Tag: microglial activation

Stress, inflammation and natural treatments

Abstract:

Stress and inflammation have become the curses of our times and are the main pathogenetic factors in multiple diseases that are often comorbid and include allergies and asthma, eczema and psoriasis, fibromyalgia syndrome, mast cell activation syndrome, irritable bowel syndrome, myalgic encephalomyelitis/chronic fatigue syndrome and autism spectrum disorder (ASD). Unfortunately, there are no effective drugs.

Cross-talk between mast cells and microglia in the hypothalamus and amygdala could explain stress-induced inflammation. We recently showed that the “alarmin” IL-33 could play a major role through its synergistic action with the neuropeptide substance P to stimulate human mast cell secretion of the pro-inflammatory molecules IL-1β, TNF and VEGF. A new formulation using pure luteolin with Ashwagandha has now been developed and could be of significant benefit to patients suffering from these diseases.

Source: Theoharides TC, Kavalioti M. Stress, inflammation and natural treatments. J Biol Regul Homeost Agents. 2018 Nov-Dec;32(6):1345-1347. https://www.ncbi.nlm.nih.gov/pubmed/30574737

Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract:

Milnacipran, a serotonin/norepinephrine reuptake inhibitor, has been approved by the US Food and Drug Administration for the treatment of fibromyalgia (FM). This report presents the results of a randomized, double-blind, placebo-controlled trial of milnacipran conducted to test the hypotheses that a) similar to patients with chronic fatigue syndrome, patients with FM have increased ventricular lactate levels at baseline; b) 8 weeks of treatment with milnacipran will lower ventricular lactate levels compared with baseline levels and with ventricular lactate levels after placebo; and c) treatment with milnacipran will improve attention and executive function in the Attention Network Test compared with placebo. In addition, we examined the results for potential associations between ventricular lactate and pain. Baseline ventricular lactate measured by proton magnetic resonance spectroscopic imaging was found to be higher in patients with FM than in healthy controls (F1,37 = 22.11, P < .0001, partial η(2) = .37). Milnacipran reduced pain in patients with FM relative to placebo but had no effect on cognitive processing.

At the end of the study, ventricular lactate levels in the milnacipran-treated group had decreased significantly compared with baseline and after placebo (F1,18 = 8.18, P = .01, partial η(2) = .31). A significantly larger proportion of patients treated with milnacipran showed decreases in both ventricular lactate and pain than those treated with placebo (P = .03). These results suggest that proton magnetic resonance spectroscopic imaging measurements of lactate may serve as a potential biomarker for a therapeutic response in FM and that milnacipran may act, at least in part, by targeting the brain response to glial activation and neuroinflammation.

PERSPECTIVE: Patients treated with milnacipran showed decreases in both pain and ventricular lactate levels compared with those treated with placebo, but, even after treatment, levels of ventricular lactate remained higher than in controls. The hypothesized mechanism for these decreases is via drug-induced reductions of a central inflammatory state.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01108731.

Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

 

Source: Natelson BH, Vu D, Mao X, Weiduschat N, Togo F, Lange G, Blate M, Kang G, Coplan JD, Shungu DC. Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial. J Pain. 2015 Nov;16(11):1211-9. doi: 10.1016/j.jpain.2015.08.004. Epub 2015 Aug 31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630071/ (Full article)

 

A chronic fatigue syndrome model demonstrates mechanical allodynia and muscular hyperalgesia via spinal microglial activation

Abstract:

Patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS) display multiple symptoms, such as chronic widespread pain, fatigue, sleep disturbance, and cognitive dysfunction. Abnormal pain sensation may be the most serious of these symptoms; however, its pathophysiology remains unknown.

To provide insights into the molecular basis underlying abnormal pain in CFS and FMS, we used a multiple continuous stress (CS) model in rats, which were housed in a cage with a low level of water (1.5 cm in depth). The von Frey and Randall-Seritto tests were used to evaluate pain levels.

Results showed that mechanical allodynia at plantar skin and mechanical hyperalgesia at the anterior tibialis (i.e., muscle pain) were induced by CS loading. Moreover, no signs of inflammation and injury incidents were observed in both the plantar skin and leg muscles. However, microglial accumulation and activation were observed in L4-L6 dorsal horn of CS rats. Quantification analysis revealed a higher accumulation of microglia in the medial part of Layers I-IV of the dorsal horn. To evaluate an implication of microglia in pain, minocycline was intrathecally administrated (via an osmotic pump). Minocycline significantly attenuated CS-induced mechanical hyperalgesia and allodynia.

These results indicated that activated microglia were involved in the development of abnormal pain in CS animals, suggesting that the pain observed in CFS and FMS patients may be partly caused by a mechanism in which microglial activation is involved.

© 2014 Wiley Periodicals, Inc.

 

Source: Yasui M, Yoshimura T, Takeuchi S, Tokizane K, Tsuda M, Inoue K, Kiyama H. A chronic fatigue syndrome model demonstrates mechanical allodynia and muscular hyperalgesia via spinal microglial activation. Glia. 2014 Sep;62(9):1407-17. doi: 10.1002/glia.22687. Epub 2014 May 23. https://www.ncbi.nlm.nih.gov/pubmed/24852223

 

Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study

Abstract:

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. Although it is hypothesized that brain inflammation is involved in the pathophysiology of CFS/ME, there is no direct evidence of neuroinflammation in patients with CFS/ME. Activation of microglia or astrocytes is related to neuroinflammation. (11)C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide ((11)C-(R)-PK11195) is a ligand of PET for a translocator protein that is expressed by activated microglia or astrocytes. We used (11)C-(R)-PK11195 and PET to investigate the existence of neuroinflammation in CFS/ME patients.

METHODS: Nine CFS/ME patients and 10 healthy controls underwent (11)C-(R)-PK11195 PET and completed questionnaires about fatigue, fatigue sensation, cognitive impairments, pain, and depression. To measure the density of translocator protein, nondisplaceable binding potential (BP(ND)) values were determined using linear graphical analysis with the cerebellum as a reference region.

RESULTS: The BP(ND) values of (11)C-(R)-PK11195 in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons were 45%-199% higher in CFS/ME patients than in healthy controls. In CFS/ME patients, the BP(ND) values of (11)C-(R)-PK11195 in the amygdala, thalamus, and midbrain positively correlated with cognitive impairment score, the BP(ND) values in the cingulate cortex and thalamus positively correlated with pain score, and the BP(ND) value in the hippocampus positively correlated with depression score.

CONCLUSION: Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms. Evaluation of neuroinflammation in CFS/ME patients may be essential for understanding the core pathophysiology and for developing objective diagnostic criteria and effective medical treatments.

© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

 

Source: Nakatomi Y, Mizuno K, Ishii A, Wada Y, Tanaka M, Tazawa S, Onoe K, Fukuda S, Kawabe J, Takahashi K, Kataoka Y, Shiomi S, Yamaguti K, Inaba M, Kuratsune H, Watanabe Y. Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study. J Nucl Med. 2014 Jun;55(6):945-50. doi: 10.2967/jnumed.113.131045. Epub 2014 Mar 24. http://jnm.snmjournals.org/content/55/6/945.long (Full article)