Sildenafil Improves Brain Injury Recovery following Term Neonatal Hypoxia-Ischemia in Male Rat Pups

2016 ◽  
Vol 38 (4) ◽  
pp. 251-263 ◽  
Author(s):  
Armin Yazdani ◽  
Zehra Khoja ◽  
Aaron Johnstone ◽  
Laura Dale ◽  
Emmanouil Rampakakis ◽  
...  
Keyword(s):  
Brain Injury ◽  
Gait Analysis ◽  
Left Hemisphere ◽  
Neurological Deficits ◽  
Male Rat ◽  
Boundary Zone ◽  
Neonatal Hypoxia ◽  
Rat Pups ◽  
Hypoxia Ischemia ◽  
Injury Recovery

Term asphyxiated newborns remain at risk of developing brain injury despite available neuropreventive therapies such as hypothermia. Neurorestorative treatments may be an alternative. This study investigated the effect of sildenafil on brain injury induced by neonatal hypoxia-ischemia (HI) at term-equivalent age. Neonatal HI was induced in male Long-Evans rat pups at postnatal day 10 (P10) by left common carotid ligation followed by a 2-hour exposure to 8% oxygen; sham-operated rat pups served as the control. Both groups were randomized to oral sildenafil or vehicle twice daily for 7 consecutive days. Gait analysis was performed on P27. At P30, the rats were sacrificed, and their brains were extracted. The surfaces of both hemispheres were measured on hematoxylin and eosin-stained brain sections. Mature neurons and endothelial cells were quantified near the infarct boundary zone using immunohistochemistry. HI caused significant gait impairment and a reduction in the size of the left hemisphere. Treatment with sildenafil led to an improvement in the neurological deficits as measured by gait analysis, as well as an improvement in the size of the left hemisphere. Sildenafil, especially at higher doses, also caused a significant increase in the number of neurons near the infarct boundary zone. In conclusion, sildenafil administered after neonatal HI may improve brain injury recovery by promoting neuronal populations.

Experimental neonatal hypoxia ischemia causes long lasting changes of oxidative stress parameters in the hippocampus and the spleen

2018 ◽  
Vol 46 (4) ◽  
pp. 433-439 ◽  
Author(s):  
Felipe Kawa Odorcyk ◽  
Janaína Kolling ◽  
Eduardo Farias Sanches ◽  
Angela T.S. Wyse ◽  
Carlos Alexandre Netto
Keyword(s):  
Oxidative Stress ◽  
Wistar Rat ◽  
Mortality And Morbidity ◽  
Neonatal Hypoxia ◽  
Oxidative Stress Parameters ◽  
Rat Pups ◽  
Hypoxia Ischemia ◽  
Anti Oxidant ◽  
Enzyme Superoxide Dismutase ◽  
Stress Parameters

Abstract Neonatal hypoxia ischemia (HI) is the main cause of mortality and morbidity in newborns. The mechanisms involved in its progression start immediately and persist for several days. Oxidative stress and inflammation are determinant factors of the severity of the final lesion. The spleen plays a major part in the inflammatory response to HI. This study assessed the temporal progression of HI-induced alterations in oxidative stress parameters in the hippocampus, the most affected brain structure, and in the spleen. HI was induced in Wistar rat pups in post-natal day 7. Production of reactive oxygen species (ROS), and the activity of the anti oxidant enzyme superoxide dismutase and catalase were assessed 24 h, 96 h and 38 days post-HI. Interestingly, both structures showed a similar pattern, with few alterations in the production of ROS species up to 96 h often combined with an increased activity of the anti oxidant enzymes. However, 38 days after the injury, ROS were at the highest in both structures, coupled with a decrease in the activity of the enzymes. Altogether, present results suggest that HI causes long lasting alterations in the hippocampus as well as in the spleen, suggesting a possible target for delayed treatments for HI.

scholarly journals Inhibition of Calcium/Calmodulin-Dependent Protein Kinase Kinase β Is Detrimental in Hypoxia–Ischemia Neonatal Brain Injury

2019 ◽  
Vol 20 (9) ◽  
pp. 2063
Author(s):  
Jia-Wei Min ◽  
Fan Bu ◽  
Li Qi ◽  
Yashasvee Munshi ◽  
Gab Seok Kim ◽  
...  
Keyword(s):  
Brain Injury ◽  
Protein Kinase ◽  
Intracellular Calcium ◽  
Infarct Volume ◽  
Dependent Protein Kinase ◽  
Neonatal Hypoxia ◽  
Calcium Calmodulin Dependent ◽  
Hypoxia Ischemia ◽  
Dependent Protein ◽  
Protein Kinase Kinase

Neonatal hypoxia–ischemia (HI) is a major cause of death and disability in neonates. HI leads to a dramatic rise in intracellular calcium levels, which was originally thought to be detrimental to the brain. However, it has been increasingly recognized that this calcium signaling may also play an important protective role after injury by triggering endogenous neuroprotective pathways. Calcium/calmodulin-dependent protein kinase kinase β (CaMKK β) is a major kinase activated by elevated levels of intracellular calcium. Here we evaluated the functional role of CaMKK β in neonatal mice after HI in both acute and chronic survival experiments. Postnatal day ten wild-type (WT) and CaMKK β knockout (KO) mouse male pups were subjected to unilateral carotid artery ligation, followed by 40 min of hypoxia (10% O2 in N2). STO-609, a CaMKK inhibitor, was administered intraperitoneally to WT mice at 5 minutes after HI. TTC (2,3,5-triphenyltetrazolium chloride monohydrate) staining was used to assess infarct volume 24 h after HI. CaMKK β KO mice had larger infarct volume than WT mice and STO-609 increased the infarct volume in WT mice after HI. In chronic survival experiments, WT mice treated with STO-609 showed increased tissue loss in the ipsilateral hemisphere three weeks after HI. Furthermore, when compared with vehicle-treated mice, they showed poorer functional recovery during the three week survival period, as measured by the wire hang test and corner test. Loss of blood–brain barrier proteins, a reduction in survival protein (Bcl-2), and an increase in pro-apoptotic protein Bax were also seen after HI with CaMKK β inhibition. In conclusion, inhibition of CaMKK β exacerbated neonatal hypoxia–ischemia injury in mice. Our data suggests that enhancing CaMKK signaling could be a potential target for the treatment of hypoxic–ischemic brain injury.

Effect of hyperbaric oxygen on apoptosis in neonatal hypoxia-ischemia rat model

2003 ◽  
Vol 95 (5) ◽  
pp. 2072-2080 ◽  
Author(s):  
John W. Calvert ◽  
Changman Zhou ◽  
Anil Nanda ◽  
John H. Zhang
Keyword(s):  
Hyperbaric Oxygen ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Neuroprotective Effect ◽  
Parp Cleavage ◽  
Artery Ligation ◽  
Neonatal Hypoxia ◽  
Rat Pups ◽  
Hypoxia Ischemia ◽  
Expression And Activity

We have previously demonstrated that a transient exposure to hyperbaric oxygen (HBO) attenuated the neuronal injury after neonatal hypoxia-ischemia. This study was undertaken to determine whether HBO offers this neuroprotection by reducing apoptosis in injured brain tissue. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2 h of hypoxia (8% oxygen). Apoptotic cell death was examined in the injured cortex and hippocampus tissue. Caspase-3 expression and activity increased at 18 and 24 h after the hypoxia-ischemia insult. At 18-48 h, poly(ADP-ribose) polymerase (PARP) cleavage occurred, which reduced the band at 116 kDa and enhanced the band at 85 kDa. There was a time-dependent increase in the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive cells. A single HBO treatment (100% oxygen, 3 ATA for 1 h) 1 h after hypoxia reduced the enhanced caspase-3 expression and activity, attenuated the PARP cleavage, and decreased the number of TUNEL-positive cells observed in the cortex and hippocampus. These results suggest that the neuroprotective effect of HBO is at least partially mediated by the reduction of apoptosis.

scholarly journals Effect of Trp53 gene deficiency on brain injury after neonatal hypoxia-ischemia

Oncotarget ◽  
2017 ◽  
Vol 8 (7) ◽  
pp. 12081-12092 ◽  
Author(s):  
Ana A. Baburamani ◽  
Kristina S. Sobotka ◽  
Regina Vontell ◽  
Carina Mallard ◽  
Veena G. Supramaniam ◽  
...  
Keyword(s):  
Brain Injury ◽  
Neonatal Hypoxia ◽  
Gene Deficiency ◽  
Hypoxia Ischemia

scholarly journals Unbiased Quantification of Subplate Neuron Loss following Neonatal Hypoxia-Ischemia in a Rat Model

2017 ◽  
Vol 39 (1-4) ◽  
pp. 171-181 ◽  
Author(s):  
Alexandra Mikhailova ◽  
Naveena Sunkara ◽  
Patrick S. McQuillen
Keyword(s):  
Brain Injury ◽  
Lower Layer ◽  
Cell Number ◽  
Cortical Layer ◽  
Rodent Model ◽  
Cortical Layers ◽  
Cortical Injury ◽  
Neonatal Hypoxia ◽  
Subplate Neurons ◽  
Hypoxia Ischemia

Background: Cellular targets of neonatal hypoxia-ischemia (HI) include both oligodendrocyte and neuronal lineages with differences in the patterns of vulnerable cells depending upon the developmental stage at which the injury occurs. Injury to the developing white matter is a characteristic feature of human preterm brain injury. Data are accumulating, however, for neuronal injury in the developing cerebral cortex. In the most widely used rodent model of preterm HI brain injury, conflicting data have been reported regarding the sensitivity of subplate neurons to early neonatal HI, with some reports of selective vulnerability and others that find no increased loss of subplate neurons in comparison with other cortical layers. Methods used to identify subplate neurons and quantify their numbers vary across studies. Objective: To use recently developed cortical layer-specific markers quantified with definitive stereologic methods to determine the magnitude and specificity of subplate neuron cell loss following neonatal HI in a rodent model. Methods: Postnatal day 2 (P2) rats underwent right common carotid artery coagulation followed by 2-3 h of hypoxia (5.6% oxygen). Categorically moderately injured brains were stained with subplate and cortical layer III-V markers (Complexin3 and Foxp1, respectively) at P8 and P21 (Foxp1 only). An Optical Fractionator was used to quantify subplate and middle/lower cortical neuronal numbers and these were compared across groups (naive control, hypoxia hemisphere, and HI hemisphere). Results: Following HI at P2 in rats, the total Complexin3-expressing subplate neuron number decreases significantly in the HI hemisphere compared with naive controls or hypoxia alone (HI vs. control 26,747 ± 7,952 vs. 35,468 ± 8,029, p = 0.04; HI vs. hypoxia, 26,747 ± 7,952 vs. 40,439 ± 7,363, p = 0.003). In contrast, the total Foxp1-expressing layer III-V cell number did not differ across the 3 conditions at P8 (HI vs. control 1,195,085 ± 436,609 vs. 1,234,640 ± 178,540, p = 0.19; HI vs. hypoxia, 1,195,085 ± 436,609 vs. 1,289,195 ± 468,941, p = 0.35) and at P21 (HI vs. control 1,265,190 ± 48,089 vs. 1,195,632 ± 26,912, p = 0.19; HI vs. hypoxia, 1,265,190 ± 48,089 vs. 1,309,563 ± 41,669, p = 0.49). Conclusions: There is significant biological variability inherent in both the subplate neuron cell number and the pattern and severity of cortical injury following HI at P2 in rats. Despite this variability, the subplate neuron cell number is lower following P2 HI in animals with mild or moderate cortical injury, whereas the middle-to-lower-layer cortical neuronal number is unchanged. In more severe cases, neurons are lost from the lower cortical layers, suggesting a relative vulnerability of subplate neurons.

Delayed, Long-Term Administration of the Caspase Inhibitor Q-VD-OPh Reduced Brain Injury Induced by Neonatal Hypoxia-Ischemia

2014 ◽  
Vol 36 (1) ◽  
pp. 64-72 ◽  
Author(s):  
Wei Han ◽  
Yanyan Sun ◽  
Xiaoyang Wang ◽  
Changlian Zhu ◽  
Klas Blomgren
Keyword(s):  
Brain Injury ◽  
Caspase Inhibitor ◽  
Neonatal Hypoxia ◽  
Hypoxia Ischemia ◽  
Term Administration

scholarly journals Bcl-x Pre-mRNA Splicing Regulates Brain Injury after Neonatal Hypoxia-Ischemia

2012 ◽  
Vol 32 (39) ◽  
pp. 13587-13596 ◽  
Author(s):  
Q. Xiao ◽  
A. L. Ford ◽  
J. Xu ◽  
P. Yan ◽  
K.-Y. Lee ◽  
...  
Keyword(s):  
Brain Injury ◽  
Mrna Splicing ◽  
Neonatal Hypoxia ◽  
Hypoxia Ischemia
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