Attenuation of Traumatic Cell Death by an Adenosine A1 Agonist in Rat Hippocampal Cells

Abstract

In a rat hippocampal cell culture, we studied the mechanism of adenosine-mediated neuroprotection in traumatic injury to neurons. When the processes and bodies of cells in culture were mechanically disrupted, neurons that were located at a distance from the damage site died. This secondary neuronal death is at least partially mediated by glutamate, because MK801, a specific N-methyl-D-aspartate glutamate channel blocker, diminished the toxic effect. Furthermore, cyclopentyl adenosine, a specific A1 adenosine receptor agonist that specifically attenuates synaptic release at the excitatory terminal, also blocked this trauma-mediated cell death. The dissemination of neurotoxicity from cell injury implies a release of a toxin by the dying cells. Consistent with this hypothesis, we found that neurotoxicity could be transferred to an uninjured neuronal culture by applying extracellular solution of the damaged culture to the healthy undamaged culture, as long as the fluid was transferred within 5 minutes. However, the glutamate concentrations in this medium were never higher than 20 nmol/L, suggesting that glutamate is not mediating the soluble and transferable toxicity. Consistent with this observation, the transferable neurotoxicity was not blocked by MK801 but was effectively blocked by cyclopentyl adenosine. Our observations suggest that traumatic cell death in culture is mediated by multiple mechanisms, including glutamate excitotoxicity.

Delayed Treatment With an Adenosine Kinase Inhibitor, GP683, Attenuates Infarct Size in Rats With Temporary Middle Cerebral Artery Occlusion

“…38 Cyclopentyladenosine, a selective A 1 receptor agonist, attenuated traumatic cell death in rat hippocampal cell cultures free of glutamate, suggesting that adenosine can reduce neuronal injury via mechanisms other than the inhibition of EAAinduced toxicity. 39 A 2 receptor activation inhibits platelet aggregation, thus reducing the potential for vessel obstruction, 40 inhibits neutrophil-mediated injury to endothelial cells Values are meanϮSD. The drug was injected intraperitoneally at 1.0 mg/kg dose to rats (nϭ6) without focal ischemia.…”

The Role and Regulation of Adenosine in the Central Nervous System

“…Acute protective effects Endogenous adenosine released by hypoxia (Gribkoff & Bauman 1992, Fowler 1993a, ischemia (Lloyd et al 1993, Latini et al 1999, electrical activity (Arvin et al 1989, Lloyd et al 1993, and hypo-or aglycemia (Fowler 1993b, Hsu et al 1994, Calabresi et al 1997 reduces the subsequent damage to neuronal tissue. This neuroprotection offered by adenosine is also effective against other kinds of damage that are not as directly related to energy metabolism, such as mechanical cell injury (Mitchell et al 1995) and methamphetamine-induced neurotoxicity (Delle Donne & Sonsalla 1994). Conversely, applying adenosine receptor antagonists in conjunction with any of these conditions exacerbates the consequent damage (Arvin et al 1989, Hsu et al 1994, Mitchell et al 1995.…”

Interstitial Adenosine, Inosine, and Hypoxanthine Are Increased after Experimental Traumatic Brain Injury in the Rat

“…Adenosine attenuates neuronal damage in a variety of forms of brain injury including cell culture, hippocampal slices, and whole animal models in multiple species. Administered to rat hippocampal cell cultures, adenosine attenuated cell death induced by traumatic disruption of axons (Mitchell et al, 1995). Hippocampal slices subjected to hypoxia or hypoglycemia release adenosine (Mori et al, 1992;Fowler, 1993;Pedata et al, 1993;Wallman-Johansson and Fredholm, 1994).…”