Abstract
During cerebral ischemia, elevation of TNF-α and glutamate to pathophysiological levels may induce dysregulation of normal synaptic processes, leading ultimately to cell death. Previous studies have shown that patients subjected to a mild transient ischemic attack within a critical time window prior to a more severe ischemic episode may show attenuation in the clinical severity of the stroke and result in a more positive functional outcome. Studies with organotypic hippocampal cultures and mixed primary hippocampal cultures have shown that prior incubation with low concentrations of glutamate and TNF-α increase the resistance of neurones to a subsequent insult from glutamate, AMPA and NMDA, while co-exposure of TNF-α and for example AMPA may have neuroprotective effects compared to cultures exposed to excitotoxic agents alone. In addition our work has shown that although glutamate and TNF-α pretreatment induces analogous levels of desensitisation of the intracellular calcium dynamics of neurons under resting conditions and in response to acute glutamate stimulation, their downstream signalling pathways involved in this response do not converge. Glutamate and TNF-α would appear to have opposing effects on resting Ca2+ levels which supports the proposal that they have distinct modes of preconditioning.
Highlights
Stroke and brain function As neurons are incapable of storing glucose, they rely on the cardiovascular system and astrocytes to deliver this source of energy
As calcium is a well known mediator of cell death, these findings suggest that TNF-a mediated neuroprotection may be as a result of decreasing conductance of these ionotrophic receptors to Ca2+, or reducing their sensitivity to these glutamatergic agents
This study found that TNF-a induced upregulation of NFkB gene transcription of neuroprotective mediators such as calbindin, a calcium chelator, and manganese superoxide dismutase (MnSOD), a powerful anti-oxidant which contribute to this neuroprotective response [60]
Summary
Stroke and brain function As neurons are incapable of storing glucose, they rely on the cardiovascular system and astrocytes to deliver this source of energy. Stellwagen and his colleagues found that treatment of hippocampal cultures with TNF-a (1 μg/ml) for 15 min was sufficient to induce a reduction in surface GABAA receptors in the same cohort of cells (most likely due to endocytosis), reducing the responsiveness of these cells to inhibitory input, which would further exacerbate excitotoxicity during an ischemic insult [47] Together, these studies highlight the vast detrimental effects of TNF-a on both glial and neuronal functioning during cerebral ischemia. Pharmacological dissection of the signalling cascades known to the activated by Ca2+, using a variety of antagonists revealed that Ca2+-mediated activation CaMK-II which in turn phosphorylates CREB, inducing CRE-mediated gene transcription of Bcl-2, a protein known to suppress apoptosis This effect was further validated in vivo using temporary middle cerebral artery occlusion (mCAO) to induce TIA-like elevation in glutamate transmission [68]. It is possible that application of exogenous glutamate may have a knock-on TNF-a mediated effect, adding a layer of complexity to the interpretation of experimental findings [74]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
