title: Tumor necrosis factor-α (TNF-α) augments AMPA-induced Purkinje neuron toxicity.
abstract: It is well recognized that exposure of neurons to excessive levels of the excitatory neurotransmitter glutamate, termed glutamate excitotoxicity, contributes to the damage and degeneration seen in many acute and chronic neurological diseases. However, it is becoming increasingly evident that inflammation also can play a role in certain neurodegenerative diseases and inflammatory mediators, such as tumor necrosis factor-α (TNF-α), may directly interact with excitotoxic processes. In a postnatal rat cerebellar slice model, we found that TNF-α exacerbated AMPA-induced excitotoxicity in Purkinje neurons in a dose-dependent manner beyond the toxicity caused by AMPA alone. It also was shown that combinations of TNF-α and AMPA increased the mean intracellular activity of calpains, calcium-activated cysteine proteases that are known to contribute to cell death in Purkinje neurons. Additionally, these combinations augmented colbalt influx, a marker for calcium entry that selectively occurs through calcium permeable AMPA receptors only. Pharmacologic blockade of calcium permeable AMPA receptors with a specific antagonist, 1-naphthyl acetyl spermine (NASPM), reversed the apparent increase in AMPA receptor calcium permeability caused by TNF-α as measured by cobalt influx; caused a reduction in the Purkinje neuron calpain activity; and reversed the enhanced neurodegeneration induced by the combination of TNF-α and AMPA. From these studies we concluded that TNF-α augmented AMPA-induced toxicity in Purkinje neurons by increasing intracellular calcium flux through calcium permeable AMPA receptors, and this increase in calcium was directly involved in enhanced activation of calpains and a greater percentage of Purkinje neuron loss.
authors.affiliation: Department of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Bliss
authors.forename: Velvet Lee
authors.initials: VL
authors.lastname: Finckbone
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Trice
authors.forename: Howard
authors.initials: H
authors.lastname: Strahlendorf
authors.forename: Jean
authors.initials: J
authors.lastname: Strahlendorf
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D018836:Inflammation Mediators / Q000502:physiology*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D009498:Neurotoxins / Q000819:agonists / Q000633:toxicity; D009924:Organ Culture Techniques; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000819:agonists / Q000633:toxicity*
chemical_list: D018836:Inflammation Mediators; D009498:Neurotoxins; D014409:Tumor Necrosis Factor-alpha; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002118:Calcium