Modulation Of Neuroinflammation Research Articles

Vitamin D as a Modulator of Neuroinflammation: Implications for Brain Health.

Neuroinflammation represents a critical immune response within the brain, playing a pivotal role in defense against injury and infection. However, when this response becomes chronic, it can contribute to the development of various neurodegenerative and psychiatric disorders. This bibliographic review delves into the role of vitamin D in modulating neuroinflammation and its implications for brain health, particularly in the context of neurological and psychiatric disorders. While vitamin D is traditionally associated with calcium homeostasis and bone health, it also exerts immunomodulatory and neuroprotective effects within the central nervous system. Through comprehensive analysis of preclinical and clinical studies, we uncover how vitamin D, acting through its receptors in glial cells, may influence the production of proinflammatory cytokines and antioxidants, potentially mitigating the cascade of events leading to neuronal damage. Clinical research has identified vitamin D deficiency as a common thread in the increased risks of multiple sclerosis, Parkinson's disease, Alzheimer's, and depression, among others. Furthermore, preclinical models suggest vitamin D's regulatory capacity over inflammatory mediators, its protective role against neuronal apoptosis, and its contribution to neurogenesis and synaptic plasticity. These insights underscore the potential of vitamin D supplementation not only in slowing the progression of neurodegenerative diseases but also in improving the quality of life for patients suffering from psychiatric conditions. Future clinical studies are essential to validate these findings and further our understanding of vitamin D's capacity to prevent or alleviate symptoms, opening new avenues for therapeutic strategies against neuroinflammation-related pathologies. Neuroinflammation is a crucial immune response in the brain against injuries or infections, but its persistence can lead to diseases such as Alzheimer's, Parkinson's, multiple sclerosis, and depression. Cholecalciferol (Vitamin D3) emerges as a regulator of neuroinflammation, present in brain cells such as astrocytes and microglia, modulating immune function. Vitamin D's mechanisms of action include cytokine modulation and regulation of nuclear and mitochondrial genes. It adjusts inflammatory mediators and antioxidants, resulting in neuroprotective effects. Additionally, vitamin D impacts neurotransmitter synthesis and brain plasticity. This positions vitamin D as a potential adjunct in treating diseases like Alzheimer's and Parkinson's. Lastly, its role in intestinal microbiota and serotonin synthesis contributes to psychiatric disorders like schizophrenia and depression. Thus, vitamin D presents a novel therapeutic approach for neuroinflammatory, neurodegenerative, and neuropsychiatric diseases.

Identification of duloxetine to treat aniridia‐related keratopathy: Link to inflammation?

Haploinsufficiency of PAX6 in humans is the main cause of congenital aniridia, a rare eye disease characterized by iris hypoplasia and reduced visual acuity. Patients have also progressive disorders including aniridia‐related keratopathy (ARK), caused by a combination of factors including limbal stem‐cell deficiency, impaired healing response, abnormal differentiation, and infiltration of conjunctival cells onto the corneal surface. It usually begins in the first decade of life resulting in recurrent corneal erosions, sub‐epithelial fibrosis with corneal decompensation and opacification. Unfortunately, current treatment options for aniridia patients are currently limited. There is no in vitro cellular model of AKT needed for drug/therapeutic tools screening and validation. We used genome editing (CRISPR/Cas9) to introduce a nonsense mutation into one allele of the PAX6 gene in limbal stem cells.The mutated cells displayed reduced cell proliferation and cell migration but enhanced cell adhesion. Known PAX6 targets expression was also altered. Of interest, recombinant PAX6 protein was sufficient to rescue the phenotype. By High Throughput Screening of a FDA‐approved library, we identified Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor antidepressant, that rescued both PAX6 endogenous protein level and altered cell migration of the mutant limbal stem cells, through specific inhibition of the ERK/MEK pathway. Furthermore, we found that Duloxetine modulates inflammation through activation of Pax6, strongly suggesting that Pax6 could be a modulator of neuroinflammation. Since Duloxetine is already used as anti‐psychotropic drugs, its repurposed use to treat topically aniridia eye and other ocular inflammatory diseases could become realistic.

Identification of duloxetine to treat aniridia‐related keratopathy: Link to inflammation?

Haploinsufficiency of PAX6 in humans is the main cause of congenital aniridia, a rare eye disease characterized by iris hypoplasia and reduced visual acuity. Patients have also progressive disorders including aniridia‐related keratopathy (ARK), caused by a combination of factors including limbal stem‐cell deficiency, impaired healing response, abnormal differentiation, and infiltration of conjunctival cells onto the corneal surface. It usually begins in the first decade of life resulting in recurrent corneal erosions, sub‐epithelial fibrosis with corneal decompensation and opacification. Unfortunately, current treatment options for aniridia patients are currently limited. There is no in vitro cellular model of AKT needed for drug/therapeutic tools screening and validation. We used genome editing (CRISPR/Cas9) to introduce a nonsense mutation into one allele of the PAX6 gene in limbal stem cells.The mutated cells displayed reduced cell proliferation and cell migration but enhanced cell adhesion. Known PAX6 targets expression was also altered. Of interest, recombinant PAX6 protein was sufficient to rescue the phenotype. By High Throughput Screening of a FDA‐approved library, we identified Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor antidepressant, that rescued both PAX6 endogenous protein level and altered cell migration of the mutant limbal stem cells, through specific inhibition of the ERK/MEK pathway. Furthermore, we found that Duloxetine modulates inflammation through activation of Pax6, strongly suggesting that Pax6 could be a modulator of neuroinflammation. Since Duloxetine is already used as anti‐psychotropic drugs, its repurposed use to treat topically aniridia eye and other ocular inflammatory diseases could become realistic.

The concept of gene therapy for glaucoma: the dream that has not come true yet.

Gene therapies, despite of being a relatively new therapeutic approach, have a potential to become an important alternative to current treatment strategies in glaucoma. Since glaucoma is not considered a single gene disease, the identified goals of gene therapy would be rather to provide neuroprotection of retinal ganglion cells, especially, in intraocular-pressure-independent manner. The most commonly reported type of vector for gene delivery in glaucoma studies is adeno-associated virus serotype 2 that has a high tropism to retinal ganglion cells, resulting in long-term expression and low immunogenic profile. The gene therapy studies recruit inducible and genetic animal models of optic neuropathy, like DBA/2J mice model of high-tension glaucoma and the optic nerve crush-model. Reported gene therapy-based neuroprotection of retinal ganglion cells is targeting specific genes translating to growth factors (i.e., brain derived neurotrophic factor, and its receptor TrkB), regulation of apoptosis and neurodegeneration (i.e., Bcl-xl, Xiap, FAS system, nicotinamide mononucleotide adenylyl transferase 2, Digit3 and Sarm1), immunomodulation (i.e., Crry, C3 complement), modulation of neuroinflammation (i.e., erythropoietin), reduction of excitotoxicity (i.e., CamKIIα) and transcription regulation (i.e., Max, Nrf2). On the other hand, some of gene therapy studies focus on lowering intraocular pressure, by impacting genes involved in both, decreasing aqueous humor production (i.e., aquaporin 1), and increasing outflow facility (i.e., COX2, prostaglandin F2α receptor, RhoA/RhoA kinase signaling pathway, MMP1, Myocilin). The goal of this review is to summarize the current state-of-art and the direction of development of gene therapy strategies for glaucomatous neuropathy.

Therapeutic Potential of Kaempferol against Sleep Deprivation-Induced Cognitive Impairment: Modulation of Neuroinflammation and Synaptic Plasticity Disruption in Mice

Therapeutic Potential of Kaempferol against Sleep Deprivation-Induced Cognitive Impairment: Modulation of Neuroinflammation and Synaptic Plasticity Disruption in Mice

Immunopathology of herpes simplex virus-associated neuroinflammation: Unveiling the mysteries.

The immunopathology of herpes simplex virus (HSV)-associated neuroinflammation is a captivating and intricate field of study within the scientific community. HSV, renowned for its latent infection capability, gives rise to a spectrum of neurological expressions, ranging from mild symptoms to severe encephalitis. The enigmatic interplay between the virus and the host's immune responses profoundly shapes the outcome of these infections. This review delves into the multifaceted immune reactions triggered by HSV within neural tissues, intricately encompassing the interplay between innate and adaptive immunity. Furthermore, this analysis delves into the delicate equilibrium between immune defence and the potential for immunopathology-induced neural damage. It meticulously dissects the roles of diverse immune cells, cytokines, and chemokines, unravelling the intricacies of neuroinflammation modulation and its subsequent effects. By exploring HSV's immune manipulation and exploitation mechanisms, this review endeavours to unveil the enigmas surrounding the immunopathology of HSV-associated neuroinflammation. This comprehensive understanding enhances our grasp of viral pathogenesis and holds promise for pioneering therapeutic strategies designed to mitigate the neurological ramifications of HSV infections.

Cannabidiol Anticonvulsant Effects Against Lithium-Pilocarpine-Induced Status Epilepticus in Male Rats Are Mediated by Neuroinflammation Modulation and Cannabinoids 1 (CB1), But Not CB2 and GABAA Receptors.

Background: Status epilepticus (SE) is a series of seizures that can lead to serious neurological damages. Cannabidiol (CBD) is extracted from the cannabis plant, which has been approved as an antiseizure medication. This study aimed to determine the efficacy of various doses of CBD on lithium-pilocarpine-induced SE in rats and possible involvement of multiple pharmacological pathways. We hypothesized that cannabinoid receptors type 1 (CB1) and CB2, as well as GABAA receptors, might have important roles in the anticonvulsant effects of CBD against SE by its anti-inflammatory effects. Methods: SE was induced by intraperitoneal (i.p.) injection of lithium (127 mg/kg, i.p.) and pilocarpine (60 mg/kg, i.p., 20 h after lithium). Forty-two male rats were divided into seven groups (including control and sham groups), and the treated groups received different doses of CBD (1, 3, 5, 10, and 25 mg/kg, i.p.). SE score was recorded over the next 2 h following pilocarpine injection. Then, we measured the levels of pro-inflammatory cytokines, including interleukin (IL)-lβ and tumor necrosis factor (TNF)-α, using ELISA kits. Also we analyzed the expression of CB1, CB2, and GABAA receptors using the Western blot technique. Results: CBD at 5 mg/kg significantly reduced Racine's scale and duration of seizures, and increased the onset time of seizure. Moreover, CBD 5 mg/kg caused significant reductions in the elevated levels of IL-lβ and TNF-α, as well as a significant increase in the decreased level of CB1 receptor expression compared to the control group. In other word, CBD reverted the effects of SE in terms of neuroinflammation and CB1 receptor. Based on the obtained results, CBD was not able to restore the declined levels of CB2 or GABAA receptors. Conclusion: Our study found anticonvulsant effects of CBD on the SE rat model induced by lithium-pilocarpine with probable involvement of CB1 receptors and anti-inflammatory effects by reducing IL-1β and TNF-α markers independent of CB2 and GABAA receptors.

Role of trigger receptor 2 expressed on myeloid cells in neuroinflammation－neglected multidimensional regulation of microglia

Neuroinflammation is an inflammatory cascade involved in various neurological disorders, including Alzheimer's disease, multiple sclerosis, and other relevant diseases. The triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane immune receptor that is primarily expressed by microglia in the central nervous system (CNS). While TREM2 is initially believed to be an anti-inflammatory factor in the CNS, increasing evidence suggests that TREM2 plays a more complex role in balancing neuroinflammation. However, the exact mechanism remains unclear. Notably, TREM2 directly regulates microglia inflammation through various signaling pathways. Additionally, studies have suggested that TREM2 mediates microglial phagocytosis, autophagy, metabolism, and microglia phenotypes, which may be involved in the modulation of neuroinflammation. In this review, we aim to discuss the critical role of TREM2 in several microglia functions and the underlying molecular mechanism the modulatory which further mediate neuroinflammation, and elaborate. Finally, we discuss the potential of TREM2 as a therapeutic target in neuroinflammatory disorders.

Interleukin-4 Modulates Neuroinflammation by Inducing Phenotypic Transformation of Microglia Following Subarachnoid Hemorrhage

Neuroinflammation, a key pathological feature following subarachnoid hemorrhage (SAH), can be therapeutically targeted by inhibiting microglia M1 polarization and promoting phenotypic transformation to M2 microglia. Interleukin-4 (IL-4) is a pleiotropic cytokine known to its regulation of physiological functions of the central nervous system (CNS) and mediate neuroinflammatory processes. However, its specific role in neuroinflammation and microglia responses following SAH remains unexplored. In this investigation, we established both in vivo and in vitro SAH models and employed a comprehensive array of assessments, including ELISA, neurofunctional profiling, immunofluorescence staining, qRT-PCR, determination of phagocytic capacity, and RNA-Seq analyses. The findings demonstrate an elevated expression of IL-4 within cerebrospinal fluid (CSF) subsequent to SAH. Furthermore, exogenous administration of IL-4 ameliorates post-SAH neurofunctional deficits, attenuates cellular apoptosis, fosters M2 microglia phenotype conversion, and mitigates neuroinflammatory responses. The RNA-Seq analysis signifies that IL-4 governs the modulation of neuroinflammation in microglia within an in vitro SAH model through intricate cascades of signaling pathways, encompassing interactions between cytokines and cytokine receptors. These discoveries not only augment comprehension of the neuropathogenesis associated with post-SAH neuroinflammation but also present novel therapeutic targets for the management thereof.Graphical

ADAR1 suppression causes interferon signaling and transposable element transcript accumulation in human astrocytes.

Neuroinflammation is a central mechanism of brain aging and Alzheimer's disease (AD), but the exact causes of age- and AD-related neuroinflammation are incompletely understood. One potential modulator of neuroinflammation is the enzyme adenosine deaminase acting on RNA 1 (ADAR1), which regulates the accumulation of endogenous double-stranded RNA (dsRNA), a pro-inflammatory/innate immune activator. However, the role of ADAR1 and its transcriptomic targets in astrocytes, key mediators of neuroinflammation, have not been comprehensively investigated. Here, we knock down ADAR1 in primary human astrocytes via siRNA transfection and use transcriptomics (RNA-seq) to show that this results in: (1) increased expression of type I interferon and pro-inflammatory signaling pathways and (2) an accumulation of transposable element (TE) transcripts with the potential to form dsRNA. We also show that our findings may be clinically relevant, as ADAR1 gene expression declines with brain aging and AD in humans, and this is associated with a similar increase in TE transcripts. Together, our results suggest an important role for ADAR1 in preventing pro-inflammatory activation of astrocytes in response to endogenous dsRNA with aging and AD.

Sulforaphane's Multifaceted Potential: From Neuroprotection to Anticancer Action.

Sulforaphane (SFN) is a naturally occurring compound found in cruciferous vegetables such as broccoli and cauliflower. It has been widely studied for its potential as a neuroprotective and anticancer agent. This review aims to critically evaluate the current evidence supporting the neuroprotective and anticancer effects of SFN and the potential mechanisms through which it exerts these effects. SFN has been shown to exert neuroprotective effects through the activation of the Nrf2 pathway, the modulation of neuroinflammation, and epigenetic mechanisms. In cancer treatment, SFN has demonstrated the ability to selectively induce cell death in cancer cells, inhibit histone deacetylase, and sensitize cancer cells to chemotherapy. SFN has also shown chemoprotective properties through inhibiting phase I metabolizing enzymes, modulating phase II xenobiotic-metabolizing enzymes, and targeting cancer stem cells. In addition to its potential as a therapeutic agent for neurological disorders and cancer treatment, SFN has shown promise as a potential treatment for cerebral ischemic injury and intracranial hemorrhage. Finally, the ongoing and completed clinical trials on SFN suggest potential therapeutic benefits, but more research is needed to establish its effectiveness. Overall, SFN holds significant promise as a natural compound with diverse therapeutic applications.

The role of biogenic amines in the modulation of monocytes in autoimmune neuroinflammation.

Multiple sclerosis (MS) is inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS) with autoimmune mechanism of development. The study of the neuroimmune interactions is one of the most developing directions in the research of the pathogenesis of MS. The influence of biogenic amines on the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and MS was shown by the modulation of subsets of T-helper cells and B-cells, which plays a crucial role in the autoimmunity of the CNS. However, along with T- and B-cells the critical involvement of mononuclear phagocytes such as dendritic cells, macrophages, and monocytes in the development of neuroinflammation also was shown. It was demonstrated that the activation of microglial cells (resident macrophages of the CNS) could initiate the neuroinflammation in the EAE, suggesting their role at an early stage of the disease. In contrast, monocytes, which migrate from the periphery into the CNS through the blood-brain barrier, mediate the effector phase of the disease and cause neurological disability in EAE. In addition, the clinical efficacy of the therapy with depletion of the monocytes in EAE was shown, suggesting their crucial role in the autoimmunity of the CNS. Biogenic amines, such as epinephrine, norepinephrine, dopamine, and serotonin are direct mediators of the neuroimmune interaction and may affect the pathogenesis of EAE and MS by modulating the immune cell activity and cytokine production. The anti-inflammatory effect of targeting the biogenic amines receptors on the pathogenesis of EAE and MS by suppression of Th17- and Th1-cells, which are critical for the CNS autoimmunity, was shown. However, the latest data showed the potential ability of biogenic amines to affect the functions of the mononuclear phagocytes and their involvement in the modulation of neuroinflammation. This article reviews the literature data on the role of monocytes in the pathogenesis of EAE and MS. The data on the effect of targeting of biogenic amine receptors on the function of monocytes are presented.

Cognitive Impairment in Parkinson's Disease: An Updated Overview Focusing on Emerging Pharmaceutical Treatment Approaches.

Cognitive impairment in patients with Parkinson's disease (PD) is one of the commonest and most disabling non-motor manifestations during the course of the disease. The clinical spectrum of PD-related cognitive impairment includes subjective cognitive decline (SCD), mild cognitive impairment (MCI) and PD dementia (PDD). As the disease progresses, cognitive decline creates a significant burden for the family members and/or caregivers of patients with PD, and has a great impact on quality of life. Current pharmacological treatments have demonstrated partial efficacy and failed to halt disease progression, and novel, effective, and safe therapeutic strategies are required. Accumulating preclinical and clinical evidence shows that several agents may provide beneficial effects on patients with PD and cognitive impairment, including ceftriaxone, ambroxol, intranasal insulin, nilotinib, atomoxetine, mevidalen, blarcamesine, prasinezumab, SYN120, ENT-01, NYX-458, GRF6021, fosgonimeton, INT-777, Neuropeptide S, silibinin, osmotin, cordycepin, huperzine A, fibroblast growth factor 21, Poloxamer 188, ginsenoside Rb1, thioredoxin-1, tangeretin, istradefylline and Eugenia uniflora. Potential underlying mechanisms include the inhibition of a-synuclein aggregation, the improvement of mitochondrial function, the regulation of synaptic plasticity, an impact on the gut-brain axis, the modulation of neuroinflammation and the upregulation of neurotrophic factors, as well as cholinergic, dopaminergic, serotoninergic and norepinephrine neurotransmission. In this updated overview, we aim to cover the clinical aspects of the spectrum of PD-related cognitive impairment and discuss recent evidence on emerging treatment approaches that are under investigation at a preclinical and clinical level. Finally, we aim to provide additional insights and propose new ideas for investigation that may be feasible and effective for the spectrum of PD-related cognitive impairment.

Bioinformatics Analysis and Experimental Verification of Exercise for Aging Mice in Different Brain Regions Based on Transcriptome Sequencing.

Physical exercise mitigates the effects of aging and cognitive decline. However, the precise neurobiological mechanisms underlying this phenomenon remain unclear. The primary aim of this study was to investigate the protective effect of exercise on age-related memory deficits in the prefrontal cortex (PFC) and hippocampus using bioinformatic analysis and biochemical verification. Young and aging mice were subjected to natural feeding or treadmill exercise (12 m/min, 8 weeks). Cognitive function was accessed using the Barnes maze and novel object recognition. Bioinformatic analysis was performed to identify co-expressed genes in different groups and brain regions. The selected genes and pathways were validated using RT-qPCR. Regular exercise significantly ameliorated age-related cognitive deficits. Four up-regulated targets (Ifi27l2a, Irf7, Oas1b, Ifit1) and one down-regulation (Septin2) were reversed by exercise, demonstrating the underlying mechanisms of cognitive functions induced by aging with exercise in the hippocampus and PFC. The Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses indicated that the NOD-like receptor signaling pathway was inhibited in the neuroinflammation effects of exercise in aging mice in both brain regions. Exercise enhances age-related learning and memory deficits. This beneficial effect may be attributed to the changes in five up/down-regulated genes and the NOD-like receptor signaling pathway in both the hippocampus and PFC. These findings establish the modulation of neuroinflammation as a pivotal molecular mechanism supporting exercise intervention in the brain aging process.

New insights on the potential anti-epileptic effect of metformin: Mechanistic pathway.

Epilepsy is a chronic neurological disease characterized by recurrent seizures. Epilepsy is observed as a well-controlled disease by anti-epileptic agents (AEAs) in about 69%. However, 30%-40% of epileptic patients fail to respond to conventional AEAs leading to an increase in the risk of brain structural injury and mortality. Therefore, adding some FDA-approved drugs that have an anti-seizure activity to the anti-epileptic regimen is logical. The anti-diabetic agent metformin has anti-seizure activity. Nevertheless, the underlying mechanism of the anti-seizure activity of metformin was not entirely clarified. Henceforward, the objective of this review was to exemplify the mechanistic role of metformin in epilepsy. Metformin has anti-seizure activity by triggering adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibiting the mechanistic target of rapamycin (mTOR) pathways which are dysregulated in epilepsy. In addition, metformin improves the expression of brain-derived neurotrophic factor (BDNF) which has a neuroprotective effect. Hence, metformin via induction of BDNF can reduce seizure progression and severity. Consequently, increasing neuronal progranulin by metformin may explain the anti-seizure mechanism of metformin. Also, metformin reduces α-synuclein and increases protein phosphatase 2A (PPA2) with modulation of neuroinflammation. In conclusion, metformin might be an adjuvant with AEAs in the management of refractory epilepsy. Preclinical and clinical studies are warranted in this regard.

MKP-1 regulates the inflammatory activation of microglia against Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases leading to dementia in elderly people. Microglia-mediated neuroinflammation plays an important role in AD pathogenesis, so modulation of neuroinflammation has emerged as an essential therapeutic method to improve AD. The current study aims to investigate whether MKP-1 can regulate microglia phenotype and inflammatory factor release in AD and explore its possible mechanisms. Amyloid precursor protein/PS1 double transgenic mice and wild-type mice were selected to study the locations of microglia and amyloid-β (Aβ) plaques in different regions of mice brains. Changes in MKP-1 of microglia were detected using AD model mice and AD model cells. Changes in phenotype and the release of inflammatory factors within immortalized BV2 murine microglia were investigated by regulating the expression of MKP-1. The distribution of microglia and Aβ plaques in the AD brain was region-specific. MKP-1 expression was downregulated in AD mice, and in vitro, with increasing Aβ concentrations, MKP-1 expression was reduced. MKP-1 over-expression increased M2 microglia but decreased M1 microglia accompanied by changes in inflammatory factors and inhibition of MKP-1 yielded the opposite result. MKP-1 regulated microglia phenotype and inflammatory factor release in AD through modulation of the p38 signaling pathway.

Under the influence: environmental factors as modulators of neuroinflammation through the IL-10/IL-10R axis.

The IL-10/IL-10 receptor (IL-10R) axis plays an important role in attenuating neuroinflammation in animal models of Multiple Sclerosis (MS) and increased IL-10 has been associated with a positive response to MS disease modifying therapy. Because environmental factors play an important role in MS susceptibility and disease course, identification of environmental factors that impact the IL-10/IL-10R axis has therapeutic potential. In this review, we provide historical and updated perspectives of how IL-10R signaling impacts neuroinflammation, discuss environmental factors and intestinal microbes with known impacts on the IL-10/IL-10R axis, and provide a hypothetical model for how B cells, via their production of IL-10, may be important in conveying environmental "information" to the inflamed central nervous system.

Fructooligosaccharide (FOS) and Galactooligosaccharide (GOS) Improve Neuroinflammation and Cognition By Up-regulating IRS/PI3K/AKT Signaling Pathway in Diet-induced Obese Mice.

Increasing evidence has indicated that prebiotics as an alternative treatment for neuropsychiatric diseases. This study evaluated the prebiotics Fructooligosaccharides (FOS) and Galactooligosaccharides (GOS) on the modulation of neuroinflammation and cognition in an experimental model of mice high-fat diet fed. Initially, mice were distributed in the following groups: (A) control standard diet (n = 15) and (B) HFD for 18 weeks (n = 30). In the 13th week, the mice were later divided into the following experimental groups: (A) Control (n = 15); (B) HFD (n = 14); and (C) HFD + Prebiotics (n = 14). From the 13th week, the HFD + Prebiotics group received a high-fat diet and a combination of FOS and GOS. In the 18th week, all animals performed the T-maze and Barnes Maze, and were later euthanized. Biochemical and molecular analyzes were performed to assess neuroinflammation, neurogenesis, synaptic plasticity, and intestinal inflammation. Mice fed HFD had higher blood glucose, triglyceridemia, cholesterolemia, and higher serum IL-1β associated with impaired learning and memory. These obese mice also showed activation of microglia and astrocytes and significant immunoreactivity of neuroinflammatory and apoptosis markers, such as TNF-α, COX-2, and Caspase-3, in addition to lower expression of neurogenesis and synaptic plasticity markers, such as NeuN, KI-67, CREB-p, and BDNF. FOS and GOS treatment significantly improved the biochemistry profile and decreased serum IL-1β levels. Treatment with FOS and GOS also reduced TNF-α, COX-2, Caspase-3, Iba-1, and GFAP-positive cells in the dentate gyrus, decreasing neuroinflammation and neuronal death caused by chronic HFD consumption. In addition, FOS and GOS promoted synaptic plasticity by increasing NeuN, p-CREB, BDNF, and KI-67, restoring spatial learning ability and memory. Moreover, FOS and GOS on HFD modulated the insulin pathway, which was proved by up-regulating IRS/PI3K/AKT signaling pathway, followed by a decreasing Aβ plate and Tau phosphorylation. Furthermore, the prebiotic intervention reshaped the HFD-induced imbalanced gut microbiota by modulating the composition of the bacterial community, markedly increasing Bacteroidetes. In addition, prebiotics decreased intestinal inflammation and leaky gut. In conclusion, FOS and GOS significantly modulated the gut microbiota and IRS/PI3K/AKT signaling pathway, decreased neuroinflammation, and promoted neuroplasticity improving spatial learning and memory. Schematic summarizing of the pathways by FOS and GOS improves memory and learning through the gut-brain axis. FOS and GOS improve the microbial profile, reducing intestinal inflammation and leaky gut in the distal colon. Specifically, the administration of FOS and GOS decreases the expression of TLR4, TNF-α, IL-1β, and MMP9 and increases the expression of occludin and IL-10. Prebiotics inhibit neuroinflammation, neuronal apoptosis, and reactive gliosis in the hippocampus but restore synaptic plasticity, neuronal proliferation, and neurogenesis.

Is it all the RAGE? Defining the role of the receptor for advanced glycation end products in Parkinson's disease.

The receptor for advanced glycation end products (RAGE) is a transmembrane receptor that belongs to the immunoglobulin superfamily and is extensively associated with chronic inflammation in non-transmissible diseases. As chronic inflammation is consistently present in neurodegenerative diseases, it was largely assumed that RAGE could act as a critical modulator of neuroinflammation in Parkinson's disease (PD), similar to what was reported for Alzheimer's disease (AD), where RAGE is postulated to mediate pro-inflammatory signaling in microglia by binding to amyloid-β peptide. However, accumulating evidence from studies of RAGE in PD models suggests a less obvious scenario. Here, we review physiological aspects of RAGE and address the current questions about the potential involvement of this receptor in the cellular events that may be critical for the development and progression of PD, exploring possible mechanisms beyond the classical view of the microglial activation/neuroinflammation/neurodegeneration axis that is widely assumed to be the general mechanism of RAGE action in the adult brain.

DPP-4 inhibitors and type 2 diabetes mellitus in Parkinson's disease: a mutual relationship.

Parkinson's disease (PD) usually occurs due to the degeneration of dopaminergic neurons in the substantia nigra (SN). Management of PD is restricted to symptomatic improvement. Consequently, a novel treatment for managing motor and non-motor symptoms in PD is necessary. Abundant findings support the protection of dipeptidyl peptidase 4 (DPP-4) inhibitors in PD. Consequently, this study aims to reveal the mechanism of DPP-4 inhibitors in managing PD. DPP-4 inhibitors are oral anti-diabetic agents approved for managing type 2 diabetes mellitus (T2DM). T2DM is linked with an increased chance of the occurrence of PD. Extended usage of DPP-4 inhibitors in T2DM patients may attenuate the development of PD by inhibiting inflammatory and apoptotic pathways. Thus, DPP-4 inhibitors like sitagliptin could be a promising treatment against PD neuropathology via anti-inflammatory, antioxidant, and anti-apoptotic impacts. DPP-4 inhibitors, by increasing endogenous GLP-1, can also reduce memory impairment in PD. In conclusion, the direct effects of DPP-4 inhibitors or indirect effects through increasing circulating GLP-1 levels could be an effective therapeutic strategy in treating PD patients through modulation of neuroinflammation, oxidative stress, mitochondrial dysfunction, and neurogenesis.