Administration Of Pentoxifylline Research Articles

1195 Influence Of Procalcitonin (PCT) Levels on the Direction of the Therapy of Perinatal Infections

Background and AimsOne the main causes of perinatal mortality is infection. PCT measurement is regularly performed in our clinical practice. Along with the clinical condition, PCT level is an important...

Effect of Pentoxifylline on Ischemia- induced Brain Damage and Spatial Memory Impairment in Rat.

The brief interruption of cerebral blood flow causes permanent brain damage and behavioral dysfunction. The hippocampus is highly vulnerable to ischemic insults, particularly the CA1 pyramidal cell layer. There is no effective pharmacological strategy for improving brain tissue damage induced by cerebral ischemia. Previous studies reported that pentoxifylline (PTX) has a neuroprotective effect on brain trauma. The possible neuroprotector effects of PTX on behavioral deficit were studied in male Wistar rats subjected to a model of transient global brain ischemia. Animals (n= 32) were assigned to control, sham-operated, vehicle, and PTX- treated (200 mg/kg IP) groups. PTX administered at 1hr before and 3 hr after ischemia. Global cerebral ischemia was induced by bilateral common carotid artery occlusion, followed by reperfusion. Morris Water maze testing revealed that PTX administration in cerebral ischemia significantly improved hippocampal-dependent memory and cognitive spatial abilities after reperfusion as compared to sham-operated and vehicle-treated animals. After the behavioral test, the rats were sacrificed and brain sections were stained with Nissl staining. There were no significant differences between number of pyramidal cells in both control and PTX groups. Our study demonstrated that pentoxifylline had a protective effect on rats with transient global ischemia and could reduce cognitive impairment.

Evaluation of nephrotoxic effects of mycotoxins, citrinin and patulin, on zebrafish (Danio rerio) embryos

Citrinin (CTN) and patulin (PAT) are fungal secondary metabolites which are found in food and feed and showed organotoxicity in mature animals. In this study zebrafish embryos were applied to investigate the developmental toxicity of CTN and PAT on embryonic kidney. In the presence of CTN and PAT, the gross morphology of kidneys from embryos with green fluorescent kidney (wt1b:GFP) was not apparently altered. Histological analysis of CTN-treated embryos indicated cystic glomerular and tubular lesions; a disorganized arrangement of renal cells was also found in the PAT-treated group. From the view point of renal function, dextran clearance abilities of embryos exposed to CTN and PAT were significantly reduced. The damaged renal function caused by CTN could be partially rescued by the administration of pentoxifylline, suggesting the reduction of glomerular blood flow contributes to CTN-induced renal dysfunction. Additionally, CTN induced the expression of proinflammation genes, including COX2a, TNF-α and IL-1β, but failed to modify the levels and distribution of wt1a transcript and Na+/K+-ATPase protein. In summary, CTN and PAT caused profound nephrotoxicity in histological structure and biological function of zebrafish embryos; the inflammatory pathway and blood rheology may involve in CTN-induced renal impairment.

Is there a therapeutic window for pentoxifylline after the onset of acute pancreatitis?

To investigate the effects of pentoxifylline (PTX) in experimental acute pancreatitis (AP) starting drug administration after the induction of the disease. One hundred male Wistar rats were submitted to taurocholate-induced AP and divided into three groups: Group Sham: sham-operated rats, Group Saline: AP plus saline solution, and Group PTX: AP plus PTX. Saline solution and PTX were administered 1 hour after induction of AP. At 3 hours after AP induction, peritoneal levels of tumor necrosis factor (TNF)-α, and serum levels of interleukin (IL)-6 and IL-10 levels were assayed by Enzyme-Linked Immunosorbent Assay (ELISA). Determinations of lung myeloperoxidase activity (MPO), histological analysis of lung and pancreas, and mortality study were performed. PTX administration 1 hour after induction of AP caused a significant decrease in peritoneal levels of TNF-α and in serum levels of IL-6 and IL-10 when compared to the saline group. There were no differences in lung MPO activity between the two groups with AP. A decrease in mortality was observed in the PTX treatment compared to the saline group. Administration of PTX after the onset of AP decreased the systemic levels of proinflammatory cytokines, raising the possibility that there is an early therapeutic window for PTX after the initiation of AP.

Mo1880 Effects of Intravenous Administration of Pentoxifylline in Pancreatic Ischemia/Reperfusion Injury

Mo1880 Effects of Intravenous Administration of Pentoxifylline in Pancreatic Ischemia/Reperfusion Injury

Current applications of oogram methodology in experimental schistosomiasis; fecundity of femaleSchistosoma mansoniand egg release in the intestine of AKR/J mice following immunomodulatory treatment with pentoxifylline

Oogram methodology permitted a direct assessment of the fecundity of Schistosoma mansoni and the passage of parasite eggs from mesenteric vessels into the intestinal lumen in AKR/J mice that had been infected via the intraperitoneal route with 60 cercariae of the trematode and later subjected to short-term subcutaneous treatments with pentoxifylline (PTX). The administration of PTX did not change oviposition kinetics, the individual fecundity of female parasites (as determined by the study of the ratio of second-stage S. mansoni eggs per g intestine/number of female parasites recovered from the portal system), nor the number of mature and dead eggs retained in the host tissue, though the drug has known immunomodulatory effects, as shown previously in experimental schistosomiasis. A better appraisal was also carried out, including the study of statistical parameters, concerning the utilization of the ratios of each stage of immature eggs (first to fourth) per g intestine/number of female worms from the portal system. The second-stage eggs had the lowest variability, confirming that the utilization of this stage as an indicator of the individual fecundity of parasite females is indeed viable. In the light of our findings, current uses of oogram methodology are discussed. Moreover, additional consideration is given to data obtained in the present study concerning intraperitoneal infection with S. mansoni cercariae in both untreated and treated mice of the AKR/J strain, such as the recovery of mature worms, eggs and free granulomas from the peritoneal cavity of these rodents.

Effect of pentoxifylline and 5-fluorouracil/triamcinolone on laryngotracheal stenosis developing as a complication of tracheostomy: study in rats

We aimed to investigate the prophylactic effect of pentoxifylline (PTX) and 5-fluorouracil (5-FU) on laryngotracheal stenosis in tracheotomised rats by evaluating blood glutathione peroxidase (GPx) and superoxide dismutase activities and by histopathological evaluation of laryngotracheal segment. Randomized prospective single-blind study. Standard vertical tracheotomy was performed on 24 rats. Then, the animals were randomly divided into three groups. Intraperitoneal PTX administered to group A (study group) for 10 days. 5-FU was injected in paratracheal tissues in group B (study group) for 10 days. In group C (control group), intraperitoneal saline was administered for 10 days. After 10 days, tracheal cannules were removed. For biochemical analysis, two blood samples were obtained. Three weeks later, all animals were euthanized and trachea specimens were harvested. Stenosis index and mean wall thickness in PTX group were lower as compared to other groups but the difference was statistically insignificant. Minimum inflammation and fibrosis plus maximum epithelial regeneration were seen in PTX group. In addition, GPx activity was at highest level in PTX group and a statistically significant difference was found between control and PTX groups (P = 0.024) though the difference between remaining groups was statistically insignificant (P = 0.121). Superoxide dismutase activity was highest in PTX group but no statistically significant difference was found between the three groups (P = 0.305). The administration of PTX increases GPx activity and it may have some effect on tracheal scar formation which develops following tracheostomy.

Effects of the administration of pentoxifylline and prednisolone on the evolution of portal fibrogenesis secondary to biliary obstruction in growing animals: immunohistochemical analysis of the expression of TGF- β and VEGF

OBJECTIVE:During the neonatal and infancy periods, some chronic liver diseases may lead to progressive hepatic fibrosis, which is a condition that can ultimately result in the loss of organ function and severe portal hypertension necessitating hepatic transplantation. In a previous report, pharmacological interventions were demonstrated to modulate hepatic fibrosis induced by bile duct ligation in young rats. The administration of pentoxifylline or prednisolone, or the combination of both, resulted in reduced fibrogenesis in portal spaces. The objectives of the present study were to evaluate the expression of transforming growth factor β and vascular endothelial growth factor after bile duct ligation in young rats and to assess the effect of those same drugs on cytokine expression.METHODS:In this experimental study, 80 young rats (21 or 22 days old) were submitted either to laparotomy and common bile duct ligation or to sham surgery. The animals were allocated into four groups according to surgical procedure, and the following treatments were administered: (1) common bile duct ligation + distilled water, (2) sham surgery + distilled water, (3) common bile duct ligation + pentoxifylline, or (4) common bile duct ligation + prednisolone. After 30 days, a hepatic fragment was collected from each animal for immunohistochemical analysis using monoclonal antibodies against transforming growth factor β and vascular endothelial growth factor. Digital morphometric and statistical analyses were performed.RESULTS:The administration of pentoxifylline reduced the transforming growth factor β-marked area and the amount of transforming growth factor β expressed in liver tissue. This effect was not observed after the administration of prednisolone. There was a significant reduction in vascular endothelial growth factor expression after the administration of either drug compared with the non-treatment group.CONCLUSIONS:The administration of pentoxifylline to cholestatic young rats resulted in the diminished expression of transforming growth factor β and vascular endothelial growth factor in liver tissue. The administration of steroids resulted in the diminished expression of vascular endothelial growth factor only. These pathways may be involved in hepatic fibrogenesis in young rats submitted to bile duct ligation and exposed to pentoxifylline or prednisolone.

Effect of Phosphodiesterase Inhibitor on Diabetic Nephropathy

Effect of Phosphodiesterase Inhibitor on Diabetic Nephropathy

Evaluating the effects of pentoxifylline administration on experimental pressure sores in rats by biomechanical examinations

This study used a biomechanical test to evaluate the effects of pentoxifylline administration on the wound healing process of an experimental pressure sore induced in rats. Under general anesthesia and sterile conditions, experimental pressure sores generated by no. 25 Halsted mosquito forceps were inflicted on 12 adult male rats. Pentoxifylline was injected intraperitoneally at a dose of 50 mg/kg daily from the day the pressure sore was generated, for a period of 20 days. At the end of 20 days, rats were sacrificed and skin samples extracted. Samples were biomechanically examined by a material testing instrument for maximum stress (N mm2), work up to maximum force (N), and elastic stiffness (N/mm). In the experimental group, maximum stress (2.05±0.15) and work up to maximum force (N/mm) (63.75±4.97) were significantly higher than the control group (1.3±0.27 and 43.3±14.96, P=0.002 and P=0.035, respectively). Pentoxifylline administration significantly accelerated the wound healing process in experimental rats with pressure sores, compared to that of the control group.

Health status of sarcoidosis patients in baseline and in 10 years under different treatment strategies (multicenter analysis)

Summary. A multicenter (12 centers) retrospective analysis of health status of 83 sarcoidosis patients in time of diagnosis and after 10 years of treatment has been performed. In 10 years after diagnosis, 47 % of the patients had complete remission of pulmonary manifestations; mean forced spirometric values have not reduced in 10 years (excluding patients initially treated with anti-TB drugs). Patients treated with systemic steroids initially or during 10 yrs were less likely to have the complete remission (36.5 %) and more likely to have recurrent sarcoidosis course (57.1 %) compared to those not treated with systemic steroids. Pentoxifylline administration positively influenced the remission rate (71.4 %) and relapse rate in patients who had not received immunosuppressive therapy (28.6 %). A tendency has been found to positive effects of essential phospholipids on relapse rate and remission rate in sarcoidosis. Anti-TB therapy or treatment of sarcoidosis patients in TB centers negatively influenced the outcome of sarcoidosis. The results disclose an urgent need to imply new approaches to treatment of sarcoidosis, eg. anti-TNF-α drugs.

Pretreatment with pentoxifylline has antidepressant-like effects in a rat model of acute myocardial infarction

We have observed that, after myocardial infarction (MI), rats display apoptosis in the limbic system that can be prevented by pentoxifylline (PTX), a proinflammatory cytokine inhibitor. We have hypothesized that reduction of apoptosis in the limbic system can attenuate the depressive behaviour occurring post-MI. The present study was, therefore, designed to assess the outcome of PTX on depressive behaviour manifesting after MI. Myocardial ischaemia, induced for 40 min in male Sprague-Dawley rats, was followed by reperfusion (MI groups). Sham groups were subjected to the same protocol without occlusion. PTX (10 mg/kg/day) or saline was administered intraperitoneally 15 min before ischaemia, and then every day until sacrifice. Two weeks after ischaemia, depression was evaluated by the forced swim test and the sucrose preference test. At the end of the experiment, the animals were sacrificed, and myocardial infarct size was examined along with plasma IL-1β concentrations. MI rats drank less sucrose in the sucrose preference test and were more immobile in the forced swim test than the sham controls. PTX reversed these behaviours in the MI group to a level similar to that in the untreated sham group, without affecting infarct size. PTX reduced plasma IL-1β concentrations in both sham and MI rats. We conclude that PTX administration significantly reverses the depressive-like behaviour seen after MI in rats.

Abstract 9673: Mesenchymal Stem Cells Modulate Inflammatory Responses in Murine Heart by Inhibition of the TNF System

Mesenchymal stem cells have been used to treat numerous different clinical conditions, although the mechanisms by which pathogenetic processes are affected are still poorly understood. We have recently demonstrated the homing of murine long-term renewing adult bone marrow-derived multipotent mesenchymal stem cells (BM-MASCs) to diseased tissues and postulated that BM-MASCs might modulate inflammatory reactions. We here show that administration of BM-MASCs modulates adverse cardiac remodeling inhibiting the TNF system in a transgenic mouse model of cardiac-specific expression of MCP-1-induced inflammatory dilative cardiomyopathy. Four-months old MCP-1 mice were analyzed before and after 4-week administration of MASCs, Etanercept (Amgen), Pentoxifylline (Sanofi-Aventis), or NaCl (sham). MRI, Histological (Masson's thricromic), immunofluorescent (CD45 and Collagen VI antibodies, and Lectin from Bandeiraera Simplicifolia), Western blot (sTNFR-I, TNF-β, Phosphorylated-nuclear factor k (NFkBp65), and Collagen VI), SILAC-base mass spectrometry, cytokine arrays, Mission shRNA system (NM_011609.2-1538s1c1, NM_011609.2-996s1c1, and NM_011609.2-1652s1c1), and survival analysis were performed. Our results show that administration of BM-MASCs to MCP-1 mice significantly reduced cardiac accumulation of infiltrating cells and fibrosis, improved capillary density and function, and extended lifespan. Comprehensive analysis of the secretome of MASCs unveiled the release of soluble tumor necrosis factor receptor I (sTNFR-I), which significantly suppressed activation of the NFκBp65 signaling pathway in MCP-1 hearts in vivo. Administration of TNFRI-knock-down BM-MASCs yielded no positive effects demonstrating the requirement of sTNFR-I for BM-MASCs-mediated improvement of inflammatory dilative cardiomyopathy. Substitution of BM-MASCs by recombinant soluble TNFR recapitulated several effects of BM-MASCs including lifespan expansion. We conclude that BM-MASCs suppress local inflammatory processes by release of numerous signaling molecules including sTNFR-I, which makes them useful tools for various clinical applications.

Effect of Pentoxifylline, administered in Preterm Labour, on the Foetal–Placental Circulation and Neonatal Outcome: A Randomized, Prospective Pilot Study

The aim of the study was to evaluate the pentoxifylline administration on the foetal-placental circulation and neonatal outcome in women with threatened preterm labour. Pentoxifylline was given as a supplement to standard tocolytic therapy in a group of 43 patients (pentoxifylline group) as an intravenous infusion and oral supplementation in a total dosage of 800 mg/day. The drug was administered within 3 weeks after admission. No pentoxifylline was given in the control group (53 patients). Doppler velocimetry of pulsatility indices (PI) of the umbilical (UA) and middle cerebral (MCA) arteries as well as cerebro-placental ratio (CPR) were calculated. Also, the neonatal outcome was estimated in both groups. From the second week of therapy with pentoxifylline, the PI decreased in umbilical artery and increased in the MCA, whereas in the control group, there were no changes. The value of PIUA, evaluated after the third week of pentoxifylline administration, was statistically significantly lower when compared to data obtained on admission (mean: 0.99 ± 0.22 versus 0.82 ± 0.12; p =0.016). Pentoxifylline significantly increased CPR values calculated after third week of drug administration, which were statistically significantly higher in the pentoxifylline group when compared with respective data in the control group (mean: 2.30 versus 1.61; p = 0.001). The risk of severe neonatal complications was significantly lower in the pentoxifylline group (p = 0.026). Pentoxifylline changed foetal-placental blood circulation in patients with threatened preterm labour and improved neonatal outcome.

Pentoxifylline decreases soluble CD40 ligand concentration and CD40 gene expression in coronary artery disease patients

Context and objective: Increased level of inflammatory mediators plays a central role in the features of coronary artery diseases (CAD). As pentoxifylline could suppress the inflammatory process and has shown some promising beneficial effects in inflammatory diseases, we evaluated the effect of 2 months pentoxifylline administration in patients with CAD. Materials and methods: A randomized placebo-controlled double-blind study design was used. Forty CAD patients (32 males and 8 females) were randomized into either 2 months of pentoxifylline treatment (1200 mg/day) (n = 20) or placebo treatment (n = 20). Blood samples were obtained before and after treatment. Gene expression analysis for mRNA of CD40, p65 and IκBα in peripheral blood mononuclear cells (PBMCs) were performed using real-time reverse-transcription polymerase chain reaction (RT-PCR). Plasma concentration of soluble CD40 (sCD40) ligand as well as protein concentration of p50 were measured by ELISA method. Results: Pentoxifylline decreased CD40 mRNA by 45% (p < 0.05) in PBMCs and sCD40 ligand level in plasma of CAD patients by 34% (p < 0.01). Discussion and conclusion: Pentoxifylline treatment can suppress the CD40/CD40 ligand system activation in CAD patients. As this system has a role in plaque progression and plaque rupture, pentoxifylline could be a good choice for future studies in preventing cardiovascular events.

Uterine artery blood flow remains unchanged in pregnant mares in response to short-term administration of pentoxifylline

The objective of this study was to use Doppler ultrasound technology to determine whether pentoxifylline administration increased uterine blood flow in normal pregnant pony mares. Thirteen pregnant pony mares between 18 and 190 d of gestation (mean ± SEM, 101 ± 55) were utilized for the study during two trial periods. In each trial, pentoxifylline (17 mg/kg by mouth every 12h, diluted in syrup) was administered to half of the mares for 3 d, while the other mares were treated with syrup only. Doppler measurements were obtained from the right and left uterine arteries from each mare for 2 d prior to treatment and throughout the treatment period. The mean Resistivity Index (RI), Pulsatility Index (PI), Uterine Artery Diameter (D), and Total Arterial Blood Flow (TABF) from each day were compared over time and between groups. Administration of pentoxifylline did not alter uterine blood flow parameters compared with controls (values for all treatment days combined were RI: 0.517 ± 0.014 vs 0.543 ± 0.016; PI: 0.876 ± 0.048 vs 0.927 ± 0.057; D: 0.388 ± 0.018 vs 0.379 ± 0.023 cm; and TABF: 35.26 ± 7.38 vs 30.73 ± 5.29 mL/min). Uterine blood flow increased over the course of the 5 d study, irrespective of treatment, and was higher in mares of greater gestational age than in early gestational mares (RI: r 2 = 0.35; PI: r 2 = 0.37; D: r 2 = 0.66; and TABF: r 2 = 0.67 – P < 0.00001). We concluded that any immediate benefits of pentoxifylline administration in the pregnant mare were not mediated through enhanced uterine artery blood flow.

Effects of pentoxifylline and H-89 on epileptogenic activity of bucladesine in pentylenetetrazol-treated mice

The present study shows interactive effects of pentoxifylline (PTX) as a phosphodiesterase (PDE) inhibitor, H-89 as a protein kinase A (PKA) inhibitor and bucladesine (db-cAMP) as a cAMP agonist on pentylenetetrazol (PTZ)-induced seizure in mice. Different doses of pentoxifylline (25, 50, 100 mg/kg), bucladesine (50, 100, 300 nM/mouse), and H-89 (0.05, 0.1, 0.2 mg/100g) were administered intraperitoneally (i.p.), 30 min before intravenous (i.v.) infusion of PTZ (0.5% w/v). In combination groups, the first and second components were injected 45 and 30 min before PTZ infusion. In all groups, the control animals received an appropriate volume of vehicle. Single administration of PTX had no significant effect on both seizure latency and threshold. Bucladesine significantly decreased seizure latency and threshold only at a high concentration (300 nM/mouse). Intraperitoneal administration of H-89 (0.2 mg/100g) significantly increased seizure latency and threshold in PTZ-treated animals. All applied doses of bucladesine in combination with PTX (50 mg/kg) caused a significant reduction in seizure latency. Pretreatment of animals with PTX (50 and 100 mg/kg) attenuated the anticonvulsant effect of H-89 (0.2 mg/100g) in PTZ-exposed animals. H-89 (0.05, 0.2 mg/100g) prevented the epileptogenic activity of bucladesine (300 nM) with significant increase of seizure latency and seizure threshold. In conclusion, we showed that seizure activities were affected by pentoxifylline, H-89 and bucladesine via interactions with intracellular cAMP and cGMP signaling pathways, cyclic nucleotide-dependent protein kinases, and related neurotransmitters.

MP-07.05 Effect of Pentoxifylline on Semen Parameters, Reproductive Hormones and Seminal Plasma Antioxidant Capacity in Men with Idiopathic Infertility: A Randomized Double-Blind Placebo-Controlled Study

Objective To determine the safety and efficacy of oral pentoxifylline (PTX) administration in improving semen parameters in infertile men with idiopathic OAT.

Pentoxifylline administration changes protein expression profile of coronary artery disease patients

Increased level of inflammatory mediators plays a central role in the features of coronary artery diseases. As pentoxifylline could suppress the inflammatory process and has shown some promising beneficial effects in inflammatory diseases, we evaluated the effect of two months pentoxifylline administration in proteome of PBMCs of patients with coronary artery disease (CAD). A randomized placebo-controlled study was used. Fourteen CAD patients were randomized to 2 months of pentoxifyline treatment (1200 mg/day) (n = 7) or placebo treatment (n = 7). Blood samples were obtained before and after treatment. A comparative 2 dimensional gel electrophoresis was performed, and gels were silver-stained. Differentially expressed protein spots were detected and were identified by MALDI-TOF spectrometry. Six differentially expressed proteins were identified as HSP70, PPIA and α-Enolase, (all up-regulated) S100-A9, PIMT and β-5 tubulin (all down-regulated), most of which had previously been shown to play a potential role in the pathogenesis of atherosclerosis. As the blood mononuclear cell proteome responds to pentoxifylline with changes in a number of atherosclerosis-relevant proteins, it seems that pentoxifylline could be a good choice for future studies for prevention of cardiovascular events.

Effect of pentoxiflline on the spinal cord glial cells activation in a rat model of postoperative pain

Objective To investigate the effect of intraperitoneal administration of pentoxifylline on the development of hyperalgesia and the activation of glial cells in a rat model of postoperative pain. Methods Sixty male SD rats weight 190 g-220 g were randomly divided into 2 groups: control group (NS group) and treatment group (PTX group), in which 50 mg/kg saline vehicle or pentoxifylline (n=30) was given intraperitoneally 15 min before surgery and continued once a day to the 5th day after the operation, respectively.The animal model of postoperative pain was established by incision hind paw. Cumulative pain score and paw withdrawal threshold were measured at 1 d before operation and then at 1, 2, 3, and 5 h and 1, 2, 3, and 5 d after operation.Spinal cord tissue samples from rats were taken for analysis of glial fibrillary acid protein (GFAP) and ionized calcium bindingadaptor molecule-1 (Iba-1) expression by means of immunohistochemistry at the following times after operation: 1, 2, 3, and 0.8, 6.6±0.5, 8.6±0.7, 10.2±0.4, 7.0±0.6 and 5.6±0.5 in the PTX group respectively, less than the NS group with 4.0±0.6, 6.0±and 3 d, the PWT were (5.8±1.6), (5.2±1.1), (4.4±0.6), (4.9±0.4), (5.2±1.1), (7.6±1.8) and (10.4±1.6) g in the PTX group respectively, more than the NS group with (2.4 ±0.8), (2.1±0.5), (2.0±0.5), (2.1±0.3), (2.3±0.5), (4.5±0.9)and(8.1±1.4) g 205.6±4.2 and 230.2±3.2 in the PTX group respectively, lower than the NS group with 244.1±4.9, 258.6±4.12 and 276.2±3.4 (P＜the PTX group respectively, lower than the NS group with 230±3 and 205±4 (P＜0.05). Conclusion Pentoxifylline can attenuate the process of mechanical allodynia in a rat model of postoperative pain, its main mechanism may be related to the inhibition of glial cells activation in the spinal cord. Key words: Pentoxifylline; Postoperative pain; Astrocyte; Microglia