title: A procyanidin type A trimer from cinnamon extract attenuates glial cell swelling and the reduction in glutamate uptake following ischemia-like injury in vitro.
abstract: Dietary polyphenols exert neuroprotective effects in ischemic injury. The protective effects of a procyanidin type A trimer (trimer 1) isolated from a water soluble cinnamon extract (CE) were investigated on key features of ischemic injury, including cell swelling, increased free radical production, increased intracellular calcium ([Ca(2+)](i)), mitochondrial dysfunction, and the reduction in glutamate uptake. Astrocyte (glial) swelling is a major component of cytotoxic brain edema in ischemia and, along with vasogenic edema, may contribute to increased intracranial pressure, brain herniation, and additional ischemic injuries. C6 glial cultures were exposed to oxygen-glucose deprivation (OGD) for 5 h, and cell swelling was determined at 90 min after the end of OGD. OGD-induced increases in glial swelling were significantly blocked by trimer 1, but not by the major nonpolyphenol fractions of CE including cinnamaldehyde and coumarin. Increased free radical production, a contributing factor in cell swelling following ischemic injury, was also significantly reduced by trimer 1. Mitochondrial dysfunction, another key feature of ischemic injury, is hypothesized to contribute to glial swelling. Depolarization of the inner mitochondrial membrane potential (ΔΨ(m)) was assessed using a fluorescent dye (tetramethylrhodamine ethyl ester [TMRE]), and was significantly attenuated by trimer 1 as was OGD-induced increased [Ca(2+)](i). Taken together with our previous observation that blockers of [Ca(2+)](i) reduce cell swelling, our results indicate that trimer 1 may attenuate cell swelling by regulating [Ca(2+)](i). Trimer 1 also significantly attenuated the OGD-induced decrease in glutamate uptake. In addition, cyclosporin A, a blocker of the mitochondrial permeability pore (mPT), but not FK506 (that does not block the mPT), reduced the OGD-induced decline in glutamate uptake indicating a role of the mPT in such effects. Thus, the effects of trimer 1 in attenuating the reduction in glutamate uptake are likely mediated through their action on the mitochondria.
authors.affiliation: United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics and Immunology Laboratory, Beltsville, MD 20705, USA. kiran.panickar@ars.usda.gov
authors.forename: K S
authors.initials: KS
authors.lastname: Panickar
authors.forename: M M
authors.initials: MM
authors.lastname: Polansky
authors.forename: D J
authors.initials: DJ
authors.lastname: Graves
authors.forename: J F
authors.initials: JF
authors.lastname: Urban
authors.forename: R A
authors.initials: RA
authors.lastname: Anderson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D044946:Biflavonoids / Q000302:isolation & purification / Q000494:pharmacology*; D002545:Brain Ischemia / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D002392:Catechin / Q000302:isolation & purification / Q000494:pharmacology*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D002935:Cinnamomum zeylanicum / Q000737:chemistry*; D016572:Cyclosporine / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology; D044945:Proanthocyanidins / Q000302:isolation & purification / Q000494:pharmacology*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D044946:Biflavonoids; D010936:Plant Extracts; D044945:Proanthocyanidins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; C017674:procyanidin; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D002392:Catechin; D005974:Glutamate-Ammonia Ligase; D005947:Glucose; D002118:Calcium