could represent a valuable tool for studying Friedreich ataxia molecular disease mechanisms and for preclinical evaluation of possible therapies.

Pharmaceutical-mediated neuroimmune modulation in psychiatric/psychological adverse events.

The therapeutic use of many pharmaceuticals, including small molecules and biological therapies, has been associated with the onset of psychiatric and psychological adverse events (PPAEs), posing substantial concerns to patients' health and safety. These events, which encompass mood (e.g., depression, schizophrenia, suicidal ideation) and cognitive changes (e.g., learning and memory impairment, dementia) often remain undetected until advanced stages of clinical trials or pharmacovigilance, mostly because the mechanisms underlying the onset of PPAEs remain poorly understood. In recent years, the role of neuroimmune modulation (comprising an intricate interplay between various cell types and signaling pathways) in PPAEs has garnered substantial interest. Indeed, understanding these complex interactions would substantially contribute to increase the ability to predict the potential onset of PPAEs during preclinical stages of a new drug's R&D. This review provides a comprehensive summary of the most recent advances in neuroimmune modulation-related mechanisms contributing to the onset of PPAEs and their association with specific pharmaceuticals. Reported data strongly support an association between neuroimmune modulation and the onset of PPAEs. Pharmaceuticals may target specific molecular pathways and pathway elements (e.g., cholinergic and serotonergic systems), which in turn may directly or indirectly impact the inflammatory status and the homeostasis of the brain, regulating inflammation and neuronal function. Also, modulation of the peripheral immune system by pharmaceuticals that do not permeate the blood-brain barrier (e.g., monoclonal antibodies) may alter the neuroimmunomodulatory status of the brain, leading to PPAEs. In summary, this review underscores the diverse pathways through which drugs can influence brain inflammation, shedding light on potential targeted interventions.

Obesity-derived macrophages upregulate TNF-α to induce apoptosis in glial cell via the NF-κB/PHLPP1 axis.

Macrophages in obese adipose tissue have been shown to damage nerve fibers, however, the mechanism underlying how macrophages cause glial cell damage remains unknown. This study aimed to characterize the mechanism by which macrophages induce apoptosis in glial cell during obesity formation in mice by single-nucleus RNA sequencing (snRNA-seq). Cells obtained from paraepididymal adipose tissue in obese mice underwent snRNA-seq. Eighteen different clusters were identified, and 12 cell types were annotated, including glial cells, macrophages, and fibroblasts. There was a negative correlation between the number of glial cells and macrophages in mouse adipose tissue during the formation of obesity. The pro-apoptotic factor PHLPP1 was identified in GO Terms. The interaction between adipose tissue glial cells and macrophages was revealed via in-depth analysis, and the cell-cell communication mechanism between the TNF-α and NF-KB/PHLPP1 axes was perfected. Apoptosis of glial cell by upregulation of TNF-α via obesity-derived macrophages and activation of the NF-κB/PHLPP1 axis. We further revealed how macrophages induce apoptosis in glial cells during obesity formation, as well as different changes in the two cell populations. This study provides valuable resources and foundations for understanding the mechanistic effects of macrophages and glial cells during obesity formation, as well as diseases and potential interventions.

Terra incognita of glial cell dynamics in the etiology of leukodystrophies: Broadening disease and therapeutic perspectives.

Neuroglial cells, also known as glia, are primarily characterized as auxiliary cells within the central nervous system (CNS). The recent findings have shed light on their significance in numerous physiological processes and their involvement in various neurological disorders. Leukodystrophies encompass an array of rare and hereditary neurodegenerative conditions that were initially characterized by the deficiency, aberration, or degradation of myelin sheath within CNS. The primary cellular populations that experience significant alterations are astrocytes, oligodendrocytes and microglia. These glial cells are either structurally or metabolically impaired due to inherent cellular dysfunction. Alternatively, they may fall victim to the accumulation of harmful by-products resulting from metabolic disturbances. In either situation, the possible replacement of glial cells through the utilization of implanted tissue or stem cell-derived human neural or glial progenitor cells hold great promise as a therapeutic strategy for both the restoration of structural integrity through remyelination and the amelioration of metabolic deficiencies. Various emerging treatment strategies like stem cell therapy, ex-vivo gene therapy, infusion of adeno-associated virus vectors, emerging RNA-based therapies as well as long-term therapies have demonstrated success in pre-clinical studies and show promise for rapid clinical translation. Here, we addressed various leukodystrophies in a comprehensive and detailed manner as well as provide prospective therapeutic interventions that are being considered for clinical trials. Further, we aim to emphasize the crucial role of different glial cells in the pathogenesis of leukodystrophies. By doing so, we hope to advance our understanding of the disease, elucidate underlying mechanisms, and facilitate the development of potential treatment interventions.

Comparative insight into the regenerative mechanisms of the adult brain in zebrafish and mouse: highlighting the importance of the immune system and inflammation in successful regeneration.

Regeneration, the complex process of restoring damaged or absent cells, tissues, and organs, varies considerably between species. The zebrafish is a remarkable model organism for its impressive regenerative abilities, particularly in organs such as the heart, fin, retina, spinal cord, and brain. Unlike mammals, zebrafish can regenerate with limited or absent scarring, a phenomenon closely linked to the activation of stem cells and immune cells. This review examines the unique roles played by the immune response and inflammation in zebrafish and mouse during regeneration, highlighting the cellular and molecular mechanisms behind their divergent regenerative capacities. By focusing on zebrafish telencephalic regeneration and comparing it to that of the rodents, this review highlights the importance of a well-controlled, acute, and non-persistent immune response in zebrafish, which promotes an environment conducive to regeneration. The knowledge gained from understanding the mechanisms of zebrafish regeneration holds great promises for the treatment of human neurodegenerative diseases and brain damage (stroke and traumatic brain injuries), as well as for the advancement of regenerative medicine approaches.

Spontaneous Calcium Transients Recorded from Striatal Astrocytes in a Preclinical Model of Autism.

Autism spectrum disorder (ASD) is known as a group of neurodevelopmental conditions including stereotyped and repetitive behaviors, besides social and sensorimotor deficits. Anatomical and functional evidence indicates atypical maturation of the striatum. Astrocytes regulate the maturation and plasticity of synaptic circuits, and impaired calcium signaling is associated with repetitive behaviors and atypical social interaction. Spontaneous calcium transients (SCT) recorded in the striatal astrocytes of the rat were investigated in the preclinical model of ASD by prenatal exposure to valproic acid (VPA). Our results showed sensorimotor delay, augmented glial fibrillary acidic protein -a typical intermediate filament protein expressed by astrocytes- and diminished expression of GABAA-ρ3 through development, and increased frequency of SCT with a reduced latency that resulted in a diminished amplitude in the VPA model. The convulsant picrotoxin, a GABAA (γ-aminobutyric acid type A) receptor antagonist, reduced the frequency of SCT in both experimental groups but rescued this parameter to control levels in the preclinical ASD model. The amplitude and latency of SCT were decreased by picrotoxin in both experimental groups. Nipecotic acid, a GABA uptake inhibitor, reduced the mean amplitude only for the control group. Nevertheless, nipecotic acid increased the frequency but diminished the latency in both experimental groups. Thus, we conclude that striatal astrocytes exhibit SCT modulated by GABAA-mediated signaling, and prenatal exposure to VPA disturbs this tuning.

Satellite glial cell manipulation prior to axotomy enhances developing dorsal root ganglion central branch regrowth into the spinal cord.

The central and peripheral nervous systems (CNS and PNS, respectively) exhibit remarkable diversity in the capacity to regenerate following neuronal injury with PNS injuries being much more likely to regenerate than those that occur in the CNS. Glial responses to damage greatly influence the likelihood of regeneration by either promoting or inhibiting axonal regrowth over time. However, despite our understanding of how some glial lineages participate in nerve degeneration and regeneration, less is known about the contributions of peripheral satellite glial cells (SGC) to regeneration failure following central axon branch injury of dorsal root ganglia (DRG) sensory neurons. Here, using in vivo, time-lapse imaging in larval zebrafish coupled with laser axotomy, we investigate the role of SGCs in axonal regeneration. In our studies we show that SGCs respond to injury by relocating their nuclei to the injury site during the same period that DRG neurons produce new central branch neurites. Laser ablation of SGCs prior to axon injury results in more neurite growth attempts and ultimately a higher rate of successful central axon regrowth, implicating SGCs as inhibitors of regeneration. We also demonstrate that this SGC response is mediated in part by ErbB signaling, as chemical inhibition of this receptor results in reduced SGC motility and enhanced central axon regrowth. These findings provide new insights into SGC-neuron interactions under injury conditions and how these interactions influence nervous system repair.

The Role of the Thalamus in Nociception: Important but Forgotten.

Pain is a complex response to noxious stimuli. Upon detection of the nociceptive stimulus by first-order neurons or nociceptors, an action potential ascends to the spinal dorsal horn, a crucial site for synapsing with second-order neurons. These second-order neurons carry the nociceptive stimulus to supraspinal regions, notably the thalamus. Although extensive research has focused on spinal-level nociceptive mechanisms (e.g., neurotransmitters, receptors, and glial cells), the thalamus is still poorly elucidated. The role of the thalamus in relaying sensory and motor responses to the cortex is well known. However, a comprehensive understanding of the mechanisms in the synapse between the second-order and third-order neurons that transmit this impulse to the somatosensory cortex, where the response is processed and interpreted as pain, is still lacking. Thus, this review investigated the thalamus's role in transmitting nociceptive impulses. Current evidence indicates the involvement of the neurotransmitters glutamate and serotonin, along with NMDA, P2X4, TLR4, FGR, and NLRP3 receptors, as well as signaling pathways including ERK, P38, NF-κB, cytokines, and glial cells at nociceptive synapses within the thalamus.

Neurological Impact of Respiratory Viruses: Insights into Glial Cell Responses in the Central Nervous System.

Respiratory viral infections pose a significant public health threat, particularly in children and older adults, with high mortality rates. Some of these pathogens are the human respiratory syncytial virus (hRSV), severe acute respiratory coronavirus-2 (SARS-CoV-2), influenza viruses (IV), human parvovirus B19 (B19V), and human bocavirus 1 (HBoV1). These viruses cause various respiratory symptoms, including cough, fever, bronchiolitis, and pneumonia. Notably, these viruses can also impact the central nervous system (CNS), leading to acute manifestations such as seizures, encephalopathies, encephalitis, neurological sequelae, and long-term complications. The precise mechanisms by which these viruses affect the CNS are not fully understood. Glial cells, specifically microglia and astrocytes within the CNS, play pivotal roles in maintaining brain homeostasis and regulating immune responses. Exploring how these cells interact with viral pathogens, such as hRSV, SARS-CoV-2, IVs, B19V, and HBoV1, offers crucial insights into the significant impact of respiratory viruses on the CNS. This review article examines hRSV, SARS-CoV-2, IV, B19V, and HBoV1 interactions with microglia and astrocytes, shedding light on potential neurological consequences.

Unveiling the Mysteries of the Blood-Brain Barrier: The Problem of the Brain/spinal Pharmacotherapy.

The most critical issue impeding the development of innovative cerebrospinal medications is the blood-brain barrier (BBB). The BBB limits the ability of most medications to penetrate the brain to the CNS. The BBB structure and functions are summarized, with the physical barrier generated by endothelial tight junctions and the transport barrier formed by transporters within the membrane and vesicular processes. The functions of connected cells, particularly the end feet of astrocytic glial cells, microglia, and pericytes, are described. The drugs that cross the blood brain barrier are explained below along with their mechanisms. Some of the associated conditions and problems are given.

Aging Microglia and Their Impact in the Nervous System.

Aging is the greatest risk factor for neurodegenerative diseases. Microglia are the resident immune cells in the central nervous system (CNS), playing key roles in its normal functioning, and as mediators for age-dependent changes of the CNS, condition at which they generate a hostile environment for neurons. Transforming Growth Factor ß1 (TGFß1) is a regulatory cytokine involved in immuneregulation and neuroprotection, affecting glial cell inflammatory activation, neuronal survival, and function. TGFß1 signaling undergoes age-dependent changes affecting the regulation of microglial cells and can contribute to the pathophysiology of neurodegenerative diseases. This chapter focuses on assessing the role of age-related changes on the regulation of microglial cells and their impact on neuroinflammation and neuronal function, for understanding age-dependent changes of the nervous system.

Modulation of sensory input to the spinal cord: Contribution of focal epidural polarization and of GABA released by interneurons and glial cells.

Modulation of input from primary afferent fibres has long been examined at the level of the first relays of these fibres. However, recent studies reveal that input to the spinal cord may also be modulated at the level of the very entry of afferent fibres to the spinal grey matter before action potentials in intraspinal collaterals of afferent fibres reach their target neurons. Such modulation greatly depends on the actions of GABA via extrasynaptic membrane receptors. In the reported study we hypothesized that the increase in excitability of afferent fibres following epidural polarization close to the site where collaterals of afferent fibres leave the dorsal columns is due to the release of GABA from two sources: not only GABAergic interneurons but also glial cells. We present evidence, primo, that GABA released from both these sources contributes to a long-lasting increase in the excitability and a shortening of the refractory period of epidurally stimulated afferent fibres and, secondo, that effects of epidural polarization on the release of GABA are more critical for these changes than direct effects of DC on the stimulated fibres. The experiments were carried out in deeply anaesthetized rats in which changes in compound action potentials evoked in hindlimb peripheral nerves by dorsal column stimulation were used as a measure of the excitability of afferent fibres. The study throws new light on the modulation of input to spinal networks but also on mechanisms underlying the restoration of spinal functions.

Schwann cell-secreted PGE2 promotes sensory neuron excitability during development.

Electrical excitability-the ability to fire and propagate action potentials-is a signature feature of neurons. How neurons become excitable during development and whether excitability is an intrinsic property of neurons remain unclear. Here, we demonstrate that Schwann cells, the most abundant glia in the peripheral nervous system, promote somatosensory neuron excitability during development. We find that Schwann cells secrete prostaglandin E2, which is necessary and sufficient to induce developing somatosensory neurons to express normal levels of genes required for neuronal function, including voltage-gated sodium channels, and to fire action potential trains. Inactivating this signaling pathway in Schwann cells impairs somatosensory neuron maturation, causing multimodal sensory defects that persist into adulthood. Collectively, our studies uncover a neurodevelopmental role for prostaglandin E2 distinct from its established role in inflammation, revealing a cell non-autonomous mechanism by which glia regulate neuronal excitability to enable the development of normal sensory functions.

Evidence for prodromal changes in neuronal excitability and neuroinflammation in the hippocampus in young alpha-synuclein (A30P) transgenic mice.

Introduction: Neuronal hyperexcitability and neuroinflammation are thought to occur at early stages in a range of neurodegenerative diseases. Neuroinflammation, notably activation of microglia, has been identified as a potential prodromal marker of dementia with Lewy bodies (DLB). Using a transgenic mouse model of DLB that over-expresses human mutant (A30P) alpha-synuclein (hα-syn) we have investigated whether early neuroinflammation is evident in the hippocampus in young pre-symptomatic animals. Methods: Previous studies have shown early hyperexcitability in the hippocampal CA3 region in male A30P mice at 2-4 months of age, therefore, in the current study we have immunostained this region for markers of neuronal activity (c-Fos), reactive astrocytes (glial fibrillary acidic protein, GFAP), microglia (ionizing calcium binding adapter protein 1, Iba-1) and reactive microglia (inducible nitric oxide synthase, iNOS). Results: We found an interesting biphasic change in the expression of c-Fos in A30P mice with high expression at 1 month, consistent with early onset of hyperexcitability, but lower expression from 2-4 months in male A30P mice compared to wild-type (WT) controls, possibly indicating chronic hyperexcitability. Neuroinflammation was indicated by significant increases in the % area of GFAP and the number of Iba-1+ cells that expressed iNOS immunoreactivity in the CA3 region in 2-4 months A30P male mice compared to WT controls. A similar increase in % area of GFAP was observed in female A30P mice, however, the Iba-1 count was not different between female WT and A30P mice. In WT mice aged 2-4 months only 4.6% of Iba-1+ cells co-expressed iNOS. In contrast, in age matched A30P mice 87% of cells co-expressed Iba-1 and iNOS. Although there was no difference in GFAP immunoreactivity at 1 month, Iba-1/iNOS co-expression was also increased in a cohort of 1 month old A30P mice. Discussion: Abnormal hα-syn expression in A30P mice caused early changes in network excitability, as indicated by c-Fos expression, and neuroinflammation which might contribute to disease progression.

Sesamin Exerts an Antioxidative Effect by Activating the Nrf2 Transcription Factor in the Glial Cells of the Central Nervous System in Drosophila Larvae.

Sesame seeds are abundant in sesamin, which exerts health-promoting effects such as extending the lifespan of adult Drosophila and suppressing oxidative stress by activating the Nrf2 transcription factor. Here, we investigated whether sesamin activated Nrf2 in larval tissues and induced the expression of Nrf2 target genes. In the sesamin-fed larvae, Nrf2 was activated in the central nervous system (CNS), gut, and salivary glands. The ectopic expression of Keap1 in glial cells inhibited sesamin-induced Nrf2 activation in the whole CNS more than in the neurons, indicating that sesamin activates Nrf2 in glia efficiently. We labeled the astrocytes as well as cortex and surface glia with fluorescence to identify the glial cell types in which Nrf2 was activated; we observed their activation in both cell types. These data suggest that sesamin may stimulate the expression of antioxidative genes in glial cells. Among the 17 candidate Nrf2 targets, the mRNA levels of Cyp6a2 and Cyp6g1 in cytochrome P450 were elevated in the CNS, gut, and salivary glands of the sesamin-fed larvae. However, this elevation did not lead to resistance against imidacloprid, which is detoxified by these enzymes. Our results suggest that sesamin may exert similar health-promoting effects on the human CNS and digestive tissues.