Effect of sugammadex with neostigmine on postoperative bowel function and on recovery of neuromuscular functions: A randomized controlled trial.

BACKGROUND: Early recovery of neuromuscular and bowel function after abdominal surgery are important clinical indicators of postoperative recovery. This study aimed to investigate the effects of sugammadex, and neostigmine added to sugammadex, on postoperative bowel function and recovery from neuromuscular blocking agents. METHODS: Ninety gynecological surgery patients, aged 18 to 65 years, with American Society of Anesthesiologists of 1 to 2 were randomly assigned to 3 groups: sugammadex 2 mg/kg (Group S), sugammadex 1 m/kg with neostigmine 20 µg/kg + atropine 10 µg/kg (Group S1N), and sugammadex 1.5 mg/kg with neostigmine 20 µg/kg + atropine 10 µg/kg (Group S2N), for reversal at the end of surgery during moderate block (train-of-four [TOF] count 1-2). Propofol, remifentanil, rocuronium, and sevoflurane were used for general anesthesia, and neuromuscular function was assessed using kinemyography. The primary outcomes assessed the effects of sugammadex alone and in combination with neostigmine on the time to first flatus. The secondary outcomes included time to first defecation and recovery time; defined as the administration of reversal agent to TOF ratio 90%. RESULTS: Data from 90 female patients who underwent abdominal gynecological surgery were analyzed. No significant differences were found between the groups in term of the time to first flatus, defecation, or postoperative nausea and vomiting after surgery. However, significant differences were observed in the time to reach a TOF ratio 90% (P < .001) and extubation time (P = .003). CONCLUSION: The addition of neostigmine to sugammadex did not affect bowel function recovery. However, combining 20 µg/kg neostigmine with 1.5 mg/kg sugammadex or 2 mg/kg sugammadex alone antagonized moderate-depth nondepolarizing neuromuscular blockade with similar efficacy.

[A case of Parkinson's disease with marked head drop after administration of donepezil hydrochloride].

A 76-year-old woman with a 2-year history of Parkinson's disease presented with dropped head, which had developed rapidly after she had been prescribed donepezil hydrochloride (DNP) at 3 |mg/day. After one month of medication, the extent of the head drop reached 90°. Examination revealed hypertrophy of the left sternocleidomastoid muscle, but no weakness of the extensor muscles in the cervical region. Surface electromyography demonstrated co-|contraction of the sternocleidomastoid and splenius capitus muscles during head flexion and extension. DNP was withdrawn, resulting in immediate amelioration of the head drop, and complete resolution was achieved after two months. Although head drop is often seen in patients with Parkinson's disease, few previous reports have documented DNP as a causative factor. If patients with Parkinson's disease develop head drop, it is important to investigate any history of DNP medication.

Fabrication of Hybrid Coated Microneedles with Donepezil Utilizing Digital Light Processing and Semisolid Extrusion Printing for the Management of Alzheimer's Disease.

Microneedle (MN) patches are gaining increasing attention as a cost-effective technology for delivering drugs directly into the skin. In the present study, two different 3D printing processes were utilized to produce coated MNs, namely, digital light processing (DLP) and semisolid extrusion (SSE). Donepezil (DN), a cholinesterase inhibitor administered for the treatment of Alzheimer's disease, was incorporated into the coating material. Physiochemical characterization of the coated MNs confirmed the successful incorporation of donepezil as well as the stability and suitability of the materials for transdermal delivery. Optical microscopy and SEM studies validated the uniform weight distribution and precise dimensions of the MN arrays, while mechanical testing ensured the MNs' robustness, ensuring efficient skin penetration. In vitro studies were conducted to evaluate the produced transdermal patches, indicating their potential use in clinical treatment. Permeation studies revealed a significant increase in DN permeation compared to plain coating material, affirming the effectiveness of the MNs in enhancing transdermal drug delivery. Confocal laser scanning microscopy (CLSM) elucidated the distribution of the API, within skin layers, demonstrating sustained drug release and transcellular transport pathways. Finally, cell studies were also conducted on NIH3T3 fibroblasts to evaluate the biocompatibility and safety of the printed objects for transdermal applications.

Brain targeting efficacy of novel drug delivery system in the treatment of Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD), a common degenerative disease of the central nervous system in the elderly, has become the third largest health killer after cardiovascular and cerebrovascular diseases and tumors. Based on the fact that Alzheimer's disease is a disease with multiple etiologies and complex pathology, a single target is bound to have a limited curative effect, and the synergy of multiple links and multiple targets is expected to achieve a better curative effect. The aim of this study is to investigate the brain targeting of a drug modified by chitosan, based on the new nanodrug delivery system for treating Alzheimer's disease developed by the research group. MATERIALS AND METHODS: Chitosan with good biocompatibility, biosorption, and degradation products that can protect and promote the regeneration of nerve cells was selected to combine with galantamine, a natural representative cholinesterase inhibitor, to develop a new nano drug delivery system for nasal delivery of anti-Alzheimer's disease with a multi-target synergistic effect. Synchronous analysis was conducted on the blood and brain tissue drug concentrations after intravenous and nasal administration of the original drug solution and system solution. The brain targeting index (DTI) is used to evaluate the brain targeting effect of the nano-drug delivery system after intranasal administration. RESULTS: The blood concentration of galantamine original drug solution and galantamine system solution after intravenous injection and nasal show that in the two administration methods of intravenous injection and nasal administration, under the same administration method, the time point of the system reaching the highest blood drug concentration is much higher than that of the original drug. The content of galantamine in plasma samples and tissue samples indicate that after intravenous administration and intranasal administration of the galantamine system, at the same time point, the drug concentration in brain tissue was far greater than that of the original drug of galantamine, and the duration was also longer. The concentration of drugs in brain tissue decreased gradually in the order of olfactory bulb, olfactory tract, brain, and cerebellum. In the brain tissues of the olfactory bulb, olfactory tract, cerebrum, and cerebellum, the drug concentration of the galantamine system after intravenous injection is lower than that after nasal administration. CONCLUSIONS: This study concludes that compared with the original drug solution, the nano drug delivery system has significant brain targeting for nasal administration, and intravenous injection also has brain targeting. In the olfactory bulb, olfactory tract, brain, and cerebellum, the brain targeting index at the olfactory bulb is the highest, and the targeting is the best.

Effect of curcumin-donepezil combination on spatial memory, astrocyte activation, and cholinesterase expressions in brain of scopolamine-treated rats.

BACKGROUND: The study investigated the effect of co-administration of curcumin and donepezil on several markers of cognitive function (such as spatial memory, astrocyte activation, cholinesterase expressions) in the brain cortex and hippocampus of scopolamine-treated rats. METHOD AND RESULTS: For seven consecutive days, a pre-treatment of curcumin (50 mg/kg) and/or donepezil (2.5 mg/kg) was administered. On the seventh day, scopolamine (1 mg/kg) was administered to elicit cognitive impairment, 30 min before memory test was conducted. This was followed by evaluating changes in spatial memory, cholinesterase, and adenosine deaminase (ADA) activities, as well as nitric oxide (NO) level were determined. Additionally, RT-qPCR for glial fibrillary acidic protein (GFAP) and cholinesterase gene expressions was performed in the brain cortex and hippocampus. Also, GFAP immunohistochemistry  of the brain tissues for neuronal injury were performed in the brain cortex and hippocampus. In comparison to the control group, rats given scopolamine had impaired memory, higher levels of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ADA activities, as well as elevated markers of oxidative stress. In addition to enhanced GFAP immunoreactivity, there was also overexpression of the GFAP and BChE genes in the brain tissues. The combination of curcumin and donepezil was, however, observed to better ameliorate these impairments in comparison to the donepezil-administered rat group. CONCLUSION: Hence, this evidence provides more mechanisms to support the hypothesis that the concurrent administration of curcumin and donepezil mitigates markers of cognitive dysfunction in scopolamine-treated rat model.

The effect of chlorpyrifos oral exposure on the histomorphometric and kidney function in Wistar rat.

BACKGROUND: Chlorpyrifos belongs to a broad-spectrum organophosphate insecticide that has high toxicity, is metabolized in the liver by the oxidation reaction, and can inhibit acetylcholinesterase activity. Acetylcholinesterase inhibition generates the reactive oxygen species and induces oxidative stress, which ultimately results in cellular damage like in the kidney. Examining blood urea nitrogen (BUN) levels, creatinine, and kidney histopathology is an appropriate indicator to assess the toxicity of chlorpyrifos to the degree of damage to cells and kidney tissue. MATERIALS AND METHODS: This research used to determine the effect of duration of exposure to chlorpyrifos and dose-response relationships is important for early detection of the effects of chlorpyrifos toxicity on health. The research study was a true experimental (completely randomized design) consisting of 30 subjects divided into 5 groups. Controlled Group (K1) given 1 mg/kg BW Tween 20 and NaCl 0, 9% until the 56th day. The chlorpyrifos exposed group (P1, P2, P3, and P4) was given chlorpyrifos 5 mg/kg BW for 7, 14, 28, and 56 days. After the treatment, BUN and creatinine levels were measured, and microscopic changes in the kidney were analyzed. The results of BUN, creatinine, and kidney histopathologic were analyzed using the analysis of variance statistical test. RESULTS: The data result showed that compared to the control group, there were significant increases of BUN and creatinine (P = 0.013 and P = 0.003). Histopathological examinations of kidney glomerulus diameter were also smaller compared to the control group (P = 0.00). All the data measurement indicates significant differences compared to the control group. CONCLUSIONS: We concluded that sub-chronic oral exposure to chlorpyrifos at low doses can damage the kidneys and cause kidney failure.

Oxime-functionalized anti-insecticide fabric reduces insecticide exposure through dermal and nasal routes, and prevents insecticide-induced neuromuscular-dysfunction and mortality.

Farmers from South Asian countries spray insecticides without protective gear, which leads to insecticide exposure through dermal and nasal routes. Acetylcholinesterase plays a crucial role in controlling neuromuscular function. Organophosphate and carbamate insecticides inhibit acetylcholinesterase, which leads to severe neuronal/cognitive dysfunction, breathing disorders, loss of endurance, and death. To address this issue, an Oxime-fabric is developed by covalently attaching silyl-pralidoxime to the cellulose of the fabric. The Oxime-fabric, when stitched as a bodysuit and facemask, efficiently deactivates insecticides (organophosphates and carbamates) upon contact, preventing exposure. The Oxime-fabric prevents insecticide-induced neuronal damage, neuro-muscular dysfunction, and loss of endurance. Furthermore, we observe a 100% survival rate in rats when repeatedly exposed to organophosphate-insecticide through the Oxime-fabric, while no survival is seen when organophosphate-insecticide applied directly or through normal fabric. The Oxime-fabric is washable and reusable for at least 50 cycles, providing an affordable solution to prevent insecticide-induced toxicity and lethality among farmers.

Implantable trilayer microneedle transdermal delivery system to enhance bioavailability and brain delivery of rivastigmine for Alzheimer treatment: A proof-of-concept study.

Alzheimer's disease (ALZ) is a neurological disorder characterized by cognitive decline. Rivastigmine (RV), an acetylcholinesterase inhibitor, is commonly used to treat ALZ. Unfortunately, RV is availablein capsule form, which is associated with low drug bioavailability, and in patch form, which can lead to skin irritation upon repeated use. This study successfully fabricated a trilayer dissolving microneedle (TDMN) containing RV with adequate mechanical strength by using the molding method. In vitro release and ex vivo permeation showed that the release and permeation of RV were significantly sustained compared to control without PCL. The release and permeation percentages were 91.34 ± 11.39 % and 13.76 ± 1.49 µg/cm2, respectively. In addition, the concentration of RV in plasma and brain after 168 h was measured to be 0.44 ± 0.09 µg/mL and 1.23 ± 0.26 µg/g, respectively, which reached the minimum concentration to inhibit AcHE and BuChe. Pharmacokinetic testing revealed higher AUC values after administration of TDMN, indicating better bioavailability and RV concentrations in the brain were twice as high as those achieved with oral administration. This study suggests TDMN may enhance the bioavailability and brain delivery of RV.

Pyridostigmine to Reduce the duration of postoperative Ileus after Colorectal surgery (PyRICo-RCT): randomized clinical trial.

BACKGROUND: Postoperative ileus, driven by the cholinergic anti-inflammatory pathway, is the most common complication in patients undergoing colorectal surgery. By inhibiting acetylcholinesterase, pyridostigmine can potentially modulate the cholinergic anti-inflammatory pathway and accelerate gastrointestinal recovery. This study aimed to assess the efficacy of pyridostigmine in improving gastrointestinal recovery after colorectal surgery. METHODS: This double-blinded RCT enrolled adult patients undergoing elective colorectal surgery at two hospitals in South Australia. Patients were randomized to 60 mg oral pyridostigmine or placebo twice daily starting 6 h after surgery until the first passage of stool. The primary outcome was GI-2, a validated composite measure of time to first stool and tolerance of oral diet. Secondary outcomes included incidence of postoperative ileus (defined as GI-2 greater than 4 days), duration of hospital stay, and 30-day complications, evaluated by intention-to-treat univariate analysis. RESULTS: Of 130 patients recruited (mean(s.d.) age 58.4(16.4) years; 73 men, 56%), 65 were allocated to each arm. The median GI-2 was 1 day shorter with pyridostigmine compared with placebo (2 (i.q.r. 1-3) versus 3 (2-4) days; P = 0.015). However, there were no significant differences in postoperative ileus (17.2 versus 21.5%; P = 0.532) or duration of hospital stay (median 5 (i.q.r. 4-8.75) versus 5 (4-7.5) days; P = 0.921). Similarly, there were no significant differences in overall complications, anastomotic leak, cardiac complications, or patient-reported side effects. CONCLUSION: Pyridostigmine resulted in a quicker return of GI-2 and was well tolerated. Larger multicentre studies are required to determine the optimal dosing and evaluate the impact of pyridostigmine in different surgical settings. Registration number: ACTRN12621000530820 (https://anzctr.org.au).

The donepezil transdermal system for the treatment of patients with mild, moderate, or severe Alzheimer's disease: a critical review.

INTRODUCTION: Cholinesterase inhibitors, along with memantine, are the mainstay of symptomatic treatment for AD (Alzheimer's disease); however, these medications are typically administered orally, which can be difficult for people with AD and their caregivers. AREAS COVERED: In this drug profile and narrative review, the authors trace the development of the new FDA-approved transdermal donepezil. The authors discuss the studies showing its bioequivalence with the oral formulation, including two double-blinded placebo controlled non-inferiority trials. The authors also compare the patch to the only other transdermal cholinesterase inhibitor on the market, rivastigmine, and highlight the potential advantages and disadvantages between these two treatments. EXPERT OPINION: While the patch is bio-equivalent, it is rather large and may not be affordable for some patients. In addition, there is no high dose (e.g. 23 mg) equivalent. Nevertheless, transdermal donepezil will be useful for people with AD and their caregivers, given its effectiveness and potential convenience.

The value of cholinesterase inhibitors for improving neuropsychiatric and functional assessment scores in patients with Alzheimer disease: a systematic review and meta-analysis of on placebo-controlled RCTs.

INTRODUCTION: At present, increasing reports from different aspects indicated that cholinesterase inhibitors (ChEIs) may be effective on improving neuropsychiatric and functional assessment scores in patients with Alzheimer disease (AD). However, no studies comprehensively and detailedly evaluated the effect of ChEIs on AD. The present analysis was designed to comprehensively evaluate the efficacy and safety of ChEIs for AD. METHODS: Two independent researchers systematically reviewed 1096 searching records in PubMed, Embase, Cochrane Library, and Web of Science from inception to 10 May 2023, and finally identified 12 randomized, double-blind, placebo-controlled trials with 6908 participants according to predetermined inclusion and exclusion criteria. The effects were assessed with standardized mean difference (SMD) or odds ratio (OR). The primary outcomes were the mean change and least squares (LS) mean change from baseline to endpoint of neuropsychiatric and functional assessment scores. The secondary outcome was adverse events of ChEIs when compared to placebo for patients with AD. All statistical analyses were performed using the standard statistical procedures provided in Review Manager 5.2 and and Stata 12.0. RESULTS: Pooled analysis indicated that ChEIs significantly improved the assessment scores of the AD Assessment Scale (ADAS) (SMD -1.57; 95% CI: -2.64 to -0.51), Clinician's Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus) (SMD -0.28; 95% CI: -0.41 to -0.15), the Neuropsychiatric Inventory (NPI) (both SMD -1.67; 95% CI: -2.88 to -0.47 for 10-tiem total score and SMD -1.83; 95% CI: -3.25 to -0.42 for 12-tiem total score), and the AD Cooperative Study-Activities of Daily Living (ADCS-ADL) total score (SMD 2.44; 95% CI: 1.29-3.59), evaluated with mean change from baseline to endpoint. In addition, when evaluated with the LS mean change from baseline to endpoint, ChEIs significantly improved Mini-Mental State Examination (MMSE) total score, the Clinician Interview-Based Impression of Severity, CIBIC-Plus, ADCS-ADL total score, NPI, ADAS. Regarding to adverse events (AEs) of patients with AD, it indicated that compared to placebo, ChEIs did not increase the frequency of severe and serious AEs (fatal or nonfatal) as well as the incidence of death. CONCLUSIONS: Our analysis indicated that ChEIs treatment generally improved neuropsychiatric and functional assessment scores in patients with AD though opposite result was observed in Wechsler Memory Scale. ChEIs had an acceptable safety profile in patients with AD without increasing of any crucial adverse or outcomes.

Effect of coadministration of 10 mg/kg calcium chloride and neostigmine on extubation time: A randomized controlled trial.

INTRODUCTION AND OBJECTIVES: Some studies investigating the effect of calcium on neostigmine-induced recovery of neuromuscular blockade have shown that this combination promotes neuromuscular recovery, but does not significantly affect the incidence of postoperative residual curarization and time to extubation. This study aimed to evaluate the effects of 10 mg/kg calcium chloride co-administered with neostigmine on early recovery and time to extubation. PATIENTS AND METHODS: This prospective, randomized, double-blinded, placebo-controlled study included 88 ASA I-II patients aged between 18 and 65 years who were scheduled for elective surgery lasting at least 1 h under general anaesthesia in which 10 mg/kg of calcium chloride or the same volume of normal saline was co-administered with 5 µg/kg of neostigmine at the end of surgery. Time to extubation (time from neostigmine administration to extubation), time from neostigmine administration to TOF ratio (TOFr) 0.9 (neuromuscular recovery), and the incidence of residual neuromuscular blockade (RNMB) and other adverse effects were recorded. RESULTS: Median (Q1, Q3) extubation time was significantly shorter in the calcium group vs. the placebo group (6.5 min [5.52-7.43] vs. 9.78 min [8.35-11]), P < .001. Median neuromuscular recovery time in the calcium group was 5 min vs. 7.1 min in the placebo group, P < .001. Patients in the calcium group had significantly higher TOFr and lower incidence of RNMB at 5 and 10 min vs. the placebo group, and no significant side effects. CONCLUSION: Calcium chloride at a dose of 10 mg/kg co-administered with neostigmine promotes early neuromuscular recovery and reduces time to extubation by about 32%.

Nose-to-Brain Targeted Delivery of Donepezil Hydrochloride via Novel Hyaluronic Acid-Doped Nanotransfersomes for Alzheimer's Disease Mitigation.

Alzheimer's disease is the most serious neurodegenerative disorder characterized by cognitive and memorial defects alongside deterioration in behavioral, thinking and social skills. Donepezil hydrochloride (DPZ) is one of the current two FDA-approved cholinesterase inhibitors used for the management of Alzheimer's disease. The current study aimed to formulate hyaluronic acid-coated transfersomes containing DPZ (DPZ-HA-TFS) for brain delivery through the intranasal pathway to surpass its oral-correlated GIT side effects. DPZ-HA-TFS were produced using a thin film hydration method and optimized with a 24 factorial design. The influence of formulation parameters on vesicle diameter, entrapment, cumulative release after 8 h, and ex vivo nasal diffusion after 24 h was studied. The optimal formulation was then evaluated for morphology, stability, histopathology and in vivo biodistribution studies. The optimized DPZ-HA-TFS formulation elicited an acceptable vesicle size (227.5 nm) with 75.83% entrapment efficiency, 37.94% cumulative release after 8 h, 547.49 µg/cm2 permeated through nasal mucosa after 24 h and adequate stability. Histopathological analysis revealed that the formulated DPZ-HA-TFS was nontoxic and tolerable for intranasal delivery. Intranasally administered DPZ-HA-TFS manifested significantly superior values for drug targeting index (5.08), drug targeting efficiency (508.25%) and direct nose-to-brain transport percentage (80.32%). DPZ-HA-TFS might be deemed as a promising intranasal nano-cargo for DPZ cerebral delivery to tackle Alzheimer's disease safely, steadily and in a non-invasive long-term pattern.

A randomized controlled trial of repetitive transcranial magnetic stimulation plus donepezil vs donepezil alone for mild to moderate cognitive impairment due to small vessel cerebrovascular disease.

OBJECTIVES: Small vessel cerebrovascular disease (SVCVD) accounts for 35% to 67% of vascular dementias, and may be overlooked by healthcare providers due to its insidious onset. SVCVD involves chronic cerebral ischemia and hypoperfusion, endothelial dysfunction, blood-brain barrier disruption, and interstitial fluid reflux. The purpose of this study was to investigate the clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) combined with donepezil hydrochloride compared to donepezil alone in the treatment of mild-to-moderate cognitive impairment in patients with SVCVD. MATERIAL AND METHODS: A cohort of 115 individuals with mild-to-moderate cognitive impairment due to SVCVD was purposefully selected and randomized into two groups: a test group and a control group. The test group received a combination of repetitive transcranial magnetic stimulation (rTMS) and oral donepezil hydrochloride (10 mg/day), while the control group received oral donepezil alone (10 mg/day). The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores were evaluated in both groups prior to and following the interventions. RESULTS: Following 6 weeks of treatment, both groups demonstrated enhancement in cognitive function. However, a statistically significant difference was observed between the test group and the control group (p < .05 on both the MMSE and the MOCA), favoring the test group. CONCLUSIONS: Compared to donepezil alone, the combination of repetitive transcranial magnetic stimulation (rTMS) and donepezil has a significantly greater effect on enhancing cognitive function among individuals experiencing mild-to-moderate cognitive impairment resulting from SVCVD.

Balanced modulation of neuromuscular synaptic transmission via M1 and M2 muscarinic receptors during inhibition of cholinesterases.

Organophosphorus (OP) compounds that inhibit acetylcholinesterase are a common cause of poisoning worldwide, resulting in several hundred thousand deaths each year. The pathways activated during OP compound poisoning via overstimulation of muscarinic acetylcholine receptors (mAChRs) play a decisive role in toxidrome. The antidotal therapy includes atropine, which is a nonspecific blocker of all mAChR subtypes. Atropine is efficient for mitigating depression in respiratory control centers but does not benefit patients with OP-induced skeletal muscle weakness. By using an ex vivo model of OP-induced muscle weakness, we studied the effects of the M1/M4 mAChR antagonist pirenzepine and the M2/M4 mAChR antagonist methoctramine on the force of mouse diaphragm muscle contraction. It was shown that weakness caused by the application of paraoxon can be significantly prevented by methoctramine (1 µM). However, neither pirenzepine (0.1 µM) nor atropine (1 µM) was able to prevent muscle weakness. Moreover, the application of pirenzepine significantly reduced the positive effect of methoctramine. Thus, balanced modulation of neuromuscular synaptic transmission via M1 and M2 mAChRs contributes to paraoxon-induced muscle weakness. It was shown that methoctramine (10 µmol/kg, i.p.) and atropine (50 µmol/kg, i.p.) were equieffective toward increasing the survival of mice poisoned with a 2xLD50 dose of paraoxon.

Coincidental Onset of Ocular Myasthenia Gravis Following ChAdOx1 n-CoV-19 Vaccine against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

BACKGROUND: The Oxford-AstraZeneca vaccine ChAdOx1 (AZD1222, Vaxzevria) is playing a crucial role in counteracting the coronavirus disease-2019 (COVID-19) pandemic [1]. Since March 2021, reports of unexpected thrombotic events associated with thrombocytopenia and vaccination have been published [2]. To the best of our knowledge there is only one report about vaccination-associated myasthenia gravis (MG) occurring after a second dose of BNT162b2 (Pfizer-BioNTech).

Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment.

AIMS: To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI). METHODS: Adult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b.i.d. (GW1) or 8.7 mg/kg/d, q.d. (GW2); topical permethrin (1.3 mg/kg), topical N,N-diethyl-meta-toluamide (33%) and restraint stress (5 min). Animals were phenotypically evaluated as described in an accompanying article [124] and sacrificed at 6.6 months post-treatment (PT) to allow measurement of brain neuroinflammation/neuropathic pain gene expression, hippocampal glial fibrillary acidic protein, brain Interleukin-6, gut dysbiosis and serum endotoxin. KEY FINDINGS: Compared to GW1, GW2 showed a more intense neuroinflammatory transcriptional signature relative to sham stress controls. Interleukin-6 was elevated in GW2 and astrogliosis in hippocampal CA1 was seen in both GW groups. Beta-diversity PCoA using weighted Unifrac revealed that gut microbial communities changed after exposure to GW2 at PT188. Both GW1 and GW2 displayed systemic endotoxemia, suggesting a gut-brain mechanism underlies the neuropathological signatures. Using germ-free mice, probiotic supplementation with Lactobacillus reuteri produced less gut permeability than microbiota transplantation using GW2 feces. SIGNIFICANCE: Our findings demonstrate that GW agents dose-dependently induce differential neuropathology and gut dysbiosis associated with cognitive, exercise fatigue and mood GWI phenotypes. Establishment of a comprehensive animal model that recapitulates multiple GWI symptom domains and neuroinflammation has significant implications for uncovering pathophysiology, improving diagnosis and treatment for GWI.

Effects of Increased Central Cholinergic Activity on the Metabolic Challenge Induced by Submaximal Exercise in Rats: Adrenomedullary Secretion Influences.

AIM: The aim of this study was to assess the influence of adrenomedullary secretion on the plasma glucose, lactate, and free fatty acids (FFAs) during running exercise in rats submitted to intracerebroventricular (i.c.v.) injection of physostigmine (PHY). PHY i.c.v. was used to activate the central cholinergic system. METHODS: Wistar rats were divided into sham-saline (sham-SAL), sham-PHY, adrenal medullectomy-SAL, and ADM-PHY groups. The plasma concentrations of glucose, lactate, and FFAs were determined immediately before and after i.c.v. injection of 20 µL of SAL or PHY at rest and during running exercise on a treadmill. RESULTS: The i.c.v. injection of PHY at rest increased plasma glucose in the sham group, but not in the ADM group. An increase in plasma glucose, lactate, and FFAs mobilization from adipose tissue was observed during physical exercise in the sham-SAL group; however, the increase in plasma glucose was greater with i.c.v. PHY. Moreover, the hyperglycemia induced by exercise and PHY in the ADM group were blunted by ADM, whereas FFA mobilization was unaffected. CONCLUSION: These results indicate that there is a dual metabolic control by which activation of the central cholinergic pathway increases plasma glucose but not FFA during rest and exercise, and that this hyperglycemic response is dependent on adrenomedullary secretion.