The Effect of Infusing Hypoxanthine or Xanthine During Cerebral Hypoxia-Ischemia on Brain Injury in Rabbits. • 1743

Pre-ischemic inhibition of xanthine oxidase (XO) improves neurologic recovery. This has been given as evidence that XO generates free radicals and causes brain damage, but other mechanisms are possible. We hypothesized that if XO causes cerebral injury by generating free radicals, then infusing the XO substrates hypoxanthine (hx) or xanthine (xan) during hypoxia-ischemia should potentiate brain damage. If the beneficial effects seen with XO inhibition are due to increased purine recovery, infusing hx should reduce brain injury, since only hx can be salvaged. METHODS: Anesthetized, immature rabbits were subjected to cerebral hypoxia-ischemia by 1st breathing 3.0% O₂ for 8 min and then raising intracranial pressure equal to mean arterial pressure for 8 min by infusing a mock CSF. XAN (n=9) or HX (n=9) rabbits received 30 mM xan or hx at 600 μmoles/kg/hr starting 30 min before injury and continuing for the 1st 30 min of the 4 hr reperfusion period. Control (CTL) animals (n=8) received the vehicle. Brain damage was assessed by somatosensory evoked potential recovery (SEP;% baseline), brain water content(drying to constant weight) and measurement of regional neurofilament (NF) 68 kD protein (dot-immunoblotting). Data are mean± SEM.RESULTS: Infusing hx significantly (p<0.05) improved SEP recovery, leading to nearly 100% improvement (12.9%±2.1 in HX vs 7.7%±0.8 in XAN & 6.5%±1.6 in CTL). NF 68 kD protein was higher (p<0.05) in the HX animals (Fig). There was no difference (p>0.05) in gray or white matter brain water content among the groups. Infusing xan did not alter SEP recovery or NF 68 kD protein(p>0.05). CONCLUSIONS: Infusing xan during hypoxia-ischemia did not increase brain damage while giving hx reduced brain injury. This study does not support a major role for free radical generation by XO in hypoxic-ischemic brain injury and suggests that the benefits of increased purine salvage outweigh any harmful effects of free radical production by XO. Funded by the United Cerebral Palsy Research & Educational Foundation& the Hearst Foundation.