Neurogenic Inflammation in the Context of Endometriosis-What Do We Know?

Endometriosis (EM) is an estrogen-dependent disease characterized by the presence of epithelial, stromal, and smooth muscle cells outside the uterine cavity. It is a chronic and debilitating condition affecting ~10% of women. EM is characterized by infertility and pain, such as dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, and dyschezia. Although EM was first described in 1860, its aetiology and pathogenesis remain uncertain. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with EM but also contribute to a growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. Here we review the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the role of this system, as well as its interactions with immune cells, will unearth novel disease-relevant pathways and targets, providing new therapeutics and better-tailored treatment options.

Chrysomycin A Attenuates Neuroinflammation by Down-Regulating NLRP3/Cleaved Caspase-1 Signaling Pathway in LPS-Stimulated Mice and BV2 Cells.

Chrysomycin A (Chr-A), an antibiotic chrysomycin, was discovered in 1955 and is used to treat cancer and tuberculosis. In the present study, the anti-neuroinflammatory effects and possible mechanism of Chr-A in BALB/c mice and in BV2 microglia cells stimulated by lipopolysaccharide (LPS) were investigated. Firstly, the cortex tissues of mice were analyzed by RNA-seq transcriptome to identify differentially expressed genes (DEGs) regulated by Chr-A in LPS-stimulated mice. Inflammatory cytokines and inflammatory proteins were detected by enzyme-linked immunosorbent assay and Western blot. In RNAseq detection, 639 differential up-regulated genes between the control group and LPS model group and 113 differential down-regulated genes between the LPS model group and Chr-A treatment group were found, and 70 overlapping genes were identified as key genes for Chr-A against neuroinflammation. Subsequent GO biological process enrichment analysis showed that the anti-neuroinflammatory effect of Chr-A might be related to the response to cytokine, cellular response to cytokine stimulus, and regulation of immune system process. The significant signaling pathways of KEGG enrichment analysis were mainly involved in TNF signaling pathway, cytokine-cytokine receptor interaction, NF-κB signaling pathway, IL-17 signaling pathway and NOD-like receptor signaling pathway. Our results of in vivo or in vitro experiments showed that the levels of pro-inflammatory factors including NO, IL-6, IL-1ß, IL-17, TNF-α, MCP-1, CXCL12, GM-CSF and COX2 in the LPS-stimulated group were higher than those in the control group, while Chr-A reversed those conditions. Furthermore, the Western blot analysis showed that its anti-neuroinflammation appeared to be related to the down-regulation of NLRP3/cleaved caspase-1 signaling pathway. The current findings provide new insights into the activity and molecular mechanisms of Chr-A for the treatment of neuroinflammation.

Pathogenesis of pelvic pain syndrome associated with endometriosis in patients resistant to surgical treatment.

AIM: Endometriosis is one of the most common gynecological diseases diagnosed in almost 70% of patients with chronic pelvic pain (CPP). However, a quarter of women with pelvic pain is diagnosed with external genital endometriosis (EGE) during laparoscopy. A special group is represented by patients with PP that did not stop after the removal of endometrial foci. The mechanisms of the pathogenesis of the formation of pain syndrome are not completely explored yet. According to several authors, a significant role in the pathogenesis of pelvic pain recurrence after surgical treatment of EGE is played by active neuroangiogenesis, both in ectopic and eutopic endometrium. The aim of the study was to expand the understanding of the pathogenesis of pelvic pain that did not stop (recurrence) after surgical treatment of external genital endometriosis. MATERIAL AND METHODS: The study involved 2 stages. At the first stage (algological), data from B&B, NRS and VRS algological questionnaires, which were completed by patients with recurrent PP after surgical treatment of EGE, were analyzed (n = 130, aged 18-45 years old, average age 32.5 ± 7.6 years). All women were operated on for EGE no later than 3-6 months after assessing the patients by the algological questionnaires; they did not receive drug therapy after surgical treatment and sought medical attention for recurrent pelvic pain. Materials for the study of the endometrium were obtained by the pipelle biopsymethod. The control group was formed from a number of women with EGE without PP, who applied for surgical treatment of infertility (n = 30). RESULTS: The results of the study have shown that the basis of pathogenesis of pelvic pain recurrence in patients who did not receive medical therapy after surgical treatment of EGE is the activation of neuro-angiogenesis processes and reduction of apoptosis. The results show a statistically significant 1.6 times increasing expression of NGF in eutopic endometrium (57.9 ± 2.5 vs 35.3 ± 2.1% of patients with the silent form of the gene and its receptor NTRK1 1.8 times (2.78 ± 0.25 versus 1.56 ± 0.21.e. respectively). Conclusion: The pathogenesis of pelvic pain in patients who did not receive medical therapy after surgical treatment of endometriosis compared to no pain form of the disease is the activation of the processes of neurogenesis in the eutopic endometrium.

Efficacy of active compounds of Chanqin granules on airway neurogenic inflammation induced by PM2.5 in vivo.

OBJECTIVE: To investigate the efficacy of active compounds of Chanqin (CQ) granules on PM2.5-induced airway neurogenic inflammation in vivo, and to elucidate the underlying mechanisms of action. METHODS: The Traditional Chinese Medicine systems pharmacology (TCMSP) database was searched, and the results were combined with oral bioavailability and drug analysis to identify the compounds in CQ granules. The pharmacophore modeling approach was used to predict the compound targets, and the diseases corresponding to the targets were obtained by searching the therapeutic target database (TTD), pharmacogenomics knowledgebase (PharmGKB) and DrugBank databases. Cytoscape software was used to construct the network pharmacological charts for Component-Target and Target-Disease interactions of the CQ granules. Then, the mechanisms of action and effectiveness of CQ granules for the treatment of PM2.5-induced airway neurogenic inflammation were analyzed. RESULTS: A total of 195 compounds and 171 targets were obtained from the analyses. A total of 569 corresponding diseases were identified for these targets. Component-target and target-disease networks were constructed. The possible mechanisms and effective components in CQ granules for treating airway neurogenic inflammation were analyzed. Quercetin, kaempferol and isorhamnetin, beta-sitosterol and sitosterol, which are typically found in the formulation, have extensive pharmacological activities, including anti-inflammatory, antioxidant and antiviral actions and neuroprotective properties. Among these targets, androgen receptor, estrogen receptor, prostaglandin G/H synthase 2, and inducible nitric oxide synthase play important pathological roles, including the induction of neurogenic inflammation. CQ granules may have therapeutic effectiveness for numerous diseases in addition to respiratory diseases, including neoplasms, digestive system diseases, cardiovascular diseases, respiratory tract diseases and nervous system diseases. In vivo, CQ granules are effective in treating pulmonary inflammation and downregulate neuropeptides in the bronchoalveolar lavage fluid after PM2.5 exposure. CQ granules significantly decreased the levels of neurokinin A, neurokinin B and calcitonin gene-related peptide in the lung and dorsal root ganglia. CQ also significantly suppressed the upregulation of p-extracellular regulated protein kinase 1/2 and p-methyl ethyl ketone 1/2 induced by PM2.5 exposure. CONCLUSION: CQ granules have potential for the treatment of neurogenic inflammation induced by PM2.5 in vivo, and the mechanism might involve downregulation of neuropeptides in the BALF, lung and dorsal root ganglia.

The role of dietary non-heme iron load and peripheral nerve inflammation in the development of peripheral neuropathy (PN) in obese non-diabetic leptin-deficient ob/ob mice.

INTRODUCTION: Here, we investigated inflammatory signs of peripheral nerves in leptin-deficient obese ob/ob mice and the modulating effects of the exogenous iron load. METHODS: Ob/ob and ob/+ control mice were fed with high, standard, or low iron diet for four months. RESULTS: We found intraepidermal nerve fiber degeneration in foot skin and low-grade neuropathic abnormalities including mildly slowed motor and compound sensory nerve conduction velocities and low-grade macrophage and T-cell infiltration without overt neuropathology in sciatic nerves of all ob/ob mice. Low dietary iron load caused more pronounced abnormalities than high iron load in ob/ob mice. DISCUSSION: Our data suggest that dietary non-heme iron deficiency may be a modulating factor in the pathogenesis of peripheral neuropathy in obese ob/ob mice with metabolic syndrome. Once the mechanisms can be further elucidated, how low dietary iron augments peripheral nerve degeneration and dysfunction via pro-inflammatory pathways and new therapeutic strategies could be developed. ABBREVIATIONS: CMAP: compound muscle action potential; cSNCV: compound sensory nerve conduction velocity; IENFD: intraepidermal nerve fiber density; LDL: low-density lipoprotein; MetS: metabolic syndrome; MNCV: motor conduction velocity; NCV: nerve conduction velocity; PN: peripheral neuropathy; PNS: peripheral nervous system; STZ: streptozotocin; T2D: type 2 diabetes mellitus; TNF alpha: tumor necrosis factor alpha; WHO: World Health Organization.

Nicotine deprivation increases pain intensity, neurogenic inflammation, and mechanical hyperalgesia among daily tobacco smokers.

An evolving reciprocal model posits that pain and tobacco smoking behavior interact in the manner of a positive feedback loop, resulting in greater pain and the maintenance of nicotine dependence. There is also reason to believe that abstaining from smoking may increase pain during the early stages of smoking cessation. The goal of this study was to test the effects of nicotine deprivation on experimental pain reactivity. Daily tobacco cigarette smokers (N = 165; 43% female) were randomized to either extended nicotine deprivation (12-24 hr smoking abstinence), minimal deprivation (2 hr smoking abstinence), or continued smoking conditions, prior to undergoing pain induction via topical capsaicin. As hypothesized, results indicated that extended deprivation (relative to continued smoking) increased capsaicin-induced pain intensity ratings, neurogenic inflammation, and mechanical hyperalgesia, thus implicating both central and peripheral mechanisms of action in the effects of smoking abstinence on pain reactivity. Pain intensity ratings were also positively correlated with nicotine withdrawal symptoms, and exploratory analyses suggest that pain sensitivity may increase with duration of smoking abstinence. Collectively, these findings indicate that smokers may experience a variety of negative pain-related sequelae during the early stages of a quit attempt. Future research should examine pain as a consequence or correlate of the nicotine withdrawal syndrome, and determine whether smokers may benefit from tailored cessation interventions that account for nicotine deprivation-induced amplification of pain. (PsycINFO Database Record

Thiamine preserves mitochondrial function in a rat model of traumatic brain injury, preventing inactivation of the 2-oxoglutarate dehydrogenase complex.

BACKGROUND AND PURPOSE: Based on the fact that traumatic brain injury is associated with mitochondrial dysfunction we aimed at localization of mitochondrial defect and attempted to correct it by thiamine. EXPERIMENTAL APPROACH: Interventional controlled experimental animal study was used. Adult male Sprague-Dawley rats were subjected to lateral fluid percussion traumatic brain injury. Thiamine was administered 1 h prior to trauma; cortex was extracted for analysis 4 h and 3 d after trauma. KEY RESULTS: Increased expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor receptor 1 (TNF-R1) by 4 h was accompanied by a decrease in mitochondrial respiration with glutamate but neither with pyruvate nor succinate. Assays of TCA cycle flux-limiting 2-oxoglutarate dehydrogenase complex (OGDHC) and functionally linked enzymes (glutamate dehydrogenase, glutamine synthetase, pyruvate dehydrogenase, malate dehydrogenase and malic enzyme) indicated that only OGDHC activity was decreased. Application of the OGDHC coenzyme precursor thiamine rescued the activity of OGDHC and restored mitochondrial respiration. These effects were not mediated by changes in the expression of the OGDHC sub-units (E1k and E3), suggesting post-translational mechanism of thiamine effects. By the third day after TBI, thiamine treatment also decreased expression of TNF-R1. Specific markers of unfolded protein response did not change in response to thiamine. CONCLUSION AND IMPLICATIONS: Our data point to OGDHC as a major site of damage in mitochondria upon traumatic brain injury, which is associated with neuroinflammation and can be corrected by thiamine. Further studies are required to evaluate the pathological impact of these findings in clinical settings.

Neuroinflammatory reactions in sickness behavior induced by bacterial infection: Protective effect of minocycline.

The neurological changes elicited by bacterial infection are called sickness behavior. Minocycline (MIN) is neuroprotective with a remarkable brain tissue penetration. MIN was orally administered at a dose 90 mg/kg for 3 days, whereas Escherichia coli was given as a single intraperitoneal injection (0.2 mL of 24 h growth) on the third day. After 24 h of bacterial infection, behavioral tests namely open field and forced swimming were carried out, then animals were decapitated. Rats infected with E. coli displayed reduced struggling time in forced swimming test, as well as, exploration and locomotion in open field test with reduction in neurotransmitters (norepinephrine, dopamine, and serotonin) versus elevation in the inflammatory (tumor necrosis factor-alpha, interferon-gamma) and oxidative stress (thiobarbituric acid reactive substance, reduced glutathione) biomarkers. Inflammatory infiltrates of nuclear cells were observed in brains of infected rats. MIN administration prevented the deleterious effects of E. coli infection, thus protects against sickness behavior possibly via defending from neuroinflammation.

Inflammatory Changes in Paravertebral Sympathetic Ganglia in Two Rat Pain Models.

Injury to peripheral nerves can lead to neuropathic pain, along with well-studied effects on sensory neurons, including hyperexcitability, abnormal spontaneous activity, and neuroinflammation in the sensory ganglia. Neuropathic pain can be enhanced by sympathetic activity. Peripheral nerve injury may also damage sympathetic axons or expose them to an inflammatory environment. In this study, we examined the lumbar sympathetic ganglion responses to two rat pain models: ligation of the L5 spinal nerve, and local inflammation of the L5 dorsal root ganglion (DRG), which does not involve axotomy. Both models resulted in neuroinflammatory changes in the sympathetic ganglia, as indicated by macrophage responses, satellite glia activation, and increased numbers of T cells, along with very modest increases in sympathetic neuron excitability (but not spontaneous activity) measured in ex vivo recordings. The spinal nerve ligation model generally caused larger responses than DRG inflammation. Plasticity of the sympathetic system should be recognized in studies of sympathetic effects on pain.

Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation.

Metastatic bone pain is the single most common form of cancer pain and persists as a result of peripheral and central inflammatory, as well as neuropathic mechanisms. Here, we provide the first characterization of sphingolipid metabolism alterations in the spinal cord occurring during cancer-induced bone pain (CIBP). Following femoral arthrotomy and syngenic tumor implantation in mice, ceramides decreased with corresponding increases in sphingosine and the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P). Intriguingly, de novo sphingolipid biosynthesis was increased as shown by the elevations of dihydro-ceramides and dihydro-S1P. We next identified the S1P receptor subtype 1 (S1PR1) as a novel target for therapeutic intervention. Intrathecal or systemic administration of the competitive and functional S1PR1 antagonists, TASP0277308 and FTY720/Fingolimod, respectively, attenuated cancer-induced spontaneous flinching and guarding. Inhibiting CIBP by systemic delivery of FTY720 did not result in antinociceptive tolerance over 7 days. FTY720 administration enhanced IL-10 in the lumbar ipsilateral spinal cord of CIBP animals and intrathecal injection of an IL-10 neutralizing antibody mitigated the ability of systemic FTY720 to reverse CIBP. FTY720 treatment was not associated with alterations in bone metabolism in vivo. Studies here identify a novel mechanism to inhibit bone cancer pain by blocking the actions of the bioactive metabolites S1P and dihydro-S1P in lumbar spinal cord induced by bone cancer and support potential fast-track clinical application of the FDA-approved drug, FTY720, as a therapeutic avenue for CIBP.

Bilateral tactile hypersensitivity and neuroimmune responses after spared nerve injury in mice lacking vasoactive intestinal peptide.

Vasoactive intestinal peptide (VIP) is one of the neuropeptides showing the strongest up-regulation in the nociceptive pathway after peripheral nerve injury and has been proposed to support neuropathic pain. Nevertheless, the story may be more complicated considering the known suppressive effects of the peptide on the immune reactivity of microglial cells, which have been heavily implicated in the onset and maintenance of pain after nerve injury. We here used mice deficient in VIP and the model of spared nerve injury, characterized by persistent tactile hypersensitivity. While tactile hypersensitivity developed similarly to wild type mice for the ipsilateral hindpaw, only transgenic mice showed a mirror-image tactile hypersensitivity in the contralateral hindpaw. This exacerbated neuropathic pain phenotype appeared to be mediated through a local mechanism acting at the level of the lumbar spinal cord as a distant nerve lesion in the front limb did not lead to hindpaw hypersensitivity in VIP-deficient mice. Innocuous tactile hindpaw stimulation was found to increase a neuronal activation marker in the bilateral superficial laminae of the lumbar dorsal horn of VIP-deficient, but not wild type mice, after SNI. A deeper study into the immune responsiveness to the nerve lesion also proved that VIP-deficient mice had a stronger early pro-inflammatory cytokine response and a more pronounced microglial reactivity compared to wild type controls. The latter was also observed at four weeks after spared nerve injury, a time at which bilateral tactile hypersensitivity persisted in VIP-deficient mice. These data suggest an action of VIP in neuropathic states that is more complicated than previously assumed. Future research is now needed for a deeper understanding of the relative contribution of receptors and fiber populations involved in the VIP-neuropathic pain link.

Chemokine CXCL13 activates p38 MAPK in the trigeminal ganglion after infraorbital nerve injury.

Recent data demonstrated that chemokine CXCL13 mediates neuroinflammation and contributes to the maintenance of neuropathic pain after nerve injury in the spinal cord. Pro-nociceptive chemokines activate mitogen-activated protein kinases (MAPKs) which are potential signaling pathways contributing to the nociceptive behavior in inflammatory or neuropathic pain. However, whether activation of p38 and JNK MAPK signaling pathway in the trigeminal ganglion (TG) are involved in CXCL13 and its receptor CXCR5-mediated orofacial pain has not yet been clarified. Here, we show that the unilateral partial infraorbital nerve ligation (pIONL) induced a profound orofacial pain in wild-type (WT) mice. Western blot results showed that pIONL induced p38 but not JNK activation in the TG of WT mice. However, the orofacial pain induced by pIONL was alleviated in Cxcr5 -/- mice, and the activation of p38 was also abrogated in Cxcr5 -/- mice. Furthermore, intra-TG injection of CXCL13 evoked mechanical hypersensitivity and increased p-p38 expression in WT mice. But CXCL13 had no effect on pain behavior or p-p38 expression in Cxcr5 -/- mice. Finally, pretreatment with p38 inhibitor, SB203580, attenuated the pIONL-induced mechanical allodynia and decreased the mRNA expression of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the TG. Taken together, our data suggest that CXCL13 acts on CXCR5 to increase p38 activation and further contributes to the pathogenesis of orofacial neuropathic pain.

PPARγ activation ameliorates postoperative cognitive decline probably through suppressing hippocampal neuroinflammation in aged mice.

Neuroinflammation plays a key role in many neurodegenerative disorders, including postoperative cognitive decline (POCD). Growing evidence has demonstrated that activation of the peroxisome proliferator-activated receptor-γ (PPARγ) attenuates the inflammatory response and improves cognitive dysfunction associated with many neuropsychiatric disorders. We hypothesize that down-regulation of PPARγ is linked to neuroinflammation and the subsequent cognitive deficits observed in an animal model of POCD. In the present study, the POCD animal model was established by performing an exploratory laparotomy under isoflurane anesthesia in 20-month-old male C57BL/6 mice. Behavioral tests, inflammatory biomarkers, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß, ionized calcium-binding adaptor molecule-1 (IBA1)-positive cells, as well as glial fibrillary acidic protein (GFAP)-positive cells and brain-derived neurotrophic factor (BDNF), were measured. Herein, we showed that surgery induced profound impairment in cognition that was associated with significant decreases in PPARγ and BDNF expression, and significant increases in IL-1ß, IBA1-positive cells, and GFAP-positive cells in the hippocampus. As expected, the PPARγ agonist pioglitazone attenuated the surgery-induced inflammatory changes and rescued the associated cognitive impairment. However, these beneficial effects were abolished by the PPARγ specific antagonist GW9662, suggesting a pivotal role of the PPARγ pathway in the pathogenesis of POCD. Taken together, our results provide evidence that down-regulation of PPARγ may be involved in neuroinflammation and subsequent POCD, and suggest that activation of PPARγ by pioglitazone may represent a new way to prevent or treat POCD.

Berberine alleviates postoperative cognitive dysfunction by suppressing neuroinflammation in aged mice.

Postoperative cognitive dysfunction (POCD) is a significant cause of morbidity after surgery, especially for the elderly. Accumulating evidence has demonstrated that neuroinflammation plays a key role in the pathogenesis of POCD. Thus, we hypothesized that berberine, an isoquinoline alkaloid with anti-inflammatory effects, could improve surgery-induced cognitive impairment. Twenty-month-old male C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to mimic the clinical human abdominal surgery. For the interventional studies, mice received berberine (10mg/kg) or vehicle intraperitoneally. For the in vitro study, we examined the effects of berberine on lipopolysaccharide (LPS)-induced inflammatory mediators by cultured BV2 cells. Behavioral tests, expressions of IBA1, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 were performed at the indicated time points. In the present study, we showed that surgery impaired the contextual fear memory, as evidenced by the significantly decreased freezing time to the context. This behavioral change coincided with marked increases in IBA1, TNF-α, IL-1ß, and IL-6 in the prefrontal cortex and hippocampus only at 24h but not 7 d after surgery. In BV2 cells, LPS induced significantly increased TNF-α and IL-1ß expressions. Notably, berberine treatment rescued surgery-induced cognitive impairment and inhibited the release of IBA1, IL-1ß, and IL-6 in the hippocampus. In line with the in vivo study, berberine treatment suppressed LPS-stimulated production of TNF-α and IL-1ß in BV2 cells. In conclusion, our study suggests that berberine could alleviate POCD by suppressing neuroinflammation in aged mice.

Effects of intermittent fasting on age-related changes on Na,K-ATPase activity and oxidative status induced by lipopolysaccharide in rat hippocampus.

Chronic neuroinflammation is a common characteristic of neurodegenerative diseases, and lipopolysaccharide (LPS) signaling is linked to glutamate-nitric oxide-Na,K-ATPase isoforms pathway in central nervous system (CNS) and also causes neuroinflammation. Intermittent fasting (IF) induces adaptive responses in the brain that can suppress inflammation, but the age-related effect of IF on LPS modulatory influence on nitric oxide-Na,K-ATPase isoforms is unknown. This work compared the effects of LPS on the activity of α1,α2,3 Na,K-ATPase, nitric oxide synthase gene expression and/or activity, cyclic guanosine monophosphate, 3-nitrotyrosine-containing proteins, and levels of thiobarbituric acid-reactive substances in CNS of young and older rats submitted to the IF protocol for 30 days. LPS induced an age-related effect in neuronal nitric oxide synthase activity, cyclic guanosine monophosphate, and levels of thiobarbituric acid-reactive substances in rat hippocampus that was linked to changes in α2,3-Na,K-ATPase activity, 3-nitrotyrosine proteins, and inducible nitric oxide synthase gene expression. IF induced adaptative cellular stress-response signaling pathways reverting LPS effects in rat hippocampus of young and older rats. The results suggest that IF in both ages would reduce the risk for deficits on brain function and neurodegenerative disorders linked to inflammatory response in the CNS.

Women of valor: post-traumatic stress disorder in the dental practice.

Dental professionals can intervene in head, neck and facial pain found in female patients who suffer from post-traumatic stress disorder (PTSD). There are three theories for why women are predisposed to pain: hormonal differences, nervous system rewiring and sympathetic issues. This article includes case studies of three patients who are representative of these theories. A rapid, nonintrusive intervention will also be described.

Whole-food diet worsened cognitive dysfunction in an Alzheimer's disease mouse model.

Food combinations have been associated with lower incidence of Alzheimer's disease. We hypothesized that a combination whole-food diet containing freeze-dried fish, vegetables, and fruits would improve cognitive function in TgCRND8 mice by modulating brain insulin signaling and neuroinflammation. Cognitive function was assessed by a comprehensive battery of tasks adapted to the Morris water maze. Unexpectedly, a "Diet × Transgene" interaction was observed in which transgenic animals fed the whole-food diet exhibited even worse cognitive function than their transgenic counterparts fed the control diet on tests of spatial memory (p < 0.01) and strategic rule learning (p = 0.034). These behavioral deficits coincided with higher hippocampal gene expression of tumor necrosis factor-α (p = 0.013). There were no differences in cortical amyloid-ß peptide species according to diet. These results indicate that a dietary profile identified from epidemiologic studies exacerbated cognitive dysfunction and neuroinflammation in a mouse model of familial Alzheimer's disease. We suggest that normally adaptive cellular responses to dietary phytochemicals were impaired by amyloid-beta deposition leading to increased oxidative stress, neuroinflammation, and behavioral deficits.

Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder.

BACKGROUND: Compelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer's disease, including increased expression of ß-amyloid protein (Aß) and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Aß protein, tau phosphorylation, and inflammatory cytokines (interleukin-1ß and tumor necrosis factor-α) in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder. METHOD: An animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Aß protein, tau phosphorylation, and inflammatory cytokines (interleukin-1ß and tumor necrosis factor-α) in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. RESULTS: These results showed that minocycline decreased expression of Aß protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein. CONCLUSION: On the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Aß generation, the decreases in Aß production and tau hyperphosphorylation by minocycline are through inhibiting neuroinflammation, which contributes to Aß production and tau hyperphosphorylation. Minocycline may also lower the self-perpetuating cycle between neuroinflammation and the pathogenesis of tau and Aß to act as a neuroprotector. Therefore, the ability of minocycline to modulate inflammatory reactions may be of great importance in the selection of neuroprotective agents, especially in chronic conditions like diabetes and Alzheimer's disease.

Effects of 900 MHz radiofrequency on corticosterone, emotional memory and neuroinflammation in middle-aged rats.

The widespread use of mobile phones raises the question of the effects of electromagnetic fields (EMF, 900 MHz) on the brain. Previous studies reported increased levels of the glial fibrillary acidic protein (GFAP) in the rat's brain after a single exposure to 900 MHz global system for mobile (GSM) signal, suggesting a potential inflammatory process. While this result was obtained in adult rats, no data is currently available in older animals. Since the transition from middle-age to senescence is highly dependent on environment and lifestyle, we studied the reactivity of middle-aged brains to EMF exposure. We assessed the effects of a single 15 min GSM exposure (900 MHz; specific absorption rate (SAR)=6 W/kg) on GFAP expression in young adults (6 week-old) and middle-aged rats (12 month-old). Brain interleukin (IL)-1ß and IL-6, plasmatic levels of corticosterone (CORT), and emotional memory were also assessed. Our data indicated that, in contrast to previously published work, acute GSM exposure did not induce astrocyte activation. Our results showed an IL-1ß increase in the olfactory bulb and enhanced contextual emotional memory in GSM-exposed middle-aged rats, and increased plasmatic levels of CORT in GSM-exposed young adults. Altogether, our data showed an age dependency of reactivity to GSM exposure in neuro-immunity, stress and behavioral parameters. Reproducing these effects and studying their mechanisms may allow a better understanding of mobile phone EMF effects on neurobiological parameters.

TLR2 is a primary receptor for Alzheimer's amyloid ß peptide to trigger neuroinflammatory activation.

Microglia activated by extracellularly deposited amyloid ß peptide (Aß) act as a two-edged sword in Alzheimer's disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering anti-inflammatory/neurotrophic M2 activation and by clearing Aß via phagocytosis. TLRs are associated with Aß-induced microglial inflammatory activation and Aß internalization, but the mechanisms remain unclear. In this study, we used real-time surface plasmon resonance spectroscopy and conventional biochemical pull-down assays to demonstrate a direct interaction between TLR2 and the aggregated 42-aa form of human Aß (Aß42). TLR2 deficiency reduced Aß42-triggered inflammatory activation but enhanced Aß phagocytosis in cultured microglia and macrophages. By expressing TLR2 in HEK293 cells that do not endogenously express TLR2, we observed that TLR2 expression enabled HEK293 cells to respond to Aß42. Through site-directed mutagenesis of tlr2 gene, we identified the amino acids EKKA (741-744) as a critical cytoplasmic domain for transduction of inflammatory signals. By coexpressing TLR1 or TLR6 in TLR2-transgenic HEK293 cells or silencing tlrs genes in RAW264.7 macrophages, we observed that TLR2-mediated Aß42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6. Using bone marrow chimeric Alzheimer's amyloid precursor transgenic mice, we observed that TLR2 deficiency in microglia shifts M1- to M2-inflammatory activation in vivo, which was associated with improved neuronal function. Our study demonstrated that TLR2 is a primary receptor for Aß to trigger neuroinflammatory activation and suggested that inhibition of TLR2 in microglia could be beneficial in Alzheimer's disease pathogenesis.