Thymoquinone Lipid Nanoparticles Cut the Gordian Knots of Depression via Neuroprotective BDNF and Downregulation of Neuro-inflammatory NF-κB, IL-6, and TNF-α in LPS Treated Rats.

BACKGROUND: In over 300 million clinical cases, antidepressant drugs seem to provide only symptomatic relief and limited protection in life-threatening depressive events. OBJECTIVES: To compare neuronal-signaling mechanism and neuroprotective roles of Thymoquinone (TQ) suspension and its SLN (TQSLN) against standard antidepressant drug fluoxetine. METHODS: This research investigated in-silico docking at NF-KB p50 active site, CLSM based gut permeation, screening of antidepressant activities and neurosignaling pathways involved. RESULTS: As compared to fluoxetine, TQ reporteda significantly better docking score (-6.83 v/s -6.22) and a better lower free binding energy of (-34.715 Kcal/mol v/s -28.537 Kcal/mol). While poorly oral bioavailable and P-gp substrate TQ reported approximately 250% higher gut permeation if delivered as TQSLN formulation. In locomotor studies, as compared to TQS, TQSLN favored more prominent (p< 0.010) elevation in average time, horizontalactivity, average-velocity, and total-movement with reduced rest time LPS treated groups. However, in the tail suspension test, TQSLN significantly reduced immobility time (p<0.010). Similarly, In the modified force swimming test, TQSLN also significantly reduced immobility time (p<0.010), but swimming time (p<0.010) and climbing time (p<0.050) were significantly elevated. Subsequently, TQSLN reported significantly elevated neuroprotective BDNF (p<0.010) as well as hippocampal 5HT/TRP; accompanied with reduced levels of hippocampal inflammatory markers TNF-α (p<0.001) and IL-6 (p<0.010) as well as lower kynurenine and tryptophan ratio (KYN/TRP). Similarly, the hippocampal CA1 region further revealed TQSL more predominantly attenuated NF-kB nuclear translocation in the brain. CONCLUSION: Despite the poor bioavailability of TQ, TQSLN potentially attenuates neuroinflammatory transmitters and favors BDNF to modulate depressive neurobehavioral states.

Interleukin-6 as potential mediator of long-term neuropsychiatric symptoms of COVID-19.

The majority of COVID-19 survivors experience long-term neuropsychiatric symptoms such as fatigue, sleeping difficulties, depression and anxiety. We propose that neuroimmune cross-talk via inflammatory cytokines such as interleukin-6 (IL-6) could underpin these long-term COVID-19 symptoms. This hypothesis is supported by several lines of research, including population-based cohort and genetic Mendelian Randomisation studies suggesting that inflammation is associated with fatigue and sleeping difficulties, and that IL-6 could represent a possible causal driver for these symptoms. Immune activation following COVID-19 can disrupt T helper 17 (TH17) and regulatory T (Treg) cell responses, affect central learning and emotional processes, and lead to a vicious cycle of inflammation and mitochondrial dysfunction that amplifies the inflammatory process and results in immuno-metabolic constraints on neuronal energy metabolism, with fatigue being the ultimate result. Increased cytokine activity drives this process and could be targeted to interrupt it. Therefore, whether persistent IL-6 dysregulation contributes to COVID-19-related long-term fatigue, sleeping difficulties, depression, and anxiety, and whether targeting IL-6 pathways could be helpful for treatment and prevention of long COVID are important questions that require investigation. This line of research could inform new approaches for treatment and prevention of long-term neuropsychiatric symptoms of COVID-19. Effective treatment and prevention of this condition could also help to stem the anticipated rise in depression and other mental illnesses ensuing this pandemic.

The Role of α7nAChR-Mediated Cholinergic Anti-Inflammatory Pathway in Vagal Nerve Regulated Atrial Fibrillation.

The aim was to investigate the role of the α7nAChR-mediated cholinergic anti-inflammatory pathway in vagal nerve regulated atrial fibrillation (AF).18 beagles (standard dogs for testing) were used in this study, and the effective refractory period (ERP) of atrium and pulmonary veins and AF inducibility were measured hourly during rapid atrial pacing at 800 beats/minute for 6 hours in all beagles. After cessation of 3 hours of RAP, the low-level vagal nerve stimulation (LL-VNS) group (n = 6) was given LL-VNS and injection of salinne (0.5 mL/GP) into four GPs, the methyllycaconitine (MLA, the antagonist of α7nAChR) group (n = 6) was given LL-VNS and injection of MLA into four GPs, and the Control group (n = 6) was given saline into four GPs and the right cervical vagal nerve was exposed without stimulation. Then, the levels of the tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), acetylcholine (ACh), STAT3, and NF-κB proteins were measured. During the first 3 hours of RAP, the ERPs gradually decreased while the dispersion of ERPs (dERPs) and AF inducibility gradually increased in all three groups. During the last 3 hours of 6 hours' RAP in this study, the ERPs in the LL-VNS group were higher, while the dERPs and AF inducibility were significantly lower when compared with the Control and MLA groups at the same time points. The levels of ACh in the serum and atrium in the LL-VNS and MLA groups were higher than in the Control group, and the levels of TNF-α and IL-6 were higher in the Control and MLA groups than in the LL-VNS group. The concentrations of STAT3 in RA and LA tissues were higher in the LL-VNS group while those of NF-κB were lower.In conclusion, the cholinergic anti-inflammatory pathway mediated by α7nACh plays an important role in low-level vagal nerve-regulated AF.

Neuroimmune Consequences of eIF4E Phosphorylation on Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect that occurs in up to 63% of patients and has no known effective treatment. A majority of studies do not effectively assess sex differences in the onset and persistence of CIPN. Here we investigated the onset of CIPN, a point of therapeutic intervention where we may limit, or even prevent the development of CIPN. We hypothesized that cap-dependent translation mechanisms are important in early CIPN development and the bi-directional crosstalk between immune cells and nociceptors plays a complementary role to CIPN establishment and sex differences observed. In this study, we used wild type and eIF4E-mutant mice of both sexes to investigate the role of cap-dependent translation and the contribution of immune cells and nociceptors in the periphery and glia in the spinal cord during paclitaxel-induced peripheral neuropathy. We found that systemically administered paclitaxel induces pain-like behaviors in both sexes, increases helper T-lymphocytes, downregulates cytotoxic T-lymphocytes, and increases mitochondrial dysfunction in dorsal root ganglia neurons; all of which is eIF4E-dependent in both sexes. We identified a robust paclitaxel-induced, eIF4E-dependent increase in spinal astrocyte immunoreactivity in males, but not females. Taken together, our data reveals that cap-dependent translation may be a key pathway that presents relevant therapeutic targets during the early phase of CIPN. By targeting the eIF4E complex, we may reduce or reverse the negative effects associated with chemotherapeutic treatments.

Dysregulation of SIRT-1 Signaling in Multiple Sclerosis and Neuroimmune Disorders: A Systematic Review of SIRTUIN Activators as Potential Immunomodulators and their Influences on other Dysfunctions.

Immune dysregulation, neuronal inflammation, and oligodendrocyte degradation are key causes for autoimmune disorders like multiple sclerosis (MS) and various other immune dysregulated neurodegenerative complications responsible for CNS-mediated immune responses. Sirtuin (SIRT-1) is a nicotinamide adenosine dinucleotide (NAD)-dependent transcriptional protein that deacetylases and removes acetyl groups from its transcription factors like P53, FOXO, NF-Κb, PGC-1α. SIRT-1 mediates a wide range of physiological functions, including gene transcription, metabolism, neuronal apoptosis, and glucose production. SIRT-1 dysregulation targets transcription factors, and other molecular alterations such as gene expression modification influence neuronal plasticity, inhibit Th17 cells, and interleukin-1ß can aggravate brain diseases. Preclinical and clinical findings show that the upregulation of SIRT-1 reduces autoimmunity, neurodegeneration, and neuroexcitation. Even though drugs are being developed for symptomatic therapies in clinical trials, there are particular pharmacological implications for improving post-operative conditions in neurodegenerative patients where intensive care is required. Understanding the SIRT-1 signaling and identifying immune-mediated neuron deterioration can detect major therapeutic interventions that could prevent neuro complications. Thus, in the current review, we have addressed the manifestations of disease by the downregulation of SIRT-1 that could potentially cause MS and other neurodegenerative disorders and provided data on existing available and effective drug therapies and disease management strategies.

Tomentosin Reduces Behavior Deficits and Neuroinflammatory Response in MPTP-Induced Parkinson's Disease in Mice.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Tomentosin is an active compound isolated from the I. viscosa plant that has extensive therapeutic value. In this exploration, the neuroprotective actions of tomentosin were investigated against MPTP-stimulated neuroinflammation in mice. PD was stimulated in C57/BL6 mice by injecting 20-mg/kg MPTP at 2-h intervals 4 times a day for 15 days simultaneously with tomentosin treatment. The rota-rod test, grasping test, and pole climbing test were executed to investigate the motor functioning of the test animals. Proinflammatory cytokines, reactive oxygen species, and myeloperoxidase were assayed using commercial ELISA kits. Superoxide dismutase enzyme levels were measured by the standard method. Expression of TLR-4/NF-κB was analyzed by Western blot. Brain tissues of investigational animals were analyzed microscopically. Tomentosin treatment of the MPTP-intoxicated PD mice promoted appreciable regains in body weight and noticeably prevented MPTP-stimulated impairments in motor function. In the PD mice, proinflammatory cytokine, ROS, and MPO levels were lowered by tomentosin, inhibited the TLR-4/NF-κB signaling pathway and prevented inflammation-mediated neuronal cell damage, and reduced glial cell damage and normalized ganglion layers. These findings confirmed the neuroprotective properties of tomentosin against MPTP-induced PD in mice.

Progesterone Attenuates Brain Inflammatory Response and Inflammation-Induced Increase in Immature Myeloid Cells in a Mouse Model.

Progesterone has been shown to regulate immunity during pregnancy, and progesterone administration may reduce inflammation-induced preterm labor. We sought to determine the maternal brain immune response to LPS-induced inflammation in pregnant and non-pregnant mice and whether additional progesterone supplementation attenuates this response. Pregnant (P: n = 9) and non-pregnant mice (NP: n = 9) were randomized to pretreatment with vaginal progesterone/carrier (Replens), daily from days 13 to 16. On days 15 and 16, LPS/saline was administered by intraperitoneal injection (Replens + saline n = 3; Replens + LPS n = 3; progesterone + LPS n = 3). Mice were sacrificed on day 16 and maternal serum analyzed for IL-6 levels and brains analyzed for nNOS, NF-kB, IL-6 protein levels and for immature myeloid cells (IMCs) and microglial activity. LPS significantly increased brain nNOS, NF-kB, and IL-6 in both NP and P mice, with significantly greater responses in P mice. In both NP and P groups, progesterone significantly attenuated LPS-induced increase of nNOS and NF-kB, however with no effect on serum IL-6. In the NP brains, LPS significantly increased IMC population and progesterone reduced the IMC phenotype to levels similar to controls. In P mice, neither LPS nor LPS + progesterone altered the brain IMC population. LPS significantly increased the microglial activity in both NP and P groups, which was attenuated by progesterone. Progesterone attenuates brain inflammatory response to LPS in both NP and P mice although it has no effect on systemic inflammation. In NP mice, progesterone attenuated the increase in brain IMC following LPS administration. Our results suggest that endogenous progesterone during pregnancy may protect the brain from LPS-induced inflammation.

Terpenoids from Abies holophylla Attenuate LPS-Induced Neuroinflammation in Microglial Cells by Suppressing the JNK-Related Signaling Pathway.

We have previously reported that phytochemicals from Abies holophylla exhibit anti-inflammatory and neuroprotective effects by decreasing nitrite production and increasing nerve growth factor production. However, the exact mechanism underscoring these effects has not been revealed. In the present study, we aimed to explore the underlying anti-inflammatory mechanisms of A. holophylla and its phytochemicals. We studied various solvent fractions of A. holophylla and found the chloroform and hexane sub-fractions showed the most significant anti-neuroinflammatory effects in lipopolysaccharide (LPS)-activated murine microglia. Concomitantly, the terpenoids isolated from chloroform and hexane fractions showed similar anti-neuroinflammatory effects with significant inhibition of NO and reactive oxygen species production, and decreased protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase. Interestingly, these terpenoids inhibited the phosphorylation of c-Jun N-terminal kinase (JNK), which further inhibited the production of pro-inflammatory mediators, including prostaglandin E2, tumor necrosis factor, and interleukins (IL-6 and IL-1ß), with a potency greater than that of the well-known iNOS inhibitor NG-mono-methyl-L-arginine (L-NMMA). These results suggest that the chloroform- and hexane-soluble fraction mediated the mitogen-activated protein kinase (MAPK) inhibition, in particular the JNK pathway, thereby lowering the inflammatory cascades in LPS-activated murine microglia. Thus, our study suggests that the chloroform and hexane fractions of A. holophylla and their terpenoids may be potential drug candidates for drug discovery against LPS-induced neuroinflammation and neuroinflammatory-related neurodegeneration.

Dietary exposure to bisphenol A affects memory function and neuroimmune biomarkers in allergic asthmatic mice.

Bisphenol A (BPA) is a raw material of polycarbonate and epoxy resin. It is used for various household electrical appliances, electronic equipment, office automation equipment, medical equipment, mobile phones, paints for automobiles, internal surface coating of cans, and adhesives for civil engineering and construction. BPA is a well-known endocrine-disrupting chemical, and it was reported that BPA has an adverse effect on the nervous and immune systems. However, BPA-induced memory impairment and changes in neuroimmune biomarkers in the allergic asthmatic subject are not known yet. We aim to investigate the dietary exposure effect of BPA on brain function and biomarkers using allergic an asthmatic mouse model. Five-week-old male C3H/HeJSlc mice were fed two doses of BPA [0.901, 9.01 µg/kg/day] contained chow diet from 5 to 11 weeks old and ovalbumin (OVA) was given by intratracheal instillation every 2 weeks. Memory function was determined by a novel object recognition test. Genes related to memory and immune markers in the hippocampus were investigated with the real-time polymerase chain reaction (RT-PCR) method. In this study, impaired novel object recognition occurred in BPA-exposed mice in the presence of an allergen. Moreover, upregulation of expression level of neuroimmune biomarkers such as N-methyl-D-aspartate receptor, tumor necrosis factor-α, ionized calcium-binding adapter molecule-1, cyclooxygenase-2, and heme oxygenase-1 in the hippocampus was observed in BPA-exposed allergic asthmatic mice. These findings show that BPA exposure can induce neuroinflammation and which triggers impairment of memory function in mice with allergic asthma. Our study indicated that dietary exposure to BPA may affect higher brain functions by modulating neuroimmune biomarkers in allergic asthmatic subjects.

Inhibition of Bruton Tyrosine Kinase Reduces Neuroimmune Cascade and Promotes Recovery after Spinal Cord Injury.

Microglia/astrocyte and B cell neuroimmune responses are major contributors to the neurological deficits after traumatic spinal cord injury (SCI). Bruton tyrosine kinase (BTK) activation mechanistically links these neuroimmune mechanisms. Our objective is to use Ibrutinib, an FDA-approved BTK inhibitor, to inhibit the neuroimmune cascade thereby improving locomotor recovery after SCI. Rat models of contusive SCI, Western blot, immunofluorescence staining imaging, flow cytometry analysis, histological staining, and behavioral assessment were used to evaluate BTK activity, neuroimmune cascades, and functional outcomes. Both BTK expression and phosphorylation were increased at the lesion site at 2, 7, 14, and 28 days after SCI. Ibrutinib treatment (6 mg/kg/day, IP, starting 3 h post-injury for 7 or 14 days) reduced BTK activation and total BTK levels, attenuated the injury-induced elevations in Iba1, GFAP, CD138, and IgG at 7 or 14 days post-injury without reduction in CD45RA B cells, improved locomotor function (BBB scores), and resulted in a significant reduction in lesion volume and significant improvement in tissue-sparing 11 weeks post-injury. These results indicate that Ibrutinib exhibits neuroprotective effects by blocking excessive neuroimmune responses through BTK-mediated microglia/astroglial activation and B cell/antibody response in rat models of SCI. These data identify BTK as a potential therapeutic target for SCI.

Methylmercury chloride exposure aggravates proinflammatory mediators and Notch-1 signaling in CD14+ and CD40+ cells and is associated with imbalance of neuroimmune function in BTBR T+ Itpr3tf/J mice.

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social interaction, communication, and repetitive behaviors. A key role for immune dysfunction has been suggested in ASD. Recent studies have indicated that inflammatory mediators and Notch-1 signaling may contribute to the development of ASD. Methylmercury chloride (MeHgCl) is an environmental pollutant that primarily affects the central nervous system, causing neurological alterations. Its effects on immunological responses have not been fully investigated in ASD. In this study, we examined the influence of MeHgCl exposure on inflammatory mediators and Notch-1 signaling in BTBR T+ Itpr3tf/J (BTBR) mice, a model of ASD. We examined the effects of MeHgCl on the IL-6-, GM-CSF-, NF-κB p65-, Notch-1-, and IL-27-producing CD14+ and CD40+ cells in the spleen. We assessed the effect of MeHgCl on IL-6, GM-CSF, NF-κB p65, Notch-1, and IL-27 mRNA levels in brain tissue. We also measured IL-6, GM-CSF, and NF-κB p65 protein expression levels in brain tissue. MeHgCl exposure of BTBR mice significantly increased IL-6-, GM-CSF-, NF-κB p65-, and Notch-1-, and decreased IL-27-producing CD14+, and CD40+ cells in the spleen. MeHgCl exposure of BTBR mice upregulated IL-6, GM-CSF, NF-κB p65, and Notch-1, and decreased IL-27 mRNA expression levels in brain tissue. Moreover, MeHgCl resulted in elevated expression of the IL-6, GM-CSF, and NF-κB p65 proteins in brain tissue. Taken together, these results indicate that MeHgCl exposure aggravates proinflammatory mediators and Notch-1 signaling which are associated with imbalance of neuroimmune function in BTBR mice.

Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis.

Rationale: Psoriasis is a chronic inflammatory disease caused by a complex interplay between the immune and nervous systems with recurrent scaly skin plaques, thickened stratum corneum, infiltration and activation of inflammatory cells, and itch. Despite an increasing availability of immune therapies, they often have adverse effects, high costs, and dissociated effects on inflammation and itch. Activation of sensory neurons innervating the skin and TRPV1 (transient receptor potential vanilloid 1) are emerging as critical components in the pathogenesis of psoriasis, but little is known about their endogenous inhibitors. Recent studies have demonstrated that resolvins, endogenous lipid mediators derived from omega-3 fatty acids, are potent inhibitors of TRP channels and may offer new therapies for psoriasis without known adverse effects. Methods: We used behavioral, electrophysiological and biochemical approaches to investigate the therapeutic effects of resolvin D3 (RvD3), a novel family member of resolvins, in a preclinical model of psoriasis consisting of repeated topical applications of imiquimod (IMQ) to murine skin, which provokes inflammatory lesions that resemble human psoriasis. Results: We report that RvD3 specifically reduced TRPV1-dependent acute pain and itch in mice. Mechanistically, RvD3 inhibited capsaicin-induced TRPV1 currents in dissociated dorsal root ganglion (DRG) neurons via the N-formyl peptide receptor 2 (i.e. ALX/FPR2), a G-protein coupled receptor. Single systemic administration of RvD3 (2.8 mg/kg) reversed itch after IMQ, and repeated administration largely prevented the development of both psoriasiform itch and skin inflammation with concomitant decreased in calcitonin gene-related peptide (CGRP) expression in DRG neurons. Accordingly, specific knockdown of CGRP in DRG was sufficient to prevent both psoriasiform itch and skin inflammation similar to the effects following RvD3 administration. Finally, we elevated the translational potential of this study by showing that RvD3 significantly inhibited capsaicin-induced TRPV1 activity and CGRP release in human DRG neurons. Conclusions: Our findings demonstrate a novel role for RvD3 in regulating TRPV1/CGRP in mouse and human DRG neurons and identify RvD3 and its neuronal pathways as novel therapeutic targets to treat psoriasis.

Prokineticin Receptor Inhibition With PC1 Protects Mouse Primary Sensory Neurons From Neurotoxic Effects of Chemotherapeutic Drugs in vitro.

Neurotoxicity is a common side effect of chemotherapeutics that often leads to the development of chemotherapy-induced peripheral neuropathy (CIPN). The peptide Prokineticin 2 (PK2) has a key role in experimental models of CIPN and can be considered an insult-inducible endangering mediator. Since primary afferent sensory neurons are highly sensitive to anticancer drugs, giving rise to dysesthesias, the aim of our study was to evaluate the alterations induced by vincristine (VCR) and bortezomib (BTZ) exposure in sensory neuron cultures and the possible preventive effect of blocking PK2 signaling. Both VCR and BTZ induced a concentration-dependent reduction of total neurite length that was prevented by the PK receptor antagonist PC1. Antagonizing the PK system also reduced the upregulation of PK2, PK-R1, TLR4, IL-6, and IL-10 expression induced by chemotherapeutic drugs. In conclusion, inhibition of PK signaling with PC1 prevented the neurotoxic effects of chemotherapeutics, suggesting a promising strategy for neuroprotective therapies against the sensory neuron damage induced by exposure to these drugs.

How oral probiotics affect the severity of an experimental model of progressive multiple sclerosis? Bringing commensal bacteria into the neurodegenerative process.

A growing number of studies support that the bidirectional interactions between the gut microbiota, the immune system and the CNS are relevant for the pathophysiology of MS. Several studies have reported alterations in the gut microbiome of MS patients. In addition, a variety of studies in animal models of MS have suggested that specific members of the gut commensal microbiota can exacerbate or ameliorate neuroinflammation. Probiotics represent oral nontoxic immunomodulatory agents that would exert benefits when using in combination with current MS therapy. Here we investigate the effect of Vivomixx on the gut microbiome and central and peripheral immune responses in a murine model of primary progressive MS. Vivomixx administration was associated with increased abundance of many taxa such as Bacteroidetes, Actinobacteria, Tenericutes and TM7. This was accompanied by a clear improvement of the motor disability of Theiler's virus infected mice; in the CNS Vivomixx reduced microgliosis, astrogliosis and leukocyte infiltration. Notably, the presence of Breg cells (CD19+CD5+CD1dhigh) in the CNS was enhanced by Vivomixx, and while spinal cord gene expression of IL-1ß and IL-6 was diminished, the probiotic promoted IL-10 gene expression. One of the most significant findings was the increased plasma levels of butyrate and acetate levels in TMEV-mice that received Vivomixx. Peripheral immunological changes were subtle but interestingly, the probiotic restricted IL-17 production by Th17-polarized CD4+ T-cells purified from the mesenteric lymph nodes of Theiler's virus infected mice. Our data reinforce the beneficial effects of oral probiotics that would be coadjuvant treatments to current MS therapies.

Immediate inhibition of spinal secretory phospholipase A2 prevents the pain and elevated spinal neuronal hyperexcitability and neuroimmune regulatory genes that develop with nerve root compression.

Cervical nerve root injury induces a host of inflammatory mediators in the spinal cord that initiate and maintain neuronal hyperexcitability and pain. Secretory phospholipase A2 (sPLA2) is an enzyme that has been implicated as a mediator of pain onset and maintenance in inflammation and neural injury. Although sPLA2 modulates nociception and excitatory neuronal signaling in vitro, its effects on neuronal activity and central sensitization early after painful nerve root injury are unknown. This study investigated whether inhibiting spinal sPLA2 at the time of nerve root compression (NRC) modulates the pain, dorsal horn hyperexcitability, and spinal genes involved in glutamate signaling, nociception, and inflammation that are seen early after injury. Rats underwent a painful C7 NRC injury with immediate intrathecal administration of the sPLA2 inhibitor thioetheramide-phosphorlycholine. Additional groups underwent either injury alone or sham surgery. One day after injury, behavioral sensitivity, spinal neuronal excitability, and spinal cord gene expression for glutamate receptors (mGluR5 and NR1) and transporters (GLT1 and EAAC1), the neuropeptide substance P, and pro-inflammatory cytokines (TNFα, IL1α, and IL1ß) were assessed. Treatment with the sPLA2 inhibitor prevented mechanical allodynia, attenuated neuronal hyperexcitability in the spinal dorsal horn, restored the proportion of spinal neurons classified as wide dynamic range, and reduced genes for mGluR5, substance P, IL1α, and IL1ß to sham levels. These findings indicate spinal regulation of central sensitization after painful neuropathy and suggest that spinal sPLA2 is implicated in those early spinal mechanisms of neuronal excitability, perhaps via glutamate signaling, neurotransmitters, or inflammatory cascades.

Common Pathways for Pain and Depression-Implications for Practice.

BACKGROUND: Pain and depression have a high impact on caring for the people who need palliative care, but both of these are neglected compared with the approach for other symptoms encountered by these patients. AREAS OF UNCERTAINTY: There are few studies in humans that support the existence of common neural circuits between depression and pain that also explore the use of drugs with effects in both conditions. More knowledge is needed about the relationship of these clinical entities that will lead to the optimization of the treatment and improvement of quality of life. DATA SOURCES: We conducted a search in PubMed to identify relevant articles and reviews that have been published in the last 5 years, concerning the topic of common pathways between depression and pain (2014-April 2019). THERAPEUTIC ADVANCES: The connections between the 2 clinical entities start at the level of the cortical regions. The hippocampus is the main site of neural changes, modification of the immune system, neuromodulators, neurotransmitters, and signaling pathways implicated in both conditions. Increased levels of peripheral proinflammatory cytokines and neuroinflammatory changes are related to the physiopathology of these entities. Inflammation links depression and pain by altering neural circuits and changes in their common cortical regions. Antidepressants are used to treat depression and chronic, pain but more experimental studies are needed to determine which antidepressant drugs are the most effective in treating the 2 entities. CONCLUSIONS: Pharmacological and nonpharmacological interventions targeting cortical changes in pain and depression are promising, but more clinical studies are needed to validate their usefulness.

Neuromodulation, Specialized Proresolving Mediators, and Resolution of Pain.

The current crises in opioid abuse and chronic pain call for the development of nonopioid and nonpharmacological therapeutics for pain relief. Neuromodulation-based approaches, such as spinal cord stimulation, dorsal root ganglion simulation, and nerve stimulation including vagus nerve stimulation, have shown efficacy in achieving pain control in preclinical and clinical studies. However, the mechanisms by which neuromodulation alleviates pain are not fully understood. Accumulating evidence suggests that neuromodulation regulates inflammation and neuroinflammation-a localized inflammation in peripheral nerves, dorsal root ganglia/trigeminal ganglia, and spinal cord/brain-through neuro-immune interactions. Specialized proresolving mediators (SPMs) such as resolvins, protectins, maresins, and lipoxins are lipid molecules produced during the resolution phase of inflammation and exhibit multiple beneficial effects in resolving inflammation in various animal models. Recent studies suggest that SPMs inhibit inflammatory pain, postoperative pain, neuropathic pain, and cancer pain in rodent models via immune, glial, and neuronal modulations. It is noteworthy that sham surgery is sufficient to elevate resolvin levels and may serve as a model of resolution. Interestingly, it has been shown that the vagus nerve produces SPMs and vagus nerve stimulation (VNS) induces SPM production in vitro. In this review, we discuss how neuromodulation such as VNS controls pain via immunomodulation and neuro-immune interactions and highlight possible involvement of SPMs. In particular, we demonstrate that VNS via auricular electroacupuncture effectively attenuates chemotherapy-induced neuropathic pain. Furthermore, auricular stimulation is able to increase resolvin levels in mice. Thus, we propose that neuromodulation may control pain and inflammation/neuroinflammatioin via SPMs. Finally, we discuss key questions that remain unanswered in our understanding of how neuromodulation-based therapies provide short-term and long-term pain relief.

Characterization of 3(3,4-dihydroxy-phenyl) propionic acid as a novel microbiome-derived epigenetic modifier in attenuation of immune inflammatory response in human monocytes.

Recent studies suggest that microbiome derived 3(3,4-dihydroxy-phenyl) propionic acid (DHCA) attenuates IL-6 cytokine production through downregulation of the epigenetic modifier DNA Methyltransferase 1 (DNMT1) expression and inhibition of DNA methylation at the 5'-C-phosphate-G-3' (CpG)-rich IL6 sequence introns 1 and 3 in a mouse model of depression. In this study, we extended the investigation of DHCA epigenetic mechanisms in IL-6 expression in human peripheral blood mononuclear cells (PBMC). Using Lucia Luciferase reporter gene system we identified CpG-rich sequences in which of methylation is influenced by DHCA similar to what observed in response to treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine. Correlation study showed that DNA methylation at select CpG motifs in the IL-6 promoter correlates with IL-6 gene expression. Our study suggests that DHCA is effective in reducing IL-6 expression in human PBMCs, in part, by regulation of methylation in the IL-6 promoter region.

Abrogating doxorubicin-induced chemobrain by immunomodulators IFN-beta 1a or infliximab: Insights to neuroimmune mechanistic hallmarks.

Chemobrain is a well-established clinical syndrome that impairs patient's daily function, in particular attentiveness, coordination and multi-tasking. Thus, it interferes with patient's quality of life. The putative pharmacological intervention against chemobrain relies on understanding the molecular mechanisms underlying it. This study aimed to examine the potential neuroprotective effects of two immunomodulators: Interferon-ß-1a (IFN-ß-1a), as well as Tumor necrosis function-alpha (TNF-α) inhibitor; Infliximab in doxorubicin (DOX)-induced chemobrain in rats. Besides, the current study targets investigating the possible molecular mechanisms in terms of neuromodulation and interference with different death routes controlling neural homeostasis. Herein, the two immunomodulators IFN-ß-1a at a dose of 300,000 units; s.c.three times per week, or Infliximab at a dose of 5 mg/kg/week; i.p. once per week were examined against DOX (2 mg/kg/w, i.p.) once per week for 4 consecutive weeks in rats.The consequent behavioral tests and markers for cognitive impairment, oxidative stress, neuroinflammation, apoptosis and neurobiological abnormalities were further evaluated. Briefly, IFN-ß-1a or Infliximab significantly protected against DOX-induced chemobrain. IFN-ß-1a or Infliximab ameliorated DOX-induced hippocampal histopathological neurodegenerative changes, halted DOX-induced cognitive impairment, abrogated DOX-induced mitochondrial oxidative, inflammatory and apoptotic stress, mitigated DOX-induced autophagic dysfunction and finally upregulated the mitophagic machineries. In conclusion, these findings suggest that either IFN-ß-1a or Infliximab offers neuroprotection against DOX-induced chemobrain which could be explained by their antioxidant, anti-inflammatory, pro-autophagic, pro-mitophagic and antiapoptotic effects. Future clinical studies are recommended to personalize either use of IFN-ß-1a or infliximab to ameliorate DOX-induced chemobrain.

Targeting CCL20 inhibits subarachnoid hemorrhage-related neuroinflammation in mice.

Recent evidence suggests that CC chemokine ligand 20 (CCL20) is upregulated after subarachnoid hemorrhage (SAH). Here, we investigated the functions of CCL20 in SAH injury and its underlying mechanisms of action. We found that CCL20 is upregulated in an SAH mouse model and in cultured primary microglia and neurons. CCL20-neutralizing antibody alleviated SAH-induced neurological deficits, decreased brain water content and neuronal apoptosis, and repressed microglial activation. We observed increased levels of CCL20, CC chemokine receptor 6 (CCR6), interleukin 1 beta (IL-1ß), and tumor necrosis factor alpha (TNF-α), as well as of microglial activation in microglia treated with oxyhemoglobin (OxyHb). CCL20 or CCR6 knockdown reversed the effects of OxyHb on microglia. Conditioned medium from OxyHb-treated microglia induced neuronal apoptosis, while the percentage of apoptotic neurons in the conditioned medium from microglia transfected with CCL20 siRNA or CCR6 siRNA was decreased. We observed no decrease in OxyHb-induced apoptosis in CCL20-knockdown neurons. Conditioned medium from OxyHb-treated neurons led to microglial activation and induced CCR6, IL-1ß and TNF-α expression, while CCL20 knockdown in neurons or CCR6 knockdown in microglia reversed those effects. Our results thus suggest CCL20 may be targeted to elicit therapeutic benefits after SAH injury.