Now showing 1 - 3 of 3
  • Publication
    Tumor necrosis factor-α potentiates long-term potentiation in the rat dentate gyrus after acute hypoxia
    An inadequate supply of oxygen in the brain may lead to an inflammatory response through neuronal and glial cells that can result in neuronal damage. Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine that is released during acute hypoxia and can have neurotoxic or neuroprotective effects in the brain. Both TNF-α and interleukin-1β (IL-1β) have been shown by a number of research groups to alter synaptic scaling and also to inhibit long-term potentiation (LTP) in the hippocampus when induced by specific high-frequency stimulation (HFS) protocols. This study examines the effects of TNF-α on synaptic transmission and plasticity in hippocampal slices after acute hypoxia using two HFS protocols. Field excitatory postsynaptic potentials were elicited in the medial perforant pathway of the dentate gyrus. Exogenous TNF-α (5 ng/ml) attenuated LTP induced by theta burst stimulation but had no effect on LTP induced by a more prolonged HFS. Pretreatment with lipopolysaccharide (100 ng/ml) or TNF-α but not IL-1β (4 ng/ml) prior to a 30-min hypoxic insult resulted in a significant enhancement of LTP post hypoxia when induced by the HFS. Anti-TNF, 3,6′-dithiothalidomide (a TNF-α synthesis inhibitor), and SB203580 (a p38 MAPK inhibitor) significantly reduced this effect. These results indicate an important modulatory role for elevated TNF-α levels on LTP in the hippocampus after an acute hypoxic event.
    Scopus© Citations 24  357
  • Publication
    Acute hypoxic exposure and prolyl-hydroxylase inhibition improves synaptic transmission recovery time from a subsequent hypoxic insult in rat hippocampus
    In the CNS short episodes of acute hypoxia can result in a decrease in synaptic transmission which may be fully reversible upon re-oxygenation. Stabilization of hypoxia-inducible factor (HIF) by inhibition of prolyl hydroxylase domain (PHD) enzymes has been shown to regulate the cellular response to hypoxia and confer neuroprotection both in vivo and in vitro. Hypoxic preconditioning has become a novel therapeutic target to induce neuroprotection during hypoxic insults. However, there is little understanding of the effects of repeated hypoxic insults or pharmacological PHD inhibition on synaptic signalling. In this study we have assessed the effects of hypoxic exposure and PHD inhibition on synaptic transmission in the rat CA1 hippocampus. Field excitatory postsynaptic potentials (fEPSPs) were elicited by stimulation of the Schaffer collatoral pathway. 30 min hypoxia (gas mixture 95% N2/5% CO2) resulted in a significant and fully reversible decrease in fEPSP slope associated with decreases in partial pressures of tissue oxygen. 15-30 min of hypoxia was sufficient to induce stabilization of HIF in hippocampal slices. Exposure to a second hypoxic insult after 60 min resulted in a similar depression of fEPSP slope but with a significantly greater rate of recovery of the fEPSP. Prior single treatment of slices with the PHD inhibitor, dimethyloxalylglycine (DMOG) also resulted in a significantly greater rate of recovery of fEPSP post hypoxia. These results suggest that hypoxia and ‘pseudohypoxia’ preconditioning may improve the rate of recovery of hippocampal neurons to a subsequent acute hypoxia.
    Scopus© Citations 8  551
  • Publication
    Effects of prolyl-hydroxylase inhibition and chronic intermittent hypoxia on synaptic transmission and plasticity in the rat CA1 and dentate gyrus
    Chronic intermittent hypoxia (CIH) is an underlying component of obstructive sleep apnoea and has been shown to have deleterious and damaging effects on central neurons and to impair synaptic plasticity in the CA1 region of the rat hippocampus.  CIH is a potent inducer of hypoxia inducible factor (HIF), a key regulator in a cell's adaptation to hypoxia that plays an important role in the fate of neurons during ischemia. Levels of HIF-1α are regulated by the activity of a group of enzymes called HIF-prolyl 4-hydroxylases (PHDs) and these have become potential pharmalogical targets for preconditioning against ischemia.  However, little is known about the effects of prolyl hydroxylase inhibition and CIH on synaptic transmission and plasticity in sub-regions of the hippocampus.  Male Wistar rats were treated for 7-days with either saline, CIH or PHD inhibition (dimethyloxaloylglycine, DMOG; 50mg/kg, i.p.). At the end of treatment all three groups showed no change in synaptic excitability or paired pulse paradigms.  However long-term potentiation (LTP) was impaired in the CA1 region of the hippocampus of both CIH and DMOG treated animals.  LTP induced in the dentate gyrus was not significantly affected by CIH or DMOG treatment. We also investigated the effect of 7-day CIH and DMOG treatment on the recovery of synaptic transmission following an acute 30 min hypoxic insult.  CIH treated animals showed an improved rate of recovery of synaptic transmission  following re-oxygentation in both the CA1 and dentate gyrus. This effect was not seen with 7-day DMOG treatment.  These results suggest that LTP induction in the CA1 region is more sensitive to both CIH and DMOG treatment than the dentate gyrus.
      1091Scopus© Citations 37