scholarly journals Dabigatran ameliorates post-haemorrhagic hydrocephalus development after germinal matrix haemorrhage in neonatal rat pups

2016 ◽  
Vol 37 (9) ◽  
pp. 3135-3149 ◽  
Author(s):  
Damon Klebe ◽  
Jerry J Flores ◽  
Devin W McBride ◽  
Paul R Krafft ◽  
William B Rolland ◽  
...  
Keyword(s):  
Water Maze ◽  
Matrix Proteins ◽  
Neonatal Rat ◽  
Therapeutic Effects ◽  
Short Term ◽  
Nissl Staining ◽  
Germinal Matrix ◽  
Thrombin Inhibition ◽  
Rat Pups

We aim to determine if direct thrombin inhibition by dabigatran will improve long-term brain morphological and neurofunctional outcomes and if potential therapeutic effects are dependent upon reduced PAR-1 stimulation and consequent mTOR activation. Germinal matrix haemorrhage was induced by stereotaxically injecting 0.3 U type VII-S collagenase into the germinal matrix of P7 rat pups. Animals were divided into five groups: sham, vehicle (5% DMSO), dabigatran intraperitoneal, dabigatran intraperitoneal + TFLLR-NH2 (PAR-1 agonist) intranasal, SCH79797 (PAR-1 antagonist) intraperitoneal, and dabigatran intranasal. Neurofunctional outcomes were determined by Morris water maze, rotarod, and foot fault evaluations at three weeks. Brain morphological outcomes were determined by histological Nissl staining at four weeks. Expression levels of p-mTOR/p-p70s6k at three days and vitronectin/fibronectin at 28 days were quantified. Intranasal and intraperitoneal dabigatran promoted long-term neurofunctional recovery, improved brain morphological outcomes, and reduced intracranial pressure at four weeks after GMH. PAR-1 stimulation tended to reverse dabigatran's effects on post-haemorrhagic hydrocephalus development. Dabigatran also reduced expression of short-term p-mTOR and long-term extracellular matrix proteins, which tended to be reversed by PAR-1 agonist co-administration. PAR-1 inhibition alone, however, did not achieve the same therapeutic effects as dabigatran administration.

scholarly journals NT-4 attenuates neuroinflammation via TrkB/PI3K/FoxO1 pathway after germinal matrix hemorrhage in neonatal rats

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Tianyi Wang ◽  
Junyi Zhang ◽  
Peng Li ◽  
Yan Ding ◽  
Jiping Tang ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Factors ◽  
Neonatal Rats ◽  
Short Term ◽  
Germinal Matrix ◽  
Expression Levels ◽  
Germinal Matrix Hemorrhage ◽  
Rat Pups ◽  
Pro Inflammatory Cytokines

Abstract Background Neuroinflammation plays an important role in pathogenesis of germinal matrix hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family and interacts with the tropomyosin receptor kinase B (TrkB). NT-4 has been shown to confer neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4-TrkB signaling, as well as its downstream signaling cascade phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/forkhead box protein O1 (FoxO1), following GMH in neonatal rats. Methods GMH was induced by intraparenchymal injection of bacterial collagenase (0.3 U) in P7 rat pups. A total of 163 pups were used in this study. Recombinant human NT-4 was administered intranasally at 1 h after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002, and FoxO1 activating CRISPR were administered intracerebroventricularly at 24 h prior to NT-4 treatment to investigate the underlying mechanism. Short-term and long-term neurobehavioral assessments, immunofluorescence staining, Nissl’s staining, and Western blot were performed. Results Expression of phosphorylated TrkB increased after GMH, reaching the peak level at day 3 after hemorrhage. TrkB receptors were observed on neurons, microglia, and astrocytes. The administration of rh-NT-4 induced phosphorylation of TrkB, expression of PI3K, and phosphorylation of Akt. Meanwhile, it decreased FoxO1 and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. FoxO1 activating CRISPR increased the expression of IL-6, suggesting that FoxO1 might be a potential inducer of pro-inflammatory factors. These results suggested that PI3K/Akt/FoxO1 signaling may be the downstream pathway of activation of TrkB. The rat pups treated with rh-NT-4 performed better than vehicle-treated animals in both short-term and long-term behavioral tests. Conclusion These data showed that rh-NT-4 reduced the expression levels of pro-inflammatory cytokines, improved neurological function, attenuated neuroinflammation, and thereby mitigated post-hemorrhagic hydrocephalus after GMH by TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic strategy to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

scholarly journals THALIDOMIDE FOR PATIENTS WITH THALASSEMIA INTERMEDIA: A RETROSPECTIVE MULTICENTER CLINICAL STUDY

2020 ◽  
Vol 12 (1) ◽  
pp. e2020021
Author(s):  
Kun Yang ◽  
Yi Wu ◽  
Yali Zhou ◽  
Tianhong Zhou ◽  
Li Wang ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Laboratory Data ◽  
Drug Discontinuation ◽  
Therapeutic Effects ◽  
Efficacy And Safety ◽  
Thalassemia Intermedia ◽  
Short Term ◽  
Long Term Follow Up

Objective: This study focused on the efficacy and safety of thalidomide for patients with thalassemia intermedia (TI) in a multicenter trial. Methods：Clinical and laboratory data of 62 patients subjected to thalidomide therapy in four centers were retrospectively analyzed. We evaluated the efficacy and safety of thalidomide in the short-term (three months) and long-term follow-up (12 and 24 months). Response to thalidomide was defined as follows: Main Responder (MaR) showing an increase in Hb level of >2.0 g/dl or removal from blood transfusion and Minor Responder (MiR) achieving elevated hemoglobin (Hb) level of 1.0-2.0 g/dl or ≥50% reduction in blood transfusion frequency. Results：The overall response rate (ORR) of 62 patients with TI was 93.5% (58/62), with MaR and MiR rates accounting for 62.9% (39/62) and 30.6% (19/62) in short-term follow-up and 66.1% (41/62) and 27.4% (17/62) in long-term follow-up, respectively. The clinical response during long-term follow-up was maintained and the Hb level remained stable during the observation period. The response was still observed in patients with dose reduction despite a slight decrease in Hb level. However, Hb decreased rapidly to the baseline level after drug discontinuation. No effect of thalidomide on spleen size in nonsplenectomized patients was evident. Minimal side-effects were documented throughout, except peripheral neurotoxicity in one patient. Nevertheless, the mean serum ferritin (SF) level was significantly increased after treatment. Conclusion: Thalidomide had significant therapeutic effects on patients with TI, and the response was sustained with acceptable short-term and long-term adverse reactions. While these preliminary results support the potential long-term efficacy and safety of thalidomide as a therapeutic agent for TI, several issues need to be addressed before its application in the clinic.

scholarly journals Long-Term Treatment with Aqueous Garlic and/or Tomato Suspensions Decreases Ehrlich Ascites Tumors

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Jenifer Bom ◽  
Patrícia Gunutzmann ◽  
Elizabeth C. Pérez Hurtado ◽  
Jussara M. R. Maragno-Correa ◽  
Silvia Regina Kleeb ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Term Treatment ◽  
Therapeutic Effects ◽  
Short Term ◽  
Volume Number ◽  
Aqueous Suspensions ◽  
Ehrlich Ascites ◽  
Long Term Treatment ◽  
Ascites Tumors

We evaluated the preventive and therapeutic effects of aqueous suspensions of garlic, tomato, and garlic + tomato in the development of experimental Ehrlich tumors in mice. The aqueous suspensions (2%) were administered over a short term for 30 days before tumor inoculation and 12 days afterward, and suspensions at 6% were administered for 180 days before inoculation and for 12 days afterward. The volume, number, and characteristics of the tumor cells and AgNOR counts were determined to compare the different treatments. Aqueous 6% suspensions of garlic, tomato, and garlic + tomato given over the long term significantly reduced tumor growth but when given over the short term, they did not alter tumor growth.

scholarly journals Activation of GPR39 With TC-G 1008 Attenuates Neuroinflammation Via SIRT1/PGC-1α/Nrf2 Pathway Post Neonatal Hypoxic-ischemic Injury in Rats

2021 ◽  
Author(s):  
Shucai Xie ◽  
Xili Jiang ◽  
Desislava Met Doycheva ◽  
Hui Shi ◽  
Peng Jin ◽  
...  
Keyword(s):  
G Protein ◽  
Sirtuin 1 ◽  
Neonatal Rat ◽  
Neurological Deficits ◽  
Dependent Manner ◽  
G Protein Coupled Receptor ◽  
Short Term ◽  
Nrf2 Pathway ◽  
G Protein Coupled

Abstract Background: Hypoxic-ischemic encephalopathy (HIE) is a severe anoxic brain injury that leads to premature mortality or long-term disabilities in infants. Neuroinflammation is a vital contributor to the pathogenic cascade post HIE and a mediator to secondary neuronal death. As a plasma membrane G-protein coupled receptor, GPR39, exhibits anti-inflammatory activity in several diseases. This study aimed to explore the neuroprotective function of GPR39 through inhibition of inflammation post hypoxic-ischemic (HI) injury and to elaborate the contribution of sirtuin 1(SIRT1)/ peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α)/ nuclear factor, erythroid 2 like 2(Nrf2) in G protein-coupled receptor 39 (GPR39)-mediated protection.Methods: A total of 206 10-day old Sprague Dawley rat pups were subjected to HIE or sham surgery. TC-G 1008 was administered intranasally at 1h, 25h, 49h, and 73h post HIE induction. SIRT1 inhibitor EX527, GPR39 CRISPR, and PGC-1α CRISPR were administered to elucidate the underlying mechanisms. Brain infarct area, short-term and long-term neurobehavioral tests, Nissl staining, western blot, and immunofluorescence staining were performed post HIE.Results: The expression of GPR39 and pathway-related proteins, SIRT1、PGC-1α and Nrf2 were increased in a time-dependent manner, peaking at 24 h or 48h post HIE. Intranasal administration of TC-G 1008 reduced the percent infarcted area and improved short-term and long-term neurological deficits. Moreover, TC-G 1008 treatment significantly increased the expression of SIRT1, PGC-1α, Nrf2, IL-6, IL-1β, and TNF-α. GPR39 CRISPR EX527 and PGC-1α CRISPR abolished GPR39’s neuroprotective effects post HIE.Conclusions:TC-G 1008 attenuated neuroinflammation in part via the SIRT1/PGC-1α/Nrf2 pathway in a neonatal rat model of HIE. TC-G 1008 may be a novel therapeutic target for treatment post neonatal HIE injury.

scholarly journals The Effects of Exposure to Repeated Minor Pain During the Neonatal Period on Formalin Pain Behavior and Thermal Withdrawal Latencies

2003 ◽  
Vol 8 (4) ◽  
pp. 213-217 ◽  
Author(s):  
C Celeste Johnston ◽  
Claire-Dominique Walker
Keyword(s):  
Formalin Test ◽  
Thermal Stimulation ◽  
Neonatal Rat ◽  
Maternal Behaviour ◽  
Long Term Effects ◽  
Thermal Thresholds ◽  
Rat Pups ◽  
Short And Long Term ◽  
Repeated Pain

Preterm infants undergoing untreated, repeated painful procedures as part of their early experience are more likely to behave differently to pain as they mature than infants who were born at term and did not experience excessive exogenous pain. The neonatal rat model was used to investigate the short- and long-term effects of repeated pain in infancy on later development of pain responses. Newborn rat pups were randomly assigned by litter to be left unhandled (UH), handled by being removed from the dam for 15 min four times daily (H), and being handled and receiving pain from a paw prick with a 26G needle four times daily (P)on postnatal days (PD) 2 through 8 (PD2-PD8). Maternal behaviour and grooming of pups on their return to the nest were recorded at PD6 for H and P pups. At PD15, PD36 and PD65, animals were first tested for latency to thermal stimulation threshold using the Hargreaves test and then for inflammatory pain using the formalin test. Pups in the HP group received significantly more grooming from their mothers (359 s) than pups in the H group (295 s, P<0.0001). When accounting for differences in maternal grooming, a decreased thermal threshold in the P group compared with the H group (6.04 s versus 5.3 s, P<0.05) was found, although the correlations were not significant between maternal grooming and thermal thresholds. No group differences were seen with the formalin test. Interestingly, age was a significant factor in both tests, with younger animals showing fewer pain behaviours regardless of group or maternal grooming of the pup. Sex was significant at one age only in latency to thermal stimulation testing. The results suggest that changes in maternal care may be an important factor mediating the long-term effects of repeated neonatal experiences of pain.

scholarly journals Long-Term Behavioral Effects of Repetitive Pain in Neonatal Rat Pups

1999 ◽  
Vol 66 (4) ◽  
pp. 627-637 ◽  
Author(s):  
K.J.S Anand ◽  
V Coskun ◽  
K.V Thrivikraman ◽  
C.B Nemeroff ◽  
P.M Plotsky
Keyword(s):  
Behavioral Effects ◽  
Neonatal Rat ◽  
Rat Pups

scholarly journals Evaluation of Spinal Toxicity and Long-term Spinal Reflex Function after Intrathecal Levobupivaciane in the Neonatal Rat

2013 ◽  
Vol 119 (1) ◽  
pp. 142-155 ◽  
Author(s):  
Emre Hamurtekin ◽  
Bethany L. Fitzsimmons ◽  
Veronica I. Shubayev ◽  
Marjorie R. Grafe ◽  
Ronald Deumens ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Caspase 3 ◽  
Cauda Equina ◽  
Safety Data ◽  
Spinal Reflex ◽  
Neonatal Rat ◽  
Spinal Cord Tissue ◽  
Drug Induced ◽  
Rat Pups

Abstract Background: Neuraxial anesthesia is utilized in children of all ages. Local anesthetics produce dose-dependent toxicity in certain adult models, but the developing spinal cord may also be susceptible to drug-induced apoptosis. In postnatal rodents, we examined the effects of intrathecal levobupivacaine on neuropathology and long-term sensorimotor outcomes. Methods: Postnatal day 3 (P3) or P7 rat pups received intrathecal levobupivacaine 2.5 mg/kg (0.5%) or saline. Mechanical withdrawal thresholds and motor block were assessed. Spinal cord tissue analysis included apoptosis counts (activated caspase-3, Fluoro-Jade C) at 24 h, glial reactivity at 7 days, and histopathology in cord and cauda equina at 24 h and 7 days. Long-term spinal function in young adults (P35) was assessed by hind limb withdrawal thresholds, electromyography responses to suprathreshold stimuli, and gait analysis. Results: Intrathecal levobupivacaine produced spinal anesthesia at P3 and P7. No increase in apoptosis or histopathological change was seen in the cord or cauda equina. In the P3 saline group, activated caspase-3 (mean ± SEM per lumbar cord section 6.1 ± 0.3) and Fluoro-Jade C (12.1 ± 1.2) counts were higher than at P7, but were not altered by levobupivacaine (P = 0.62 and P = 0.11, two-tailed Mann–Whitney test). At P35, mechanical withdrawal thresholds, thermal withdrawal latency, and electromyographic reflex responses did not differ across P3 or P7 levobupivacaine or saline groups (one way ANOVA with Bonferroni comparisons). Intrathecal bupivacaine at P3 did not alter gait. Conclusion: Single dose intrathecal levobupivacaine 0.5% did not increase apoptosis or produce spinal toxicity in neonatal rat pups. This study provides preclinical safety data relevant to neonatal use of neuraxial local anesthesia.

scholarly journals NT-4 attenuates neuroinflammation via TrkB/PI3K/FoxO1 pathway after germinal matrix hemorrhage in neonatal rats

2019 ◽  
Author(s):  
Tianyi Wang ◽  
Junyi Zhang ◽  
Peng Li ◽  
Yan Ding ◽  
Jiping Tang ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Factors ◽  
Neonatal Rats ◽  
Germinal Matrix ◽  
Germinal Matrix Hemorrhage ◽  
Trkb Receptor ◽  
Rat Pups ◽  
Short And Long Term ◽  
Pro Inflammatory Cytokines

Abstract Background: Neuroinflammation plays an important role in pathogenesis of germinal matrix hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family, and it interacts with the tyrosine kinase B (TrkB) receptor. It has been studied that NT-4 has neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4 and it’s high affinity receptor TrkB as well as its downstream mediator phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/Forkhead box protein O1 (FoxO1) following GMH in neonatal rats, with a specific focus on inflammation. Methods: GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U) in P7 rat pups. A total of 163 seven-day-old pups were used in this study. The recombinant human NT-4 was administered intranasally at 1 hour after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002 and FoxO1 activating CRISPR were administered intracerebroventricularly at 24 hours prior to NT-4 treatment to investigate the potential mechanism. Short-and-long-term neurobehavior assessments, immunofluorescence staining, Nissl’s staining and Western blot were performed. Results：The expression of p-TrkB increased after GMH with a peak at day3. The TrkB receptor was expressed by neurons, microglia, and astrocytes. The administration of rh-NT-4 increased phosphorylation of TrkB, expression of PI3K, phosphorylation of Akt and decreased FoxO1, IL-1beta and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. The use of FoxO1 activation CRISPR increased the expression of IL-6, suggesting that FoxO1 might potentially induce pro-inflammatory factors. These results demonstrated that PI3K/Akt/FoxO1 may be the downstream pathway of TrkB phosphorylation. The rat pups treated with rh-NT-4 performed better than untreated animals both in short-and-long-term behavior test. Conclusion：These data showed that rh-NT-4 can reduce the expression of pro-inflammatory cytokines, improve neurological function, attenuate neuroinflammation and post-hemorrhagic hydrocephalus after GMH by promoting TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic target to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

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