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Brain, Behavior, and Immunity Mar 2018Diminished cognitive and mood function are among the most conspicuous symptoms of Gulf War Illness (GWI). Our previous studies in a rat model of GWI have demonstrated...
Curcumin treatment leads to better cognitive and mood function in a model of Gulf War Illness with enhanced neurogenesis, and alleviation of inflammation and mitochondrial dysfunction in the hippocampus.
Diminished cognitive and mood function are among the most conspicuous symptoms of Gulf War Illness (GWI). Our previous studies in a rat model of GWI have demonstrated that persistent cognitive and mood impairments are associated with substantially declined neurogenesis, chronic low-grade inflammation, increased oxidative stress and mitochondrial dysfunction in the hippocampus. We tested the efficacy of curcumin (CUR) to maintain better cognitive and mood function in a rat model of GWI because of its neurogenic, antiinflammatory, antioxidant, and memory and mood enhancing properties. Male rats were exposed daily to low doses of GWI-related chemicals, pyridostigmine bromide, N,N-diethyl-m-toluamide (DEET) and permethrin, and 5-minutes of restraint stress for 28 days. Animals were next randomly assigned to two groups, which received daily CUR or vehicle treatment for 30 days. Animals also received 5'-bromodeoxyuridine during the last seven days of treatment for analysis of neurogenesis. Behavioral studies through object location, novel object recognition and novelty suppressed feeding tests performed sixty days after treatment revealed better cognitive and mood function in CUR treated GWI rats. These rats also displayed enhanced neurogenesis and diminished inflammation typified by reduced astrocyte hypertrophy and activated microglia in the hippocampus. Additional studies showed that CUR treatment to GWI rats enhanced the expression of antioxidant genes and normalized the expression of multiple genes related to mitochondrial respiration. Thus, CUR therapy is efficacious for maintaining better memory and mood function in a model of GWI. Enhanced neurogenesis, restrained inflammation and oxidative stress with normalized mitochondrial respiration may underlie better memory and mood function mediated by CUR treatment.
Topics: Affect; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cognition; Curcumin; DEET; Disease Models, Animal; Hippocampus; Inflammation; Male; Mitochondria; Neurogenesis; Oxidative Stress; Permethrin; Persian Gulf Syndrome; Rats
PubMed: 29454881
DOI: 10.1016/j.bbi.2018.01.009 -
Frontiers in Psychiatry 2020Gulf War Illness is a chronic multisystem disorder affecting approximately a third of the Veterans of the Gulf War, manifesting with physical and mental health symptoms... (Review)
Review
Gulf War Illness is a chronic multisystem disorder affecting approximately a third of the Veterans of the Gulf War, manifesting with physical and mental health symptoms such as cognitive impairment, neurological abnormalities, and dysregulation of mood. Among the leading theories into the etiology of this multisystem disorder is environmental exposure to the various neurotoxins encountered in the Gulf Theatre, including organophosphates, nerve agents, pyridostigmine bromide, smoke from oil well fires, and depleted uranium. The relationship of toxin exposure and the pathogenesis of Gulf War Illness converges on the innate immune system: a nonspecific form of immunity ubiquitous in nature that acts to respond to both exogenous and endogenous insults. Activation of the innate immune system results in inflammation mediated by the release of cytokines. Cytokine mediated neuroinflammation has been demonstrated in a number of psychiatric conditions and may help explain the larger than expected population of Gulf War Veterans afflicted with a mood disorder. Several of the environmental toxins encountered by soldiers during the first Gulf War have been shown to cause upregulation of inflammatory mediators after chronic exposure, even at low levels. This act of inflammatory priming, by which repeated exposure to chronic subthreshold insults elicits robust responses, even after an extended period of latency, is integral in the connection of Gulf War Illness and comorbid mood disorders. Further developing the understanding of the relationship between environmental toxin exposure, innate immune activation, and pathogenesis of disease in the Gulf War Veterans population, may yield novel therapeutic targets, and a greater understanding of disease pathology and subsequently prevention.
PubMed: 32848904
DOI: 10.3389/fpsyt.2020.00704 -
American Journal of Ophthalmology Case... Jun 2022Cerebrospinal fluid hypovolemia syndrome (CHS) is a rare clinical entity that can be caused by spontaneous cerebrospinal fluid (CSF) leakage. The aim of this study is to...
PURPOSE
Cerebrospinal fluid hypovolemia syndrome (CHS) is a rare clinical entity that can be caused by spontaneous cerebrospinal fluid (CSF) leakage. The aim of this study is to report a rare case of CHS after a traffic accident in a patient who presented with diplopia and ptosis with fluctuation and was initially diagnosed with ocular myasthenia gravis.
OBSERVEATIONS
A 29-year-old man exhibited fluctuating left ptosis and diplopia after a traffic accident. Although he was suspected of having myasthenia gravis and was treated using oral pyridostigmine bromide, his symptoms did not improve. He also had orthostatic headaches and malaise after the accident. His symptoms were suspected to be associated with traumatic cerebrospinal fluid hypovolemia. After 1000-mL fluid replacement, his diplopia and ptosis improved, and orbital T2-weghted MRI detected a high-signal zone around the optic nerve. We diagnosed him with oculomotor nerve paresis associated with cerebrospinal fluid hypovolemia. The symptoms, including ptosis, diplopia, orthostatic headaches, and malaise, disappeared after epidural blood patch therapy.
CONCLUSIONS AND IMPORTANCE
When treating patients with fluctuating ocular symptoms, such as diplopia and ptosis, who have a history of trauma and orthostatic headaches, the possibility of CHS should be considered in the differential diagnosis.
PubMed: 35313471
DOI: 10.1016/j.ajoc.2022.101478 -
Neurologia Mar 2023Myasthenia gravis (MG) is an autoimmune disease affecting nerve transmission at the level of the neuromuscular junction, and typically causes fluctuating muscle...
INTRODUCTION
Myasthenia gravis (MG) is an autoimmune disease affecting nerve transmission at the level of the neuromuscular junction, and typically causes fluctuating muscle weakness. Epidemiological studies show an increase in MG prevalence, particularly among the older population.
OBJECTIVE
We performed a retrospective epidemiological study to determine the incidence and prevalence of MG in the province of Ourense (Galicia, Spain), characterised by population ageing.
MATERIAL AND METHODS
Patients were selected from our clinical neuromuscular diseases database by searching for patients with an active prescription for pyridostigmine bromide. Incidence was estimated for the period 2009-2018. We calculated prevalence at 31/12/2018. According to census data for the province of Ourense, the population on 1/1/2019 was 307 651, of whom 96 544 (31.4%) were aged ≥ 65 years.
RESULTS
We identified 80 cases of MG, with a prevalence rate of 260 cases/1 000 000 population (95% CI, 202.7-316.4), rising to 517.9/1 000 000 population in those aged ≥ 65 (95% CI, 363.2-672.9). Cumulative incidence in the study period was 15.4 cases per 1 000 000 person-years. Early onset (≤ 50 years) was recorded in 29.1% of cases.
CONCLUSION
The prevalence of MG in our health district is one of the highest published figures, and the disease is highly prevalent in the older population.
Topics: Humans; Spain; Retrospective Studies; Myasthenia Gravis; Prevalence; Incidence
PubMed: 35249845
DOI: 10.1016/j.nrleng.2020.06.013 -
Korean Journal of Anesthesiology Apr 2020Acetylcholinesterase inhibitors (e.g., pyridostigmine bromide) are used for neuromuscular blockade (NMB) reversal in patients undergoing surgery under general anesthesia... (Comparative Study)
Comparative Study Randomized Controlled Trial
Neuromuscular blockade reversal with sugammadex versus pyridostigmine/glycopyrrolate in laparoscopic cholecystectomy: a randomized trial of effects on postoperative gastrointestinal motility.
BACKGROUND
Acetylcholinesterase inhibitors (e.g., pyridostigmine bromide) are used for neuromuscular blockade (NMB) reversal in patients undergoing surgery under general anesthesia (GA). Concurrent use of anticholinergic agents (e.g., glycopyrrolate) decreases cholinergic side effects but can impede bowel movements. Sugammadex has no cholinergic effects; its use modifies recovery of gastrointestinal (GI) motility following laparoscopic cholecystectomy compared to pyridostigmine/glycopyrrolate. This study evaluated the contribution of sugammadex to the recovery of GI motility compared with pyridostigmine and glycopyrrolate.
METHODS
We conducted a prospective study of patients who underwent laparoscopic cholecystectomy. Patients were randomly allocated to the experimental group (sugammadex, Group S) or control group (pyridostigmine-glycopyrrolate, Group P). After anesthesia (propofol and rocuronium, and 2% sevoflurane), recovery was induced by injection of sugammadex or a pyridostigmine-glycopyrrolate mixture. As a primary outcome, patients recorded the time of their first passage of flatus ('gas-out time') and defecation. The secondary outcome was stool types.
RESULTS
One-hundred and two patients participated (Group S, 49; Group P, 53). Mean time from injection of NMB reversal agents to gas-out time was 15.03 (6.36-20.25) h in Group S and 20.85 (16.34-25.86) h in Group P (P = 0.001). Inter-group differences were significant. Time until the first defecation as well as types of stools was not significantly different.
CONCLUSIONS
Sugammadex after laparoscopic cholecystectomy under GA resulted in an earlier first postoperative passage of flatus compared with the use of a mixture of pyridostigmine and glycopyrrolate. These findings suggest that the use of sugammadex has positive effects on the recovery of GI motility.
Topics: Adult; Cholecystectomy, Laparoscopic; Cholinesterase Inhibitors; Drug Therapy, Combination; Female; Gastrointestinal Motility; Glycopyrrolate; Humans; Male; Middle Aged; Muscarinic Antagonists; Neuromuscular Blockade; Neuromuscular Nondepolarizing Agents; Postoperative Complications; Prospective Studies; Pyridostigmine Bromide; Sugammadex
PubMed: 31636242
DOI: 10.4097/kja.19360 -
JCI Insight Jun 2019Whereas prior studies have demonstrated an important immunomodulatory role for the neuronal cholinergic system in the heart, the role of the non-neuronal cholinergic...
Whereas prior studies have demonstrated an important immunomodulatory role for the neuronal cholinergic system in the heart, the role of the non-neuronal cholinergic system is not well understood. To address the immunomodulatory role of the non-neuronal cholinergic system in the heart we used a previously validated diphtheria toxin (DT)-induced cardiomyocyte ablation model (Rosa26-DTMlc2v-Cre mice). DT-injected Rosa26-DTMlc2v-Cre mice were treated with diluent or Pyridostigmine Bromide (PYR), a reversible cholinesterase inhibitor. PYR treatment resulted in increased survival and decreased numbers of MHC-IIlowCCR2+ macrophages in DT-injected Rosa26-DTMlc2v-Cre mice compared to diluent treated Rosa26-DTMlc2v-Cre mice. Importantly, the expression of CCL2/7 mRNA and protein was reduced in the hearts of PYR-treated mice. Backcrossing Rosa26-DTMlc2v-Cre mice with a transgenic mouse line (Chat-ChR2) that constitutively overexpresses the vesicular acetylcholine transporter (VAChT) resulted in decreased expression of Ccl2/7 mRNA and decreased numbers of CD68+ cells in DT-injured Rosa26-DTMlc2v-Cre/Chat-ChR2 mouse hearts, consistent with the pharmacologic studies with PYR. In vitro studies with cultures of LPS-stimulated peritoneal macrophages revealed a concentration-dependent reduction in CCL2 secretion following stimulation with ACh, nicotine and muscarine. Viewed together, these findings reveal a previously unappreciated immunomodulatory role for the non-neuronal cholinergic system in regulating homeostatic responses in the heart following tissue injury.
Topics: Animals; Chemokine CCL2; Chemokine CCL7; Chemokines; Cholinergic Agents; Diphtheria Toxin; Disease Models, Animal; Female; Heart Injuries; Homeostasis; Inflammation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Monocytes; Myocytes, Cardiac; Neurons; RNA, Messenger; Vesicular Acetylcholine Transport Proteins
PubMed: 31162139
DOI: 10.1172/jci.insight.128961 -
Journal of Neurovirology Aug 2019Small intestinal bacterial overgrowth (SIBO) is common among patients with HIV-associated autonomic neuropathies (HIV-AN) and may be associated with increased bacterial... (Clinical Trial)
Clinical Trial
Small intestinal bacterial overgrowth (SIBO) is common among patients with HIV-associated autonomic neuropathies (HIV-AN) and may be associated with increased bacterial translocation and elevated plasma inflammatory biomarkers. Pyridostigmine is an acetylcholinesterase inhibitor which has been used to augment autonomic signaling. We sought preliminary evidence as to whether pyridostigmine could improve proximal gastrointestinal motility, reduce SIBO, reduce plasma sCD14 (a marker of macrophage activation and indirect measure of translocation), and reduce the inflammatory cytokines IL-6 and TNFα in patients with HIV-AN. Fifteen participants with well-controlled HIV, HIV-AN, and SIBO were treated with 8 weeks of pyridostigmine (30 mg PO TID). Glucose breath testing for SIBO, gastric emptying studies (GES) to assess motility, plasma sCD14, IL-6, and TNFα, and gastrointestinal autonomic symptoms were compared before and after treatment. Thirteen participants (87%) experienced an improvement in SIBO following pyridostigmine treatment; with an average improvement of 50% (p = 0.016). There was no change in gastrointestinal motility; however, only two participants met GES criteria for gastroparesis at baseline. TNFα and sCD14 levels declined by 12% (p = 0.004) and 19% (p = 0.015), respectively; there was no significant change in IL-6 or gastrointestinal symptoms. Pyridostigmine may ameliorate SIBO and reduce levels of sCD14 and TNFα in patients with HIV-AN. Larger placebo-controlled studies are needed to definitively delineate how HIV-AN affects gastrointestinal motility, SIBO, and systemic inflammation in HIV, and whether treatment improves clinical outcomes.
Topics: Autonomic Pathways; Bacterial Translocation; Cholinesterase Inhibitors; Drug Administration Schedule; Female; Gastrointestinal Motility; Gene Expression; HIV Infections; Humans; Interleukin-6; Intestine, Small; Lipopolysaccharide Receptors; Macrophage Activation; Macrophages; Male; Middle Aged; Neuroprotective Agents; Pyridostigmine Bromide; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 31098925
DOI: 10.1007/s13365-019-00756-9 -
Life Sciences Jan 2022To characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic...
AIMS
To characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic Gulf War Illness (GWI) mouse model. The latter have been described in an accompanying paper [1].
MAIN METHODS
Adult male C57Bl/6N mice were exposed for 28 days (5 days/week) to pyridostigmine bromide: 6.5 mg/kg, b.i.d., P.O. (GW1) or 8.7 mg/kg, q.d., P.O. (GW2); topical permethrin (1.3 mg/kg in 100% DMSO) and N,N-diethyl-meta-toluamide (DEET 33% in 70% EtOH) and restraint stress (5 min). Exercise, metabolic and behavioral endpoints were compared to sham stress control (CON/S).
KEY FINDINGS
Relative to CON/S, GW2 presented persistent exercise intolerance (through post-treatment (PT) day 161), deficient associative learning/memory, and transient insulin insensitivity. In contrast to GW2, GW1 showed deficient long-term object recognition memory, milder associative learning/memory deficit, and behavioral despair.
SIGNIFICANCE
Our findings demonstrate that GW chemicals dose-dependently determine the presentation of exercise fatigue and severity/type of cognitive/mood-deficient phenotypes that show persistence. Our comprehensive mouse model of GWI recapitulates the major multiple symptom domains characterizing GWI, including fatigue and cognitive impairment that can be used to more efficiently develop diagnostic tests and curative treatments for ill Gulf War veterans.
Topics: Animals; Disease Models, Animal; Fatigue; Glucose; Humans; Learning Disabilities; Male; Mice; Persian Gulf Syndrome; Pyridostigmine Bromide
PubMed: 34710444
DOI: 10.1016/j.lfs.2021.120094 -
Frontiers in Physiology 2018Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Exercise training and pharmacological treatments are important strategies to...
Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Exercise training and pharmacological treatments are important strategies to minimize the deleterious effects of MI. However, little is known about the effects of resistance training combined with pyridostigmine bromide (PYR) treatment on cardiac and autonomic function, as well as on the inflammatory profile after MI. Thus, in the present study, male Wistar rats were randomly assigned into: control (Cont); sedentary infarcted (Inf); PYR - treated sedentary infarcted rats (Inf+P); infarcted rats undergoing resistance exercise training (Inf+RT); and infarcted rats undergoing PYR treatment plus resistance training (Inf+RT+P). After 12 weeks of resistance training (15-20 climbs per session, with a 1-min rest between each climb, at a low to moderate intensity, 5 days a week) and/or PYR treatment (0.14 mg/mL of drink water), hemodynamic function, autonomic modulation, and cytokine expressions were evaluated. We observed that 3 months of PYR treatment, either alone or in combination with exercise, can improve the deleterious effects of MI on left ventricle dimensions and function, baroreflex sensitivity, and autonomic parameters, as well as systemic and tissue inflammatory profile. Furthermore, additional benefits in a maximal load test and anti-inflammatory state of skeletal muscle were found when resistance training was combined with PYR treatment. Thus, our findings suggest that the combination of resistance training and PYR may be a good therapeutic strategy since they promote additional benefits on skeletal muscle anti-inflammatory profile after MI.
PubMed: 29483876
DOI: 10.3389/fphys.2018.00053 -
The American Journal of Case Reports Sep 2019BACKGROUND Pyridostigmine is a quaternary amine parasympathomymetic which inhibits acetylcholinesterase for the treatment of various conditions such as myasthenia...
BACKGROUND Pyridostigmine is a quaternary amine parasympathomymetic which inhibits acetylcholinesterase for the treatment of various conditions such as myasthenia gravis. Previously, no cases of pyridostigmine toxicity in human beings have been reported except the cases reported among the troops of Persian Gulf War. CASE REPORT A 47-year-old female intentionally ingested a high dose of pyridostigmine (Mestinon) and developed its toxic symptoms within 1 hour of ingestion. She was treated with injections of atropine and pralidoxime. The patient made an excellent recovery and responded to the classical treatment using atropine and pralidoxime. She was discharged on the second day of admission. CONCLUSIONS The authors demonstrated that pyridostigmine poisoning is self-limiting and well tolerated by young adults; however, unwanted effects of pyridostigmine on the heart has still to be considered which may become profound to the point of generating heart failure, syncope, or stress particularly in elderly patients. As the literature on human toxicity with pyridostigmine is scarce, not much data is available on its toxicity. However, prompt and specific management of pyridostigmine toxicity promises safety.
Topics: Atropine; Cholinesterase Inhibitors; Cholinesterase Reactivators; Female; Humans; Middle Aged; Muscarinic Antagonists; Myasthenia Gravis; Pralidoxime Compounds; Pyridostigmine Bromide; Suicide, Attempted
PubMed: 31554781
DOI: 10.12659/AJCR.917308