Rifaximin Prevents T-Lymphocytes and Macrophages Infiltration in Cerebellum and Restores Motor Incoordination in Rats with Mild Liver Damage

In patients with liver cirrhosis, minimal hepatic encephalopathy (MHE) is triggered by a shift in peripheral inflammation, promoting lymphocyte infiltration into the brain. Rifaximin improves neurological function in MHE by normalizing peripheral inflammation. Patients who died with steatohepatitis showed T-lymphocyte infiltration and neuroinflammation in the cerebellum, suggesting that MHE may already occur in these patients. The aims of this work were to assess, in a rat model of mild liver damage similar to steatohepatitis, whether: (1) the rats show impaired motor coordination in the early phases of liver damage; (2) this is associated with changes in the immune system and infiltration of immune cells into the brain; and (3) rifaximin improves motor incoordination, associated with improved peripheral inflammation, reduced infiltration of immune cells and neuroinflammation in the cerebellum, and restoration of the alterations in neurotransmission. Liver damage was induced by carbon tetrachloride (CCl4) injection over four weeks. Peripheral inflammation, immune cell infiltration, neuroinflammation, and neurotransmission in the cerebellum and motor coordination were assessed. Mild liver damage induces neuroinflammation and altered neurotransmission in the cerebellum and motor incoordination. These alterations are associated with increased TNFa, CCL20, and CX3CL1 in plasma and cerebellum, IL-17 and IL-15 in plasma, and CCL2 in cerebellum. This promotes T-lymphocyte and macrophage infiltration in the cerebellum. Early treatment with rifaximin prevents the shift in peripheral inflammation, immune cell infiltration, neuroinflammation, and motor incoordination. This report provides new clues regarding the mechanisms of the beneficial effects of rifaximin, suggesting that early rifaximin treatment could prevent neurological impairment in patients with steatohepatitis.

Pharmacological connection of Histamine-1 (H1) Receptor Mediated Neuroprotective mechanism of Ischemic preconditioning in rat

Cerebral ischemia and ischemia-reperfusion is an essential contributor to acute cerebral stroke. Ischemic preconditioning (IPC) has been proven to provide neuroprotection in ischemia-reperfusion injury in rats, but their mechanism behind neuroprotection in cerebral stroke are still unclear. Central histaminergic pathway has crucial role in the pathogenesis of cerebral stroke, but their neuroprotective role in IPC is still unidentified. This research explores the role of histamine-1 receptor in IPC induced neuroprotection against ischemia-reperfusion induced cerebral injury. Rat were subjected to 17 min of global cerebral ischemia (GCI) by occluding both carotid arteries followed by reperfusion for 24 h, to produce ischemia-reperfusion induced cerebral injury. TTC staining was used to measure cerebral infarct size. Morris water maze test was used to assess memory. Inclined beam-walk, hanging wire, lateral push and rota-rod tests were used to assess degree of motor incoordination. Brain acetylcholinesterase activity, nitrite/nitrate, glutathione, TBARS and MPO levels were also examined. GCI has produced a significant increase in cerebral infarction, brain nitrite/nitrate, MPO, TBARS and AChE activity along with a reduction in glutathione content. Impairment of memory and motor coordination were also noted in GCI induced rat. IPC was employed that consist of 3 preceding episodes of ischemia (1 min) and reperfusion (1 min) both immediately before GCI significantly decreased cerebral infarction, motor incoordination, memory impairment and biochemical impairment. Pretreatment with L-histidine mimicked the neuroprotective effects of IPC. L-histidine induced neuroprotection were significantly abolished by chlorpheniramine, a H1 receptor antagonist. We conclude that neuroprotective effects of IPC, probably occurs through the central histaminergic pathway, and histamine-1 receptor could be a new target behind the neuroprotective mechanism of IPC.

Examining Whether Onfield Motor Incoordination Is Associated With Worse Performance on the SCAT5 and Slower Clinical Recovery Following Concussion

Objective: To examine the relationship between video-identified onfield motor incoordination, the acute assessment of concussion, and recovery time during three seasons of National Rugby League (NRL) play.Methods: Blows to the head (“head impact events”) were recorded by sideline video operators and medical staff. Any player with a suspected concussion underwent a Head Injury Assessment in which he was taken off the field and medically evaluated, including the administration of the Sports Concussion Assessment Tool, 5th Edition (SCAT5). Video footage was later examined to determine the presence or absence of onfield motor incoordination following the head impact event.Results: Motor incoordination was identified in 100/1,706 head impact events (5.9%); 65 of the 100 instances of motor incoordination (65.0%) were ultimately medically diagnosed with a concussion. In 646 athletes for whom SCAT5 data were available, those with motor incoordination were more likely to report both dizziness and balance problems than those without motor incoordination, but there were no group differences on an objective balance test. Additionally, there was no relationship between presence/absence of motor incoordination and number of games missed or time to medical clearance for match play.Conclusion: In NRL players, motor incoordination is a readily observable onfield sign that is strongly associated with a medical diagnosis of concussion and with self-reported dizziness/balance problems. However, onfield motor incoordination is not associated with objective balance performance and it is not predictive of time to recover following concussion.

Natural Poisoning by Xanthium cavanillesii in Cattle in the Southern Region of the State of Rio Grande do Sul

Background: Poisoning by Xanthium spp. plants are important causes of deaths of cattle in the state of Rio Grande do Sul. This plant has as toxic principle a triterpenoide glycoside that acts inhibiting the transport of adenosine diphosphate and adenosine triphosphate across the mitochondrial membrane, responsible for causing acute liver failure. Clinical signs occur within hours of ingesting the plant. However, the knowledge of the metabolic disorders that these animals suffer are poorly described, so the objective of the reports is to describe an outbreak of spontaneous intoxication by Xanthium cavanillesii and demonstrate the clinical, metabolic and anatomopathological changes of a poisoned bovine.Case: An 8-month-old male bovine, Aberdeen Angus breed, was sent to the Veterinary Hospital of Clinics of Federal University of Pelotas (HCV-UFPel). The animal came from a property located in the southern region of Rio Grande do Sul, belonged to a herd of 506 animals, of which 258 were nulliparous cows and 248 calves, in total 92 died, being 20 cows and 62 calves in a period of 3 days. The clinical course ranged from 3 to 72 h and was characterized by neurological signs (pedaling movements, opisthotonus and motor incoordination), sternal decubitus, muscle tremors, apathy, anorexia, hypersalivation, dehydration, tenesmus and death. In the field where the animals were, there was the present of Xanthium cavanillesii in the dicotyledonouns sprouting phase, with signs of ingestion. During the clinical examination of the animal sent to the hospital, sternal decubitus, muscle tremor, motor incoordination, apathy, anorexia, hypersalivation and opisthotone were observed, heart rate of 60 beats per minute, respiratory rate of 15 movements per minute, 2 ruminal movements incomplete at every 2 minutes, moderate dehydration and temperature of 37.9º C. For laboratory exams, blood samples were collected in vacuum tubes with 10% EDTA, to perform blood count with hemoparasite research, and without anticoagulant, to perform serum biochemistry tests, liver and kidney function. Highlighting the increase in liver enzymes (aspartate aminotransferase, gamma glutamyltranferase and alkaline phosphatase), hypoglycemia, elevation of total bilirubin and direct bilirubin, hypoalbuminemia, increase in triglycerides with leukocytosis by neutrophilia with regenerative left shift. Due to advanced clinical condition of the animal, was realized euthanasia for post-mortem examination. At necropsy, the main diagnostic macroscopic lesions were an accentuation of the lobular pattern of the organ parenchyma with the appearance of “nutmeg” and centrilobular coagulative necrosis accompanied by congestion and hemorrhages, characterizing a picture of acute liver failure. In addition, X. cavanillesii fruits were detected in the rumen content.Discussion: The diagnosis was based on epidemiological, clinical-anatomopathological, laboratory data and experimental reproduction of the disease in cattle and sheep. Regarding the epidemiological findings, the presence of the plant with signs of ingestion stands out in addition to the absence of other plants capable of producing similar cases on the farm. The metabolic changes described, if analyzed in isolation, do not confirm the diagnosis, but combined with other parameters, it contributes to the assessment and prognosis of the patient, becoming of great importance in elucidating and conducting the clinical condition.

SCA7 mouse cerebellar pathology reveals preferential downregulation of key Purkinje cell-identity genes and shared disease signature with SCA1 and SCA2.

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination and visual impairment due to progressive cerebellar and retinal degeneration. Alteration of other nervous tissues also contributes to symptoms. The mechanisms underlying motor incoordination of SCA7 remain to be characterized. SCA7 is caused by a polyglutamine (polyQ) expansion in ATXN7, a member of the transcriptional coactivator SAGA complex, which harbors histone modification activities. PolyQ expansion in other proteins is responsible for 5 other SCAs (SCA1-3, 6 and 17). However, the converging and diverging pathophysiological points remain poorly understood. Using a new SCA7 knock-in model carrying 140 glutamines in ATXN7, we analyzed cell-type specific gene expression in the cerebellum. We show that gene deregulation affects all cerebellar cell types, although at variable degree, and correlates with alterations of SAGA-dependent epigenetic marks histone H3 acetylation and H2B ubiquitination. Our results further show that Purkinje cells (PCs) are far the most affected neurons: unlike other cerebellar cell types, PCs show reduced expression of 83 cell-type identity genes, critical for their spontaneous firing activity and synaptic functions. PC gene downregulation precedes morphological alterations, pacemaker dysfunction and motor incoordination. Strikingly, most PC identity genes downregulated in SCA7 mice are also decreased in early symptomatic SCA1 and SCA2 mice, revealing a common signature of early PC pathology involving cGMP-PKG and phosphatidylinositol signaling pathways and long-term depression. Our study thus points out molecular targets for therapeutic development which may prove beneficial for several SCAs. Finally, we show that unlike previous SCA7 mouse models, SCA7140Q/5Q mice exhibit the major disease features observed in patients, including cerebellar damage, cerebral atrophy, peripheral nerves pathology and photoreceptor dystrophy, which account for progressive impairment of behavior, motor and vision functions. Therefore, SCA7140Q/5Q mice represent an accurate model for the investigation of different aspects of SCA7 pathogenesis.

Extracellular Vesicles from Hyperammonemic Rats Induce Neuroinflammation and Motor Incoordination in Control Rats

Minimal hepatic encephalopathy is associated with changes in the peripheral immune system which are transferred to the brain, leading to neuroinflammation and thus to cognitive and motor impairment. Mechanisms by which changes in the immune system induce cerebral alterations remain unclear. Extracellular vesicles (EVs) seem to play a role in this process in certain pathologies. The aim of this work was to assess whether EVs play a role in the induction of neuroinflammation in cerebellum and motor incoordination by chronic hyperammonemia. We characterized the differences in protein cargo of EVs from plasma of hyperammonemic and control rats by proteomics and Western blot. We assessed whether injection of EVs from hyperammonemic to normal rats induces changes in neuroinflammation in cerebellum and motor incoordination similar to those exhibited by hyperammonemic rats. We found that hyperammonemia increases EVs amount and alters their protein cargo. Differentially expressed proteins are mainly associated with immune system processes. Injected EVs enter Purkinje neurons and microglia. Injection of EVs from hyperammonemic, but not from control rats, induces motor incoordination, which is mediated by neuroinflammation, microglia and astrocytes activation and increased IL-1β, TNFα, its receptor TNFR1, NF-κB in microglia, glutaminase I, and GAT3 in cerebellum. Plasma EVs from hyperammonemic rats carry molecules necessary and sufficient to trigger neuroinflammation in cerebellum and the mechanisms leading to motor incoordination.