MODULATION OF ANOXIC INJURY IN CNS WHITE-MATTER BY ADENOSINE AND INTERACTION BETWEEN ADENOSINE AND GABA

1. We examined the role of adenosine in the development of anoxic inju ry in a CNS white matter tract, the rat optic nerve. Application of ad enosine protected the rat optic nerve from anoxic injury; 2.5 mu M ade nosine increased compound action potential (CAP) recovery after a stan dard 60-min anoxic period from 28.6 +/- 2.5%, mean +/- SE, to 51.0 +/- 3.1% (P < 0001). The protective effect of adenosine was abolished by the adenosine receptor antagonist theophylline (100 mu M). 2. The prot ective effect of adenosine evolved slowly after adenosine application; maximum protection required 60 min of adenosine exposure before the o nset of anoxia. The concentration dependence of the protective effect was parabolic, with maximum protection at 2.5 mu M. Neither high nor v ery low adenosine concentrations protected against anoxia. These chara cteristics are similar to those previously found for the inhibitory ne urotransmitter gamma-aminobutyric acid (GABA) in the same preparation. 3. Inhibition of adenosine receptors( 100 mu M theophylline) reduced the level of recovery from that found under control conditions (24.3 /- 4.8% compared with 36.2 +/- 2.5%, P < 0.05). The adenosine uptake i nhibitor propentofylline, which potentiates release of endogenous aden osine during brain anoxia, significantly increased CAP recovery after anoxia. This effect was abolished by theophylline. It appeared therefo re that release of endogenous adenosine limited injury in the optic ne rve during anoxia. 4. The protective effect of adenosine was removed b y pretreatment with the protein kinase C (PKC) inhibitor staurosporine (10 nM), indicating that activation of PKC was required for protectio n after exposure to adenosine. 5. Coadministration of low nanomolar co ncentrations of GABA shifted the concentration dependence of the prote ctive effect of adenosine to lower concentrations. In the presence of 20 nM GABA, maximum protection was found at 2.5 mu M adenosine; in 40 nM GABA, maximum protection was found at 1.5 mu M adenosine; and in 10 0 nM GABA, maximum protection was observed at 900 nM adenosine. 6. The data suggest that adenosine and GABA can act synergistically at nanom olar concentrations to recruit a PKC-mediated protective mechanism dur ing anoxia in white matter. Synergism between the two receptor types m ay be necessary to activate this autoprotective mechanism during small increases in the concentration of adenosine and GABA that occur in an oxic white matter.