Luteolin as a therapeutic option for multiple sclerosis

Multiple sclerosis (MS) remains without an effective treatment in spite of intense research efforts. Interferon-beta (IFN-β) reduces duration and severity of symptoms in many relapsing-remitting MS patients, but its mechanism of action is still not well understood. Moreover, IFN-β and other available treatments must be given parenterally and have a variety of adverse effects. Certain naturally occurring flavonoids, such as luteolin, have anti-oxidant and anti-inflammatory effects, including inhibition of activated peripheral blood leukocytes from MS patients. Luteolin also inhibits mast cells, as well as mast cell-dependent T cell activation, recently implicated in MS pathogenesis. Moreover, luteolin and structurally similar flavonoids can inhibit experimental allergic allergic encephalomyelitis (EAE), an animal model of MS in rodents. An appropriate luteolin formulation that permits sufficient absorption and reduces its metabolism could be a useful adjuvant to IFN-β for MS therapy

Neuro-inflammation, blood-brain barrier, seizures and autism

Many children with Autism Spectrum Diseases (ASD) present with seizure activity, but the pathogenesis is not understood. Recent evidence indicates that neuro-inflammation could contribute to seizures. We hypothesize that brain mast cell activation due to allergic, environmental and/or stress triggers could lead to focal disruption of the blood-brain barrier and neuro-inflammation, thus contributing to the development of seizures. Treating neuro-inflammation may be useful when anti-seizure medications are ineffective

Migraine Headaches: the Immunologist???s View

Objective: Review evidence supporting the role of mast cells in migraine pathophysiology. Background: Mast cells are known for their role in allergic reactions, but they are also important in immunity and inflammatory diseases, especially those precipitated or worsened by stress. Such are migraine headaches that are associated with spreading neuronal depression and neurogenic inflammation intracranially.  Migraines are also comorbid with allergies and could precipitate acute coronary syndromes (ACS). Mast cells are located perivascularly, in close association with neurons, especially in the meninges.  Mast cells can be activated by trigeminal nerve stimulation and by acute stress, leading to increased vascular permeability and neurogenic inflammation dependent on NK-1 receptors, but not necessarily on substance P (SP). Methods: We reviewed relevant literature and summarized our own findings. Results: Corticotropin-releasing hormone (CRH), a mediator of the stress response released from the hypothalamus, can activate CRH receptors either on the sensory nuclei of the trigeminal nerve or directly on the mast cells.  They, then release proinflammatory, nociceptive and vasoactive mediators including histamine, tryptase and vascular endothelial growth factor (VEGF), thereby triggering migraine headaches.  Conclusions: These results indicate that there are several novel points of intervention for the development of therapeutic agents to help alleviate migraines. Preliminary clinical studies with brain mast cell blockers and CRH receptor antagonists suggest that they could be useful prophylactically

The Role of Mast Cells in Acute Coronary Syndromes

OBJECTIVE:Review evidence supporting the role of mast cells in cardiovascular pathophysiology. BACKGROUND: Cardiovascular inflammation has emerged as a key pathogenetic factor in coronary artery disease (CAD) and myocardial ischemia reperfusion (IR) injury. IR complicates all forms of coronary artery revascularization. Cardiac mast cells have been implicated in CAD, IR and myocardial infarction (MI) through the release of pro-arrhythmogenic and inflammatory mediators, especially interleukin-6 (IL-6), considered an independent risk factor. METHODS:We reviewed relevant literature and summarized our own findings. RESULTS: We showed that CAD is associated with high intracoronary release of IL-6. Acute stress triggers mast cell- dependent release of histamine and IL-6. Moreover, acute stress in ApoE -/- mice leads to ischemia. Mast cells express corticotropin-releasing-hormone (CRH) receptors, activation of which leads to selective release of vascular endothelial growth factor (VEGF), an isoform of which is vasodilatory. In a randomized prospective study, we investigated serum IL-6 levels and cardiac tissue susceptibility in the mast cell deficient (W/Wv) mice (n=12) and their normal littermates (+/+). When the left coronary artery (LCA) was ligated followed by 6 hr of reperfusion IL-6 levels increased significantly after reperfusion only in the +/+ mice, but not in mast cell deficient W/Wv mice; cardiac muscle viability was significantly higher in W/Wv than the +/+ mice. CONCLUSION: These results support targeting selective inhibition of cardiac mast cell activation as prophylactic therapy in clinical situations involving myocardial inflammation and/or revascularization

The Role of Mast Cells in Acute Coronary Syndromes

Background: Cardiovascular inflammation has emerged as a key pathogenetic factor in coronary artery disease (CAD) and myocardial ischemia reperfusion injury. Ischemia reperfusion injury complicates all forms of coronary artery revascularization. Cardiac mast cells have been implicated in CAD, reperfusion injury and myocardial infarction (MI) through the release of pro-arrhythmogenic and inflammatory mediators, especially interleukin-6 (IL-6), considered an independent risk factor. Objective: Review evidence supporting the role of mast cells in cardiovascular pathophysiology. Methods: We reviewed relevant literature and summarized our own findings. Results: We showed that CAD is associated with high intracoronary release of IL-6. Acute stress triggers mast cell- dependent release of histamine and IL-6. Moreover, acute stress in ApoE -/- mice leads to ischemia. Mast cells express corticotropin-releasing-hormone (CRH) receptors, activation of which leads to selective release of vascular endothelial growth factor (VEGF), an isoform of which is vasodilatory.  In a randomized prospective study, we investigated serum IL-6 levels and cardiac tissue susceptibility in the mast cell deficient (W/Wv) mice (n=12) and their normal littermates (+/+). When the left coronary artery (LCA) was ligated followed by 6 hours of reperfusion, IL-6 levels increased significantly after reperfusion only in the +/+ mice, but not in mast cell deficient W/Wv mice; cardiac muscle viability was significantly higher in W/Wv than the +/+ mice. Conclusion: These results support targeting selective inhibition of cardiac mast cell activation as prophylactic therapy in clinical situations involving myocardial inflammation and/or revascularization

Response of spinal myoclonus to a combination therapy of autogenic training and biofeedback

<p>Abstract</p> <p>Introduction</p> <p>Clinical evidence indicates that certain types of movement disorders are due to psychosomatic factors. Patients with myoclonic movements are usually treated by a variety of therapeutic agents. Autogenic training (AT), a recognized form of psychosomatic therapies, is suitable for certain types of neurological diseases. We describe a patient with myoclonus who failed to respond to conventional medical therapy. His symptoms were exaggerated by psychogenic factors, especially anger.</p> <p>Case presentation</p> <p>A 42-year-old man was admitted to our hospital, Preventive Welfare Clinic, for severe paroxysmal axial myoclonus of the left shoulder and abdominal muscles. The initial diagnosis was "combination of spinal segmental myoclonus and propriospinal myoclonus". The myoclonic movements did not occur during sleep but were aggravated by bathing, alcohol drinking, and anger. Psychological examination indicated hostile attribution. Although considered not to be a case of psychogenic myoclonus, a "<it>psychogenic factor</it>" was definitely involved in the induction of the organic myoclonus. The final diagnosis was "combination of spinal segmental myoclonus and propriospinal myoclonus accompanied by features of psychosomatic disorders". The patient underwent psychosomatic therapy including AT and surface electromyography (EMG)-biofeedback therapy and treatment with clonazepam and carbamazepine.</p> <p>Results</p> <p>AT and EMG-biofeedback resulted in shortening the duration and reducing the amplitude and frequency of the myoclonic discharges.</p> <p>Conclusion</p> <p>Psychosomatic therapy with AT and surface EMG-biofeedback produced excellent improvement of myoclonic movements and allowed the reduction of the dosage of conventional medications.</p

Lack of c-kit receptor promotes mammary tumors in N-nitrosomethylurea-treated Ws/Ws rats

<p>Abstract</p> <p>Background</p> <p>c-<it>kit </it>is expressed in various cell types during development and it has been linked to the promotion of cellular migration, proliferation and/or survival of melanoblasts, hematopoietic progenitors and primordial germ cells. Several reports have proposed a role for the c-<it>kit </it>gene on carcinogenesis. Gain-of-function mutations are associated with diseases such as mastocytosis and gastrointestinal stromal tumors among others. However, very little is known about pathologies associated with loss-of-function mutations. Regarding breast cancer, c-kit protein and mRNA are highly expressed in normal breast but their expression decreases or is absent in the presence of breast cancer. We studied the role of <it>c-kit </it>in mammary carcinogenesis in the Ws/Ws rats carrying spontaneous lack-of-function mutation in the c-<it>kit </it>gene. Fifty day-old virgin female Ws/Ws rats and their wild type counterparts were injected with either 50 mg/kg body weight of the chemical carcinogen N-nitrosomethylurea or with vehicle. The animals were followed-up for 6 months. Fisher 344 rats were used as positive controls for tumor development.</p> <p>Results</p> <p>Eleven weeks after treatment, palpable tumors were detected in the Ws/Ws rats. The tumor incidence was 80% in Ws/Ws rats, while no tumors were observed in the wild type rats (p = 0.006). Our data show that the lack of c-kit is permissive for the development of mammary tumor in Ws/Ws rats treated with carcinogen.</p> <p>Conclusion</p> <p>We conclude that the lack of c-kit may contribute to an imbalanced homeostatic state in the mammary gland either by affecting signaling between stroma and epithelium, or through the lack of mast cells.</p

Perinatal Stress, Brain Inflammation and Risk of Autism-Review and Proposal

Background: Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by varying deficits in social interactions, communication, and learning, as well as stereotypic behaviors. Despite the significant increase in ASD, there are few if any clues for its pathogenesis, hampering early detection or treatment. Premature babies are also more vulnerable to infections and inflammation leading to neurodevelopmental problems and higher risk of developing ASD. Many autism “susceptibility” genes have been identified, but “environmental” factors appear to play a significant role. Increasing evidence suggests that there are different ASD endophenotypes. Discussion: We review relevant literature suggesting in utero inflammation can lead to preterm labor, while insufficient development of the gut-blood–brain barriers could permit exposure to potential neurotoxins. This risk apparently may increase in parents with “allergic” or autoimmune problems during gestation, or if they had been exposed to stressors. The presence of circulating auto-antibodies against fetal brain proteins in mothers is associated with higher risk of autism and suggests disruption of the blood–brain-barrier (BBB). A number of papers have reported increased brain expression or cerebrospinal fluid (CSF) levels of pro-inflammatory cytokines, especially TNF, which is preformed in mast cells. Recent evidence also indicates increased serum levels of the pro-inflammatory mast cell trigger neurotensin (NT), and of extracellular mitochondrial DNA (mtDNA), which is immunogenic. Gene mutations of phosphatase and tensin homolog (PTEN), the negative regulator of the mammalian target of rapamycin (mTOR), have been linked to higher risk of autism, but also to increased proliferation and function of mast cells. Summary: Premature birth and susceptibility genes may make infants more vulnerable to allergic, environmental, infectious, or stress-related triggers that could stimulate mast cell release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in an endophenotype of ASD patients

Mercury induces inflammatory mediator release from human mast cells

<p>Abstract</p> <p>Background</p> <p>Mercury is known to be neurotoxic, but its effects on the immune system are less well known. Mast cells are involved in allergic reactions, but also in innate and acquired immunity, as well as in inflammation. Many patients with Autism Spectrum Disorders (ASD) have "allergic" symptoms; moreover, the prevalence of ASD in patients with mastocytosis, characterized by numerous hyperactive mast cells in most tissues, is 10-fold higher than the general population suggesting mast cell involvement. We, therefore, investigated the effect of mercuric chloride (HgCl₂) on human mast cell activation.</p> <p>Methods</p> <p>Human leukemic cultured LAD2 mast cells and normal human umbilical cord blood-derived cultured mast cells (hCBMCs) were stimulated by HgCl2 (0.1-10 μM) for either 10 min for beta-hexosaminidase release or 24 hr for measuring vascular endothelial growth factor (VEGF) and IL-6 release by ELISA.</p> <p>Results</p> <p>HgCl₂induced a 2-fold increase in β-hexosaminidase release, and also significant VEGF release at 0.1 and 1 μM (311 ± 32 pg/10⁶cells and 443 ± 143 pg/10⁶cells, respectively) from LAD2 mast cells compared to control cells (227 ± 17 pg/10⁶cells, n = 5, p < 0.05). Addition of HgCl₂(0.1 μM) to the proinflammatory neuropeptide substance P (SP, 0.1 μM) had synergestic action in inducing VEGF from LAD2 mast cells. HgCl₂also stimulated significant VEGF release (360 ± 100 pg/10⁶cells at 1 μM, n = 5, p < 0.05) from hCBMCs compared to control cells (182 ± 57 pg/10⁶cells), and IL-6 release (466 ± 57 pg/10⁶cells at 0.1 μM) compared to untreated cells (13 ± 25 pg/10⁶cells, n = 5, p < 0.05). Addition of HgCl₂(0.1 μM) to SP (5 μM) further increased IL-6 release.</p> <p>Conclusions</p> <p>HgCl₂stimulates VEGF and IL-6 release from human mast cells. This phenomenon could disrupt the blood-brain-barrier and permit brain inflammation. As a result, the findings of the present study provide a biological mechanism for how low levels of mercury may contribute to ASD pathogenesis.</p