Adolescent neuroimmune function and its interaction with alcohol.

Adolescence is an evolutionarily conserved developmental period associated with behavioral change, including increased risk-taking and alcohol use. Experimentation with alcohol typically begins in adolescence and transitions to binge-like patterns of consumption. Alcohol exposure during adolescence can alter normative changes in brain structure and function. Understanding mechanisms by which ethanol impacts neurodevelopmental processes is important for preventing and ameliorating the deleterious consequences of adolescent alcohol abuse. This review focuses on the neuroimmune system as a key contributor to ethanol-induced changes in adolescent brain and behavior. After brief review of neuroimmune system development, acute and chronic effects of ethanol on adolescent neuroimmune functioning are addressed. Comparisons between stress/immunological challenges and ethanol on adolescent neuroimmunity are reviewed, as cross-sensitization is relevant during adolescence. The mechanisms by which ethanol alters neuroimmune functioning are then discussed, as they may portend development of neuropathological consequences and thus increase vulnerability to subsequent challenges and potentiate addictive behaviors.

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.

Cardiovascular comorbidities, inflammation, and cerebral small vessel disease.

Cerebral small vessel disease (cSVD) is the most common cause of vascular cognitive impairment and affects all levels of the brain's vasculature. Features include diverse structural and functional changes affecting small arteries and capillaries that lead to a decline in cerebral perfusion. Due to an ageing population, incidence of cSVD is continually rising. Despite its prevalence and its ability to cause multiple debilitating illnesses, such as stroke and dementia, there are currently no therapeutic strategies for the treatment of cSVD. In the healthy brain, interactions between neuronal, vascular, and inflammatory cells are required for normal functioning. When these interactions are disturbed, chronic pathological inflammation can ensue. The interplay between cSVD and inflammation has attracted much recent interest, and this review discusses chronic cardiovascular diseases, particularly hypertension, and explores how the associated inflammation may impact on the structure and function of the small arteries of the brain in cSVD. Molecular approaches in animal studies are linked to clinical outcomes in patients, and novel hypotheses regarding inflammation and cSVD are proposed that will hopefully stimulate further discussion and study in this important area.

Galantamine prevents and reverses neuroimmune induction and loss of adult hippocampal neurogenesis following adolescent alcohol exposure.

BACKGROUND: Binge ethanol exposure during adolescence reduces hippocampal neurogenesis, a reduction which persists throughout adulthood despite abstinence. This loss of neurogenesis, indicated by reduced doublecortin+ immunoreactivity (DCX+IR), is paralleled by an increase in hippocampal proinflammatory signaling cascades. As galantamine, a cholinesterase inhibitor, has anti-inflammatory actions, we tested the hypothesis that galantamine would prevent (study 1) or restore (study 2) AIE induction of proinflammatory signals within the hippocampus as well as AIE-induced loss of hippocampal neurogenesis. METHODS: Galantamine (4 mg/kg) or vehicle (saline) was administered to Wistar rats during adolescent intermittent ethanol (AIE; 5.0 g/kg ethanol, 2 days on/2 days off, postnatal day [P] 25-54) (study 1, prevention) or after AIE during abstinent maturation to adulthood (study 2, restoration). RESULTS: Results indicate AIE reduced DCX+IR and induced cleaved caspase3 (Casp3) in DCX-expressing immature neurons. Excitingly, AIE induction of activated Casp3 in DCX-expressing neurons is both prevented and reversed by galantamine treatment, which also resulted in prevention and restoration of neurogenesis (DCX+IR). Similarly, galantamine prevented and/or reversed AIE induction of proinflammatory markers, including the chemokine (C-C motif) ligand 2 (CCL2), cyclooxygenase-2 (COX-2), and high mobility group box 1 (HMGB1) protein, suggesting that AIE induction of proinflammatory signaling mediates both cell death cascades and hippocampal neurogenesis. Interestingly, galantamine treatment increased Ki67+IR generally as well as increased pan-Trk expression specifically in AIE-treated rats but failed to reverse AIE induction of NADPH-oxidase (gp91phox). CONCLUSIONS: Collectively, our studies suggest that (1) loss of neurogenesis after AIE is mediated by persistent induction of proinflammatory cascades which drive activation of cell death machinery in immature neurons, and (2) galantamine can prevent and restore AIE disruptions in the hippocampal environmental milieu to then prevent and restore AIE-mediated loss of neurogenesis.

The Chemically-Modified Tetracycline COL-3 and Its Parent Compound Doxycycline Prevent Microglial Inflammatory Responses by Reducing Glucose-Mediated Oxidative Stress.

We used mouse microglial cells in culture activated by lipopolysaccharide (LPS) or α-synuclein amyloid aggregates (αSa) to study the anti-inflammatory effects of COL-3, a tetracycline derivative without antimicrobial activity. Under LPS or αSa stimulation, COL-3 (10, 20 µM) efficiently repressed the induction of the microglial activation marker protein Iba-1 and the stimulated-release of the pro-inflammatory cytokine TNF-α. COL-3's inhibitory effects on TNF-α were reproduced by the tetracycline antibiotic doxycycline (DOX; 50 µM), the glucocorticoid dexamethasone, and apocynin (APO), an inhibitor of the superoxide-producing enzyme NADPH oxidase. This last observation suggested that COL-3 and DOX might also operate themselves by restraining oxidative stress-mediated signaling events. Quantitative measurement of intracellular reactive oxygen species (ROS) levels revealed that COL-3 and DOX were indeed as effective as APO in reducing oxidative stress and TNF-α release in activated microglia. ROS inhibition with COL-3 or DOX occurred together with a reduction of microglial glucose accumulation and NADPH synthesis. This suggested that COL-3 and DOX might reduce microglial oxidative burst activity by limiting the glucose-dependent synthesis of NADPH, the requisite substrate for NADPH oxidase. Coherent with this possibility, the glycolysis inhibitor 2-deoxy-D-glucose reproduced the immunosuppressive action of COL-3 and DOX in activated microglia. Overall, we propose that COL-3 and its parent compound DOX exert anti-inflammatory effects in microglial cells by inhibiting glucose-dependent ROS production. These effects might be strengthened by the intrinsic antioxidant properties of DOX and COL-3 in a self-reinforcing manner.

Modulation of preeclampsia by the cholinergic anti-inflammatory pathway: Therapeutic perspectives.

The cholinergic anti-inflammatory pathway (CAP) is vital for the orchestration of the immune and inflammatory responses under normal and challenged conditions. Over the past two decades, peripheral and central circuits of CAP have been shown to be critically involved in dampening the inflammatory reaction in a wide array of inflammatory disorders. Additionally, emerging evidence supports a key role for CAP in the regulation of the female reproductive system during gestation as well as in the advent of serious pregnancy-related inflammatory insults such as preeclampsia (PE). Within this framework, the modulatory action of CAP encompasses the perinatal maternal and fetal adverse consequences that surface due to antenatal PE programming. Albeit, a considerable gap still exists in our knowledge of the precise cellular and molecular underpinnings of PE/CAP interaction, which hampered global efforts in safeguarding effective preventive or therapeutic measures against PE complications. Here, we summarize reports in the literature regarding the roles of peripheral and reflex cholinergic neuroinflammatory pathways of nicotinic acetylcholine receptors (nAChRs) in reprogramming PE complications in mothers and their progenies. The possible contributions of α7-nAChRs, cholinesterases, immune cells, adhesion molecules, angiogenesis, and endothelial dysfunction to the interaction have also been reviewed.

Dopaminergic Receptor Targeting in Multiple Sclerosis: Is There Therapeutic Potential?

Dopamine is a neurotransmitter that mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of dopamine on the cells of innate and adaptive immune systems, including Th17 cells, which play a critical role in inflammatory diseases of the CNS. This article reviews the literature data on the role of dopamine in the regulation of neuroinflammation in multiple sclerosis (MS). The influence of dopaminergic receptor targeting on experimental autoimmune encephalomyelitis (EAE) and MS pathogenesis, as well as the therapeutic potential of dopaminergic drugs as add-on pathogenetic therapy of MS, is discussed.

Cholinergic anti-inflammatory pathway and connective tissue diseases.

Connective tissue diseases (CTDs) consist of an extensive range of heterogeneous medical conditions, which are caused by immune-mediated chronic inflammation and influences the various connective tissues of the body. They include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis, Sjögren's syndrome, Behcet's disease, and many other autoimmune CTDs. To date, several anti-inflammatory approaches have been developed to reduce the severity of inflammation or its subsequent organ manifestations. As a logical mechanism to harnesses the undesired inflammation, some studies investigated the role of the intrinsic cholinergic anti-inflammatory pathway (CAP) in the modulation of chronic inflammation. Many different experimental and clinical models have been developed to evaluate the therapeutic significance of the CAP in CTDs. On the other hand, an issue that is less emphasized in this regard is the presence of autonomic neuropathy in CTDs, which influences the efficiency of CAP in such clinical settings. This condition occurs during CTDs and is a well-known complication of patients suffering from them. The advantages and limitations of CAP in the control of inflammatory responses and its possible therapeutic benefits in the treatment of CTDs are the main subjects of the current study. Therefore, this narrative review article is provided based on the recent findings of the complicated role of CAP in CTDs which were retrieved by searching Science Direct, PubMed, Google Scholar, and Web of Science. It seems that delineating the complex influences of CAP would be of great interest in designing novel surgical or pharmacological therapeutic strategies for CTDs therapy.

Society on NeuroImmune Pharmacology COVID-19 Virtual Workshop.

This brief report collects the program and abstracts of the Society on NeuroImmune Pharmacology (SNIP) COVID-19 Virtual Workshop held on April 9, 2021. The workshop consisted of four symposia: Symposium 1: Molecular approaches to COVID-19 pathogenesis and underlying mechanisms; Symposium 2: Therapeutic and vaccine approaches to COVID-19; Symposium 3: Early Career Investigator talks; and Symposium 4: Diversity and Inclusion SNIP Committee (DISC) program: Well-being and reflections. The workshop also featured four special talks on COVID-19 and funding opportunities from the National Institute on Alcohol Abuse and Alcoholism (NIAAA); COVID-19 and funding opportunities from the National Institute on Drug Abuse (NIDA); opportunities from NIH for early career investigator (ECI) fellows; and neurologic and psychiatric complications of SARS-CoV-2 infection. Presenters included NIH officials, SNIP members, and non-member scientists whose abstracts were submitted and accepted for inclusion in the virtual event hosted by the University of Nebraska Medical Center via Zoom webinar. A special theme issue of SNIP's official journal, the Journal of Neuroimmune Pharmacology (JNIP), will collect select papers from the workshop along with other related manuscripts in a special theme issue titled "Neuroimmune Pharmacology of SARS-CoV-2."

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.

Effect of aprepitant on kynurenine to tryptophan ratio in cART treated and cART naïve adults living with HIV.

ABSTRACT: Changes in tryptophan metabolism affect human physiology including the immune system, mood, and sleep and are associated with human immunodeficiency virus (HIV) pathogenesis. This study investigates whether the treatment of HIV-infected individuals with the neurokinin-1 receptor antagonist, aprepitant, alters tryptophan metabolism.This study utilized archival samples from 3 phase 1B clinical trials "Anti-HIV Neuroimmunomodulatory Therapy with Neurokinin-1 Antagonist Aprepitant"-2 double-blinded, placebo-controlled, and 1 open-label study. We tested samples from a total of 57 individuals: 26 combination antiretroviral therapy (cART) naïve individuals receiving aprepitant, 19 cART naïve individuals receiving placebo, and 12 individuals on a ritonavir-containing cART regimen receiving aprepitant. We evaluated the effect of aprepitant on tryptophan metabolism by measuring levels of kynurenine and tryptophan in archival plasma samples and calculating the kynurenine to tryptophan ratio.Aprepitant treatment affected tryptophan metabolism in both cART treated and cART naïve individuals with more profound effects in patients receiving cART. While aprepitant treatment affected tryptophan metabolism in all HIV-infected patients, it only significantly decreased kynurenine to tryptophan ratio in cART treated individuals. Aprepitant treatment offers an opportunity to target inflammation and mood disorders frequently co-existing in chronic HIV infection.

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.

Neuroimmunological therapies for treating spinal cord injury: Evidence and future perspectives.

Spinal cord injury (SCI) has a complex pathophysiology. Following the initial physical trauma to the spinal cord, which may cause vascular disruption, hemorrhage, mechanical injury to neural structures and necrosis, a series of biomolecular cascades is triggered to evoke secondary injury. Neuroinflammation plays a major role in the secondary injury after traumatic SCI. To date, the administration of systemic immunosuppressive medications, in particular methylprednisolone sodium succinate, has been the primary pharmacological treatment. This medication is given as a complement to surgical decompression of the spinal cord and maintenance of spinal cord perfusion through hemodynamic augmentation. However, the impact of neuroinflammation is complex with harmful and beneficial effects. The use of systemic immunosuppressants is further complicated by the natural onset of post-injury immunosuppression, which many patients with SCI develop. It has been hypothesized that immunomodulation to attenuate detrimental aspects of neuroinflammation after SCI, while avoiding systemic immunosuppression, may be a superior approach. To accomplish this, a detailed understanding of neuroinflammation and the systemic immune responses after SCI is required. Our review will strive to achieve this goal by first giving an overview of SCI from a clinical and basic science context. The role that neuroinflammation plays in the pathophysiology of SCI will be discussed. Next, the positive and negative attributes of the innate and adaptive immune systems in neuroinflammation after SCI will be described. With this background established, the currently existing immunosuppressive and immunomodulatory therapies for treating SCI will be explored. We will conclude with a summary of topics that can be explored by neuroimmunology research. These concepts will be complemented by points to be considered by neuroscientists developing therapies for SCI and other injuries to the central nervous system.

Brain-immune interactions in neuropsychiatric disorders: Lessons from transcriptome studies for molecular targeting.

Understanding the pathophysiological mechanisms of neuropsychiatric disorders has been a challenging quest for neurobiologists. Recent years have witnessed enormous technological advances in the field of neuroimmunology, blurring boundaries between the central nervous system and the periphery. Consequently, the discipline has expanded to cover interactions between the nervous and immune systems in health and diseases. The complex interplay between the peripheral and central immune pathways in neuropsychiatric disorders has recently been documented in various studies, but the genetic determinants remain elusive. Recent transcriptome studies have identified dysregulated genes involved in peripheral immune cell activation, blood-brain barrier integrity, glial cell activation, and synaptic plasticity in major depressive disorder, bipolar disorder, autism spectrum disorder, and schizophrenia. Herein, the key transcriptomic techniques applied in investigating differentially expressed genes and pathways responsible for altered brain-immune interactions in neuropsychiatric disorders are discussed. The application of transcriptomics that can aid in identifying molecular targets in various neuropsychiatric disorders is highlighted.

The role of Toll-like receptors in neurobiology of alcoholism.

Alcoholism is a global socially significant problem and still remains one of the leading causes of disability and premature death. One of the main signs of the disease is the loss of cognitive control over the amount of alcohol consumed. Among the mechanisms of the development of this pathology, changes in neuroimmune mechanisms occurring in the brain during prolonged alcohol consumption and its withdrawal have recently become the focus of numerous studies. Ethanol consumption leads to the activation of neuroimmune signaling in the central nervous system through many subtypes of Toll-like receptors (TLRs), as well as release of their endogenous agonists (high-mobility group protein B1 (HMGB1), S100 protein, heat shock proteins (HSPs), and extracellular matrix degradation proteins). TLR activation triggers intracellular molecular cascades of reactions leading to increased expression of genes of the innate immune system, particularly, proinflammatory cytokines, causing further development of a persistent neuroinflammatory process in the central nervous system. This leads to death of neurons and neuroglial cells in various brain structures, primarily in those associated with the development of a pathological craving for alcohol. In addition, there is evidence that some subtypes of TLRs (TLR3, TLR4) are able to form heterodimers with neuropeptide receptors, thereby possibly playing other roles in the central nervous system, in addition to participating in the activation of the innate immune system.

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.

Interaction of maternal immune activation and genetic interneuronal inhibition.

Genes and environment interact during intrauterine life, and potentially alter the developmental trajectory of the brain. This can result in life-long consequences on brain function. We have previously developed two transgenic mouse lines that suppress Gad1 expression in parvalbumin (PVALB) and neuropeptide Y (NPY) expressing interneuron populations using a bacterial artificial chromosome (BAC)-driven miRNA-based silencing technology. We were interested to assess if maternal immune activation (MIA), genetic interneuronal inhibition, and the combination of these two factors disrupt and result in long-term changes in neuroinflammatory gene expression, sterol biosynthesis, and acylcarnitine levels in the brain of maternally exposed offspring. Pregnant female WT mice were given a single intraperitoneal injection of saline or polyinosinic-polycytidilic acid [poly(I:C)] at E12.5. Brains of offspring were analyzed at postnatal day 90. We identified complex and persistent neuroinflammatory gene expression changes in the hippocampi of MIA-exposed offspring, as well in the hippocampi of Npy/Gad1 and Pvalb/Gad1 mice. In addition, both MIA and genetic inhibition altered the post-lanosterol sterol biosynthesis in the neocortex and disrupted the typical acylcarnitine profile. In conclusion, our findings suggest that both MIA and inhibition of interneuronal function have long-term consequences on critical homeostatic mechanisms of the brain, including immune function, sterol levels, and energy metabolism.

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.