Potent effect of interleukin-1β to evoke ATP and adenosine release from rat hippocampal slices
Introduction
IL-1β is well known as a cellular mediator of inflammation, acute and chronic neuronal degeneration, and the following repair process in the brain Allan and Rothwell, 2001, Rothwell and Luheshi, 2000, Szelenyi, 2001. Thus, the diverse actions of IL-1β upon inflammatory stimuli are extensively characterized, including neurotoxic action, fever and sickness behavior. Although the basal expression level and the exact source of IL-1β in the normal brain is controversial (Vitkovic et al., 2000), receptors sensitive to low level of IL-1β are constitutively expressed in the rodent hippocampus Ban et al., 1991, Cunningham et al., 1991, Ericsson et al., 1995, Parnet et al., 1994, Takao et al., 1990. Furthermore IL-1β exert remarkable electrophysiological actions in this brain area: in higher concentration it inhibits (O'Connor and Coogan, 1999), whilst in lower concentrations it contributes to the maintenance of long-term potentiation Schneider et al., 1998, Ross et al., 2003, and inhibits excitatory synaptic transmission in the CA1 region (Luk et al., 1999) with a presynaptic site of action. This latter effect, however, seems to be indirect, being sensitive to A1-adenosine receptor blockade. Adenosine is well known as an endogenous neuroprotectant (Ribeiro et al., 2003) and anti-inflammatory mediator (Cronstein, 1994) and this finding implies that there is a functional link between IL-1β and adenosinergic signalling in the hippocampus, and that IL-1β might release adenosine or a related purine. Adenosine A1 receptors are strongly expressed in the hippocampus at presynaptic nerve terminals Deckert and Jorgensen, 1988, Fastbom et al., 1987, Rebola et al., 2003; their activation decreases glutamate release from excitatory nerve terminals Burke and Nadler, 1988, Corradetti et al., 1984, Sehmisch et al., 2001, and previous studies demonstrated the stimulation dependent release of ATP and adenosine and their extracellular interconversion in this brain area Cunha et al., 1996, Cunha et al., 1998. Nevertheless, the exact link between the effect of IL-1β and adenosine receptor activation have not been explored. Therefore our aim was to determine how IL-1β affect the extracellular level of purines in superfused hippocampal slices, preloaded with [3H]adenosine.
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Materials and methods
All studies were conducted in accordance with the principles and procedures outlined in the NIH Guide for the Care and use of Laboratory animals and were approved by the local Animal Care Committee of the Institute of Experimental Medicine (Budapest, Hungary).
Results
The radioactivity uptake of the hippocampal slices was 1.124±0.14×106 Bq/g (n=12) and the basal [3H]purine efflux was 0.35±0.02% (n=12). Electrical field stimulation elicited a TTX-sensitive and reproducible elevation of tritium efflux (EFS1=1.34±0.23%, n=6) resulting in an EFS2/EFS1 ratio closed to one (1.09±0.22%, n=6). Ten-minute superfusion of the slices with IL-1β (5×10−15 M) significantly elevated the basal [3H]purine level in the effluent, and this effect was concentration-dependent
Discussion
Our data demonstrate that low concentration of IL-1β releases [3H]purines from rat hippocampal slices and this release involves (1) glutamate receptor mediated excitatory synaptic transmission, (2) IL-1RI receptor and subsequent p38 MAP kinase activation, (3) reversal of the equilibrative nucleoside carrier.
The effect of IL-1β on [3H]purine release was concentration-dependent, reversible, and was observed with similar time frame to its depressant effect on hippocampal EPSC recordings (Luk et
Acknowledgements
This study was supported by the grants of the Hungarian Research Foundation (OTKA T037457, TS040736), Hungarian Medical Research Council, National Institutes of Health grant GM66189 (G. Hasko), the Centre of Excellence Grant of EU Framework Program 5 (ICA1-CT-2000-70004) and by the Volkswagen Foundation. The authors are grateful to Ms. Zsuzsanna Körössy for excellent technical assistance.
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